46,XY partial gonadal dysgenesis

Mendelian MONDO:0016674 Pathograph 49 Show in embeddings browser Disorder of sex development Gonadal development disorder

46,XY partial gonadal dysgenesis (PGD) is a genetically heterogeneous disorder of testicular development with variable dysgenetic gonadal tissue and testicular hormone production. External genitalia range from female appearance to varying degrees of masculinization; Müllerian structures may be present or absent. Presentation may occur with atypical genitalia in infancy, pubertal delay or virilization, or impaired fertility. Some retained gonads support spontaneous puberty, but later hormone replacement may still be needed. Dysgenetic gonads can contain gonadoblastoma, germ cell neoplasia in situ, or invasive tumors. Genotype, gonadal function and anatomy, age, and the individual's goals inform care.

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Mappings

MONDO

MONDO:0016674 46,XY partial gonadal dysgenesis

MONDO:0016674 is the exact disease anchor and carries the corresponding Orphanet:251510 cross-reference.

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Definitions

46,XY partial gonadal dysgenesis case definition

A 46,XY karyotype with evidence of incomplete or disordered testicular development, assessed through the genital phenotype, endocrine function, histology when available, and molecular findings. Atypical external genitalia are common but are not obligatory: the I-DSD study also included individuals with female external genitalia, absent uterus, and evidence of gonadal dysfunction. No single hormone value or histological pattern separates every partial and complete presentation.

CASE_DEFINITION This entry covers partial gonadal dysgenesis, including gene-specific syndromic forms. Complete gonadal dysgenesis, 45,X/46,XY mosaicism, ovotesticular DSD, testicular regression, androgen insensitivity, and steroid synthesis defects require distinction. A blood 46,XY result does not exclude low-level or tissue-confined sex-chromosome mosaicism.

Show evidence (3 references)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"A small group of patients (n = 10) had typical female genitalia but without a uterus and evidence of gonadal dysfunction from biochemical, genetic, or histological investigations."

The registry explicitly included this exception to an atypical-genitalia definition.

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"As 46,XY PGD is a heterogeneous disorder without clearly defined diagnostic criteria, we used the diagnostic criteria from a previous study which requires evidence of testicular dysgenesis, either in a biochemical test (e.g., low testosterone response after hCG stimulation, low AMH or inhibin..."

Documents the study-specific combination of clinical, biochemical, histological and genetic criteria.

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Furthermore, standard karyotyping techniques may miss mosaicism such as 46,XY/45,X."

The registry authors explicitly identify a limitation of conventional karyotyping; a blood result does not exclude every mosaic cell line.

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Inheritance

Autosomal dominant inheritance HP:0000006

Established heterozygous causes include NR5A1, MAP3K1, WT1 and DHX37. Transmission, penetrance and associated features are gene- and variant-dependent. An unaffected carrier parent can transmit a pathogenic allele; 50% transmission risk for an autosomal dominant allele is not equivalent to 50% risk of the same gonadal phenotype.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:33296094 SUPPORT PRIMARY RESULT Human Clinical

"Segregation analysis across three generations showed incomplete penetrance (<50%) and phenotypic variability among the carriers of NR5A1 c.991-1G > C."

Directly documents dominant transmission with reduced penetrance in partial disease.

PMID:35290982 SUPPORT REVIEW SYNTHESIS Other

"Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance in 46,XY individuals."

Supports sex-limited dominant inheritance with gene-specific penetrance for MAP3K1.

Autosomal recessive inheritance HP:0000007

Biallelic DHH variants underlie a recessive form with sex-chromosome-dependent gonadal manifestations and possible peripheral neuropathy.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:11017805 SUPPORT PRIMARY RESULT Human Clinical

"a homozygous missense mutation (ATG-->ACG) at the initiating codon in exon 1 of the desert hedgehog (DHH) gene"

Homozygosity in the proband supports recessive inheritance.

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Subtypes

gene

NR5A1/SF-1-related 46,XY partial gonadal dysgenesis

NR5A1 hgnc:7983 Autosomal dominant inheritance

Heterozygous NR5A1 variants, including truncating, missense and splice-site alleles, cause variable partial gonadal dysgenesis. NR5A1 was the most frequent molecular finding in the partial groups of the I-DSD registry. Spontaneous puberty and unaffected transmitting relatives are reported, but neither gonadal function nor fertility is guaranteed. Adrenal insufficiency is uncommon in the broader NR5A1-related DSD spectrum and should be evaluated when clinically indicated.

Show evidence (3 references)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"A genetic etiology was identified in 42% of the cohort, with common gene defects in SRY and WT1 in CGD and NR5A1 in PGD."

Directly identifies NR5A1 as the gene most characteristically implicated in the partial form, in contrast to SRY/WT1 in complete disease.

PMID:27463801 SUPPORT PRIMARY RESULT Human Clinical

"3 novel NR5A1 mutations were identified in 3 patients with 46,XY partial gonadal dysgenesis"

Directly documents NR5A1 variants in molecularly defined partial disease.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"may need to be managed for adrenal insufficiency."

Broader NR5A1-related DSD guidance, not a measured frequency in partial disease.

DHH-related 46,XY partial gonadal dysgenesis with minifascicular neuropathy

DHH hgnc:2865 Autosomal recessive inheritance

Biallelic DHH variants can cause partial or complete gonadal dysgenesis. Reported partial cases include a dysgenetic testis with streak regions, abnormal Leydig-cell differentiation, and gonadal neoplasia. Peripheral neuropathy may accompany the gonadal disorder and can become apparent in adulthood; its absence in childhood does not exclude DHH-related disease.

Show evidence (3 references)

PMID:11017805 SUPPORT PRIMARY RESULT Human Clinical

"mutation of the DHH gene may cause 46, XY PGD associated with minifascicular neuropathy."

Directly links biallelic DHH defects to partial disease with neuropathy.

PMID:25927242 SUPPORT PRIMARY RESULT Human Clinical

"We identified a novel homozygous R124Q mutation in the desert hedgehog gene (DHH)"

An independent consanguineous family, so the subtype no longer rests on a single 2000 case report.

PMID:25927242 SUPPORT PRIMARY RESULT Human Clinical

"Mutations in DHH play a role in 46,XY gonadal dysgenesis and are associated with seminoma formation and a neuropathy with minifascicle formation."

Confirms the gonad-plus-neuropathy pairing and adds seminoma risk to this subtype's profile.

molecular

Molecularly unresolved 46,XY partial gonadal dysgenesis

A clinical diagnosis may remain without molecular confirmation. In the historical I-DSD registry, a likely gene or chromosome alteration was reported in 59.0% of screened PGDf individuals and 50.0% of screened PGDm individuals. Testing methods and variant classification varied; these selected-cohort results are not a fixed yield for current panels or genome sequencing.

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Of those who underwent screening, 48.3% of individuals with CGD, 59.0% with PGDf, and 50.0% with PGDm had a gene or chromosome alteration identified."

Reports tested-subgroup yields; not a plateau or all-patient diagnostic sensitivity.

Discussions and Knowledge Gaps

What is the prospective, age-specific neoplasia risk in retained gonads in 46,XY partial gonadal dysgenesis, and how reliably can monitoring detect clinically significant lesions?

KNOWLEDGE GAP OPEN gap_xy_pgd_gonad_retention_risk_benefit

Attached to

treatments#Individualized gonadal management (retention versus gonadectomy)

Registry estimates arise from selected histology subsets with different gonadectomy ages and inconsistent monitoring, not person-time follow-up of all retained gonads. Neither gonadal position nor hCG responsiveness is a validated rule for safe retention. Endocrine value and patient goals must be weighed against uncertain neoplasia risk.

Proposed experiments

Prospective registry follow-up of retained gonads in 46,XY partial gonadal dysgenesis

exp_xy_pgd_retained_gonad_incidence

Follow retained gonads prospectively within a multinational DSD registry using protocolized imaging, tumor markers, and (where performed) biopsy, reporting neoplasia incidence per gonad-year stratified by gonadal position and hCG-stimulated testosterone response, rather than prevalence at gonadectomy.

Immunohistochemical germ-cell marker triage of gonadal biopsy material

exp_xy_pgd_ihc_germ_cell_marker_triage

Evaluate whether immunohistochemical germ-cell markers (for example OCT3/4, TSPY, SALL4) on gonadal biopsy material can stratify premalignant risk well enough to serve as a triage test for gonad retention versus removal.

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"However, there was significant variation in monitoring practice amongst centers and only one third (n = 34/92) of individuals with PGDm had histology assessment."

Primary study identifies ascertainment and surveillance limitations.

Which unsolved partial-gonadal-dysgenesis cases are explained by noncoding variants, tissue-confined mosaicism, additional genes or true multilocus effects?

KNOWLEDGE GAP OPEN gap_xy_pgd_molecular_yield

Attached to

diagnosis#Broad molecular testing including WT1

The I-DSD study identified a likely gene or chromosome alteration in 131/310 across complete and partial disease, but only 78.7% underwent screening and methods and variant classification varied. This is not evidence of a fixed diagnostic-yield plateau. SOX9 regulatory architecture is relevant broader DSD biology; the cited enhancer paper does not establish every deletion as partial disease. The NR5A1/DHX37 dual-variant cases include uncertain or likely-benign DHX37 findings and do not prove a multilocus explanation.

Proposed experiments

Genome sequencing with targeted gonadal-enhancer interrogation

exp_xy_pgd_enhancer_genome_sequencing

Apply genome sequencing to exome-negative partial-dysgenesis cases with explicit interrogation of known gonadal enhancer regions, including the testis-specific enhancers upstream of SOX9, to test whether non-coding regulatory variation explains part of the diagnostic gap.

Deep sequencing of gonadal tissue for gonad-confined mosaicism

exp_xy_pgd_gonadal_mosaicism_sequencing

Deep-sequence gonadal tissue obtained at gonadectomy alongside matched blood to test whether mosaic variants confined to the gonad account for cases undiagnosed on peripheral-blood testing.

Show evidence (3 references)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Genetic screening was performed in 78.7% of the cohort with various methods; targeted gene screening (71%), gene panels (13%), and whole exome sequencing (15%)."

Defines testing ascertainment.

PMID:37240737 SUPPORT PRIMARY RESULT Human Clinical

"Secondly, patient 3 also carries a loss-of-function variant in NR5A1, which could fully explain the PGD phenotype, making the p.Val999Met variant a chance finding."

Explicit uncertainty about a dual-variant interpretation.

PMID:30552336 SUPPORT BACKGROUND Other

"Here, we identified four DSD patients with overlapping duplications or deletions upstream of SOX9."

Broader human SOX9 enhancer biology motivates a noncoding hypothesis, without asserting partial-specific clinical causation.

Do mouse Nr5a1 models faithfully reproduce the human NR5A1 gonadal phenotype, given that the same p.R92W substitution induces testicular development in human 46,XX gonads but produces no masculinization in XX mice?

HUMAN MODEL MISMATCH OPEN mismatch_xy_pgd_nr5a1_mouse_model_divergence

Attached to

pathophysiology#NR5A1 sequence alteration

The p.Arg92Trp comparison showed species differences, including absence of XX masculinization in mice despite human 46,XX testicular development. This is a caution about translating allele-specific sex-development models, not a claim that the mouse directly models every human PGD presentation.

Proposed experiments

Human gonadal organoid or iPSC titration of NR5A1 dosage

exp_xy_pgd_human_gonadal_organoid_nr5a1_dosage

Titrate NR5A1 dosage and introduce patient-specific alleles in human-derived gonadal somatic cell models (iPSC-derived or fetal gonadal organoid) to establish the human-specific dose-response threshold that separates partial from complete testis-determination failure, and compare it directly against the corresponding murine threshold.

Show evidence (1 reference)

PMID:27833742 SUPPORT PRIMARY RESULT Model Organism

"Importantly, mutation-positive XX mice showed no signs of masculinization."

Directly documents the species divergence for the identical allele that masculinizes human 46,XX gonads.

Do established PGD-associated DHX37 alleles alter RNA-dependent ATPase activity, ribosome maturation, or another cell function in developing human gonadal cells?

KNOWLEDGE GAP OPEN gap_xy_pgd_dhx37_biochemical_mechanism

Attached to

pathophysiology#DHX37 sequence alteration

The original study used structural modeling and expression/localization analysis. Later overexpression experiments measured abundance and selected signaling readouts, with unchanged p53 and no increase in apoptosis for p.Ser408Leu. The proposed ribosomopathy mechanism and the route from altered protein abundance to gonadal differentiation remain unproven.

Show evidence (2 references)

PMID:31337883 SUPPORT PRIMARY RESULT Other

"This raises the possibility that some forms of DSD may be a ribosomopathy."

The authors propose ribosomopathy as a hypothesis in their conclusion; they do not demonstrate variant-dependent ribosome dysfunction.

PMID:37065748 SUPPORT PRIMARY RESULT In Vitro

"Surprisingly, we did not see increases in the p53 protein and cell apoptosis by DHX37 mutation"

Negative experimental observations constrain the proposed stress mechanism.

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Pathophysiology

NR5A1 sequence alteration

Heterozygous pathogenic NR5A1 variants occur in partial gonadal dysgenesis. Early truncating alleles are predicted to reduce functional SF-1; other alleles have variant-specific effects. Nonsense-mediated decay and splice changes in the cited partial cases were predicted rather than directly measured.

NR5A1 hgnc:7983

Downstream

Reduced SF-1 transcriptional activity Selected NR5A1 missense variants reduce a steroidogenic-promoter reporter in transfected cells; this does not establish the effect of every allele.

Incomplete testicular differentiation The genetic association establishes a developmental effect, but the causal fetal targets and thresholds vary and are not resolved for each allele.

Show evidence (1 reference)

PMID:27463801 SUPPORT PRIMARY RESULT Human Clinical

"3 novel NR5A1 mutations were identified in 3 patients with 46,XY partial gonadal dysgenesis: p.Lys38* and p.Leu80Trpfs*8 lead to premature translation termination codons within the SF1 DNA-binding domain"

Directly documents loss-of-function NR5A1 variants in partial disease.

Reduced SF-1 transcriptional activity

p.Gly22Asp and p.Leu420Pro reduced Cyp11a1 promoter activation in kidney-derived tsa201 cells. This is an experimental readout of variant-dependent transcriptional function; it does not directly measure fetal Sertoli differentiation or all SF-1 target genes.

NR5A1 hgnc:7983

Experimental models

NR5A1 variant promoter-reporter assays CELL LINE

Show evidence (1 reference)

PMID:31745530 SUPPORT PRIMARY RESULT In Vitro

"Transient transfection assays showing activation of a Cyp11a1 promoter by WT SF-1 and impaired transcriptional activity by the p.G22D and p.L420P mutants."

Cyp11a1 reporter in tsa201 kidney-derived cells; the clinical cohort used a broader partially virilized DSD category.

MAP3K1 sequence alteration

Heterozygous MAP3K1 variants are associated with partial and complete gonadal dysgenesis. Functional consequences below are allele- and assay-specific. The p.Arg186Gly family had severe 46,XY DSD with streak gonads or tumors; its cellular results inform a broader gene mechanism rather than prove the mechanism of every partial presentation.

MAP3K1 hgnc:6848

Downstream

Enhanced MAP3K1-RHOA association Patient-derived and transfected-cell assays identify increased association for selected variants.

Reduced MAP3K1 ubiquitination The p.Arg186Gly construct shows reduced ubiquitination in HEK293T cells; mediation by increased RHOA binding remains an interpretation.

Increased MAP3K1 protein abundance The p.Arg186Gly construct produces more MAP3K1 protein in NT2/D1 and KGN cells.

Increased ERK1/2 phosphorylation Selected patient lymphoblastoid lines show altered ERK phosphorylation after serum refeeding.

Increased p38 phosphorylation The response occurs in selected patient lines and p.Arg186Gly overexpression models, with allele-dependent differences.

Increased beta-catenin-dependent transcription The p.Arg186Gly construct increases TCF/LEF reporter activity; intervening signaling was not dissected by epistasis.

Incomplete testicular differentiation Human pedigrees and cases support MAP3K1-related partial dysgenesis. The observed signaling changes propose, but do not experimentally reconstruct, the human fetal developmental route.

Show evidence (1 reference)

PMID:21129722 SUPPORT PRIMARY RESULT Human Clinical

"mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination."

Directly names partial gonadal dysgenesis as a MAP3K1 outcome.

Enhanced MAP3K1-RHOA association

Selected MAP3K1 variants increase RHOA association in protein-interaction assays. The p.Arg186Gly study used both NanoBiT and co-immunoprecipitation. Stronger association alone does not prove that RHOA mediates all downstream signaling changes.

MAP3K1 hgnc:6848

Experimental models

MAP3K1 patient lymphoblastoid phosphorylation assays CELL LINE

MAP3K1 p.Arg186Gly overexpression assays CELL LINE

Show evidence (2 references)

PMID:21129722 SUPPORT PRIMARY RESULT In Vitro

"these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex."

Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association; p38 effects differed among alleles.

PMID:35309143 SUPPORT PRIMARY RESULT In Vitro

"Our Co-IP assay confirmed that the binding capacity of MAP3K1R186G to RhoA was 2.57 times that of the wild-type protein (Figures 5A,A'), and the ubiquitination degree of the wild-type MAP3K1 protein was 3.6-fold that of the MAP3K1R186G variant (Figures 5B,B')."

Selected p.Arg186Gly variant in HEK293T cells; binding and ubiquitination measurements, not gonadal epistasis.

Reduced MAP3K1 ubiquitination

The p.Arg186Gly MAP3K1 protein showed less ubiquitination than wild type in transfected HEK293T cells. Reduced turnover is a proposed explanation for greater abundance, but protein half-life and dependence on RHOA competition were not directly established.

MAP3K1 hgnc:6848

Experimental models

MAP3K1 p.Arg186Gly overexpression assays CELL LINE

Show evidence (1 reference)

PMID:35309143 SUPPORT PRIMARY RESULT In Vitro

Selected p.Arg186Gly variant in HEK293T cells; binding and ubiquitination measurements, not gonadal epistasis.

Increased MAP3K1 protein abundance

MAP3K1 p.Arg186Gly protein abundance was increased 6.4-fold in KGN and 2.0-fold in NT2/D1 cells relative to wild type. This measured steady-state difference is separated from the unmeasured degradation-rate explanation.

MAP3K1 hgnc:6848

Experimental models

MAP3K1 p.Arg186Gly overexpression assays CELL LINE

Show evidence (1 reference)

PMID:35309143 SUPPORT PRIMARY RESULT In Vitro

"The protein expression of the MAP3K1R186G variant was 6.4 and 2.0 times higher than that of the wild type in the KGN and NT2/D1 cells, respectively (Figures 6A–D)."

Measured abundance in KGN and NT2/D1 overexpression models; not a direct half-life measurement.

Increased ERK1/2 phosphorylation

Serum-refed patient-derived lymphoblastoid cells carrying selected MAP3K1 variants showed increased ERK1/2 phosphorylation. These cells are not fetal gonadal cells, and phosphorylation does not by itself identify the developmental fate change.

MAP3K1 hgnc:6848

Experimental models

MAP3K1 patient lymphoblastoid phosphorylation assays CELL LINE

Show evidence (1 reference)

PMID:21129722 SUPPORT PRIMARY RESULT In Vitro

"these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex."

Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association; p38 effects differed among alleles.

Increased p38 phosphorylation

p38 phosphorylation increased in selected MAP3K1 variant assays, including p.Arg186Gly-transfected NT2/D1 and KGN cells. The original lymphoblastoid study did not find the same p38 response for every tested allele.

MAP3K1 hgnc:6848

Experimental models

MAP3K1 patient lymphoblastoid phosphorylation assays CELL LINE

MAP3K1 p.Arg186Gly overexpression assays CELL LINE

Show evidence (2 references)

PMID:21129722 SUPPORT PRIMARY RESULT In Vitro

"these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex."

Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association; p38 effects differed among alleles.

PMID:35309143 SUPPORT PRIMARY RESULT In Vitro

"Similarly, in the NT2/D1 testicular cells, phosphorylated p38 and GSK3β proteins were significantly elevated in the mutant group, which were 2.3 and 2.2 times higher than those in the wild-type group, respectively."

Measured phosphorylation responses in an overexpression model.

Increased beta-catenin-dependent transcription

MAP3K1 p.Arg186Gly increased TCF/LEF reporter activity in HEK293T cells. The same study observed GSK3beta phosphorylation, greater WNT4/beta-catenin protein and altered sex-development gene expression. Those parallel measurements suggest an ovarian-signaling bias, but do not establish a necessary linear cascade or ovarian tissue formation in partial human disease.

MAP3K1 hgnc:6848

Experimental models

MAP3K1 p.Arg186Gly overexpression assays CELL LINE

Show evidence (1 reference)

PMID:35309143 SUPPORT PRIMARY RESULT In Vitro

"The data showed that at 48 h after transfection, the relative activity of TCF/LEF in the mutant group reached its peak, which was 9.78 ± 0.57 times that of the wild-type group (Figures 6E,F)."

TCF/LEF reporter assay measures beta-catenin-dependent transcription in HEK293T cells.

Biallelic DHH sequence alteration

Biallelic DHH variants are associated with gonadal dysgenesis and, in some patients, peripheral neuropathy. Initiating-codon translation failure and altered p.Arg124Gln ligand interactions were predicted; a universal complete loss of hedgehog signaling was not directly demonstrated in these cases.

DHH hgnc:2865

Downstream

Incomplete testicular differentiation Human biallelic DHH cases include histologically confirmed partial dysgenesis.

Impaired Leydig-cell maturation Loss of mature Leydig-cell staining in one partial gonad supports a developmental differentiation abnormality; the intervening paracrine mechanism remains inferred.

Peripheral neuropathy The original molecularly characterized patient had minifascicular nerve pathology; the intermediate human developmental signaling was not measured.

Show evidence (2 references)

PMID:11017805 SUPPORT PRIMARY RESULT Human Clinical

"a homozygous missense mutation (ATG-->ACG) at the initiating codon in exon 1 of the desert hedgehog (DHH) gene, which predicts a failure of translation of the gene."

Directly documents a causal biallelic DHH lesion in partial disease.

PMID:25927242 SUPPORT PRIMARY RESULT Human Clinical

"The gonads of one patient showed partial gonadal dysgenesis with loss of Leydig cells in tubular areas with seminoma in situ and a hyperplasia of Leydig cell-like cells expressing CYP17A1 in more dysgenetic parts of the gonad."

Human gonadal pathology with biallelic DHH p.Arg124Gln; the molecular signaling defect was not directly assayed.

Impaired Leydig-cell maturation

In one DHH p.Arg124Gln partial-dysgenesis gonad, CYP17A1-positive Leydig-like nodules were present but mature INSL3-positive Leydig cells were absent from tubular interstitium. This supports abnormal differentiation rather than absence of every steroidogenic cell. The finding is postnatal histology, not a direct fetal hormone measurement.

Leydig cell CL:0000178

DHH hgnc:2865

Show evidence (1 reference)

PMID:25927242 SUPPORT PRIMARY RESULT Human Clinical

Human gonadal pathology with biallelic DHH p.Arg124Gln; the molecular signaling defect was not directly assayed.

DHX37 sequence alteration

Recurrent heterozygous DHX37 variants, including p.Arg308Gln, occur in partial gonadal dysgenesis and testicular regression. Genetic association is established more strongly than the biochemical route. The proposed ribosomopathy mechanism must be distinguished from measured protein abundance and from uncertain variants.

DHX37 hgnc:17210

Downstream

Reduced DHX37 protein abundance Overexpression experiments found lower protein abundance for p.Arg308Gln and selected other variants. The effect is assay-specific and does not prove reduced helicase activity.

Incomplete testicular differentiation The p.Arg308Gln patient had biopsy-documented bilateral dysgenetic testes. Intermediates between the variant and fetal gonadal development remain unknown.

Show evidence (1 reference)

PMID:37240737 SUPPORT PRIMARY RESULT Human Clinical

"In DHX37, the variant p.(Arg308Gln), recurrent associated with DSD, was identified in one patient"

Directly documents the recurrent DHX37 allele in a partial-disease cohort.

Reduced DHX37 protein abundance

In transfected HEK293T cells, p.Arg308Gln and p.Arg671Thr showed lower DHX37 protein expression than wild type. A separate p.Ser408Leu Sertoli-cell assay also found lower transcript and protein abundance. p.Arg671Thr and p.Ser408Leu were listed as VUS in the later study table. These assays do not demonstrate variant-dependent ATPase failure, defective 18S rRNA maturation, or a causal connection from protein reduction to human gonadal dysgenesis.

DHX37 hgnc:17210

Experimental models

DHX37 variant expression and localization assays CELL LINE

DHX37 p.Ser408Leu human Sertoli-cell overexpression CELL LINE

Show evidence (2 references)

PMID:38769888 SUPPORT PRIMARY RESULT In Vitro

"The results indicated that mutant DHX37 decreased the protein levels of DHX37."

Selected-variant overexpression assay; not an ATPase or ribosome-biogenesis assay.

PMID:37065748 SUPPORT PRIMARY RESULT In Vitro

"compared with the cells transfected with pcDNA3.1-WT, those with pcDNA3.1-S408L displayed decreased DHX37 expression both at the mRNA and protein levels."

Variant overexpression effect in a human Sertoli-cell line, with uncertain clinical classification.

WT1 sequence alteration

Pathogenic heterozygous WT1 variants can cause partial testicular dysgenesis within a variable renal and tumor-predisposition disorder. Effects differ between zinc-finger missense, splice, truncating and deletion alleles; a single generic haploinsufficiency mechanism cannot represent all of them.

WT1 hgnc:12796

Downstream

Incomplete testicular differentiation The whole-gene deletion case directly documents severe partial dysgenesis; the disrupted fetal transcriptional program was not assayed.

Steroid-resistant nephrotic syndrome Pathogenic WT1 variants predispose to glomerular disease within WT1 disorder. This is restricted to the WT1-related subtype; intervening renal cellular mechanisms are not modeled here.

Nephroblastoma Wilms tumor occurred in the child with a WT1 whole-gene deletion and partial gonadal dysgenesis. This genotype-qualified link does not imply that every variant or affected person develops a tumor, or that the somatic initiating events were measured.

Show evidence (1 reference)

PMID:25613702 SUPPORT PRIMARY RESULT Human Clinical

"We found a heterozygous WT1 whole-gene deletion but no other gene defects."

Directly documents a causal heterozygous WT1 lesion in partial disease.

Incomplete testicular differentiation

The gonads can contain hypoplastic or disorganized testicular tissue, streak tissue and regressed regions in varying combinations. Sertoli, Leydig and germ-cell compartments need not be affected equally. Preserved testosterone, AMH or spontaneous puberty is compatible with partial dysgenesis and does not demonstrate normal fertility or absence of neoplasia.

male gonad development GO:0008584 ⚠ ABNORMAL

Animal models

Sox9-Cre conditional Nr5a1 knockout mice Mouse recapitulates

Downstream

Gonadal dysgenesis Histology is a direct readout of abnormal tissue differentiation.

Reduced fetal AMH activity Müllerian retention in a subset is consistent with insufficient fetal AMH action; this is a developmental inference, not a fetal serum measurement.

Reduced fetal androgen activity Undervirilized external genital development is consistent with inadequate fetal testicular androgen activity; timing and output are inferred rather than measured.

Impaired spermatogenesis Abnormal tubular and germ-cell architecture plausibly contributes to the semen abnormalities observed in clinical follow-up; patient-specific mediation is not experimentally demonstrated.

Delayed gonadal germ-cell maturation OCT3/4-positive luminal cells in a MAP3K1-associated partial gonad demonstrate delayed maturation within dysgenetic tissue.

Decreased testicular size Underdeveloped testicular tissue is consistent with reduced volume in the reported NR5A1 case. The contribution of each histological compartment was not quantified.

Hypergonadotropic hypogonadism Primary gonadal dysfunction can reduce sex-steroid output and feedback, producing elevated gonadotropins with low testosterone in a subset; preserved androgen production in other partial cases remains compatible with dysgenesis.

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Features of dysgenetic testis noted were reduced tubular diameter, thickened basal membrane, increased interstitial stroma, intracapsular growth, irregular shaped tubules, Leydig cell micronodules or hyperplasia, Sertoli cell only tubules, reduced germ cell number, absent spermatogenesis, and..."

Expert histological review documents the heterogeneous tissue-level lesion.

Reduced fetal AMH activity

Insufficient anti-Müllerian hormone activity during the fetal differentiation window is a physiological interpretation of Müllerian retention in some partial cases. Other patients lack Müllerian structures, indicating that fetal AMH action may have been sufficient despite later gonadal dysfunction. Postnatal AMH measurements cannot retrospectively quantify the fetal exposure.

Downstream

Presence of uterus in 46,XY individual Insufficient fetal AMH action permits Müllerian structures to persist; regression failure is the omitted developmental intermediate.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"In a 46,XY individual, absence of virilization and presence of müllerian structures implies that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and anti-müllerian hormone, during fetal life and are unlikely to do so during postnatal life."

General developmental interpretation in GeneReviews; applied only to the deficient-hormone presentations, not every PGD case.

Reduced fetal androgen activity

Inadequate testicular androgen action during genital differentiation can produce undervirilized external genital anatomy. The degree and timing vary, and a female external phenotype is possible. Fetal steroid levels were not measured in the cited clinical cohorts.

Downstream

Ambiguous genitalia Incomplete androgen-dependent external genital differentiation is the physiological interpretation of the partial phenotype.

Penoscrotal hypospadias Incomplete androgen-dependent urethral development is an inferred developmental explanation for this observed feature.

Micropenis Insufficient androgen-dependent phallic growth provides the developmental interpretation of reduced phallic size.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

General developmental interpretation in GeneReviews; applied only to the deficient-hormone presentations, not every PGD case.

Impaired spermatogenesis

Sperm production may be severely reduced or absent despite retained androgen production. Severe oligozoospermia and low motility occurred in the three semen-tested participants of one ten-patient follow-up cohort; azoospermia is documented in individual molecularly characterized partial cases.

Downstream

Azoospermia Severe failure of sperm production can result in an azoospermic ejaculate; observed in individual cases, not all PGD.

Male infertility Impaired sperm production can limit fertility; individual reproductive potential is not determined by androgen production alone.

Oligozoospermia Reduced sperm production is reflected by the severe oligozoospermia observed in the three semen-tested participants.

Show evidence (2 references)

PMID:25580123 SUPPORT PRIMARY RESULT Human Clinical

"Three patients had a sperm count; all had severe oligozoospermia and low motility, and two had also abnormal semen viscosity."

All three tested patients had severe oligozoospermia and low motility; denominator is not all ten.

PMID:33296094 SUPPORT PRIMARY RESULT Human Clinical

"presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and azoospermia in P2"

Directly documents azoospermia.

Delayed gonadal germ-cell maturation

In a partial gonad with a MAP3K1 defect, luminal OCT3/4-positive cells were interpreted as delayed maturation and peripheral cells as preneoplastic. Delayed maturation is not itself synonymous with neoplasia. The molecular steps linking a dysgenetic Y-bearing gonadal environment to a tumor remain incompletely defined.

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"OCT3/4 staining (B.2) shows peripheral preneoplastic cells (gray arrow) and luminal OCT3/4-positive delayed maturation in white arrow."

Human histology differentiates maturation delay from preneoplastic location.

✶

Histopathology

Dysgenetic testis with hypoplastic seminiferous tubules

Partial disease can include dysgenetic testes, streak tissue or regressed gonads. Observed testicular abnormalities include reduced tubular diameter, thick basement membranes, irregular tubules, interstitial fibrosis, Sertoli-cell-only tubules and reduced germ cells. Histology contributes to diagnosis and neoplasia assessment but does not by itself classify every partial versus complete case; small biopsies can miss heterogeneous tissue.

Show evidence (2 references)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

Direct expert histological review of the registry material.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"Results may be inaccurate because of biopsy sampling error; gonadal biopsy may harm the future growth and development of the gonad."

Broader testicular-development guidance warns about sampling and potential harm.

Gonadoblastoma and germ cell neoplasia in situ in dysgenetic gonads

Gonadoblastoma and germ cell neoplasia in situ are distinct lesions reported in partial gonadal dysgenesis. DHH-related partial disease included GCNIS with incipient stromal invasion and gonadoblastoma. These are pathological findings, not an obligatory sequential progression in every gonad.

Show evidence (2 references)

PMID:25927242 SUPPORT PRIMARY RESULT Human Clinical

"At another site a gonadoblastoma with Call Exner bodies was seen."

Direct DHH-case pathology.

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"The common types of tumors in all 3 groups were gonadoblastoma (47.8%, n = 32/67), dysgerminoma/seminoma (28.4%, n = 19/67), and germ cell neoplasia in situ (11.9%, n = 8/67)."

Lists the lesion classes across the GD cohort; subgroup counts are in Table 6.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Endocrine 3

Decreased circulating anti-Mullerian hormone concentration Decreased circulating antimullerian hormone circulation HP:0031103

No edge or readout link to Reduced fetal AMH activity is assigned: the cited postnatal measurement cannot reconstruct fetal AMH secretion or action.

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"| Low | 95.7% (n = 22/23) | 48.0% (n = 12/25) | 58.1% (n = 18/31) | CGD vs PGDf .0003 CGD vs PGDm .002 PGDf vs PGDm ns |"

AMH row in Table 3: CGD, PGDf, PGDm; age-specific reference ranges and small tested subsets.

Hypergonadotropic hypogonadism HP:0000815

Show evidence (1 reference)

PMID:37240737 SUPPORT PRIMARY RESULT Human Clinical

"Hormonal evaluation indicated high levels of FSH (72.1 IU/L) and LH (13.9 IU/L), and low levels of total testosterone (70 ng/dL)."

Patient 2 had elevated gonadotropins and low testosterone; directly supports the combined endocrine phenotype.

Delayed puberty HP:0000823

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"18% of PGDf presented with delayed puberty and 8% with virilization."

Reports the proportion presenting with delayed puberty in the selected PGDf group, not lifetime prevalence.

Genitourinary 16

Ambiguous genitalia HP:0000062

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Most individuals with PGD presented with atypical genitalia in infancy"

Documents the common infant presentation; no pooled arithmetic or population frequency is inferred from the abstract.

Gonadal dysgenesis HP:0000133

Show evidence (1 reference)

PMID:38206718 SUPPORT PRIMARY RESULT Human Clinical

"Pathology show testes dysgenesis, composed mainly of hypoplastic seminiferous tubules"

Directly documents dysgenetic testicular histology.

Penoscrotal hypospadias HP:0000808

Show evidence (1 reference)

PMID:33296094 SUPPORT PRIMARY RESULT Human Clinical

"presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and azoospermia in P2"

Directly documents penoscrotal hypospadias in molecularly confirmed partial disease.

Cryptorchidism HP:0000028

Show evidence (1 reference)

PMID:33296094 SUPPORT PRIMARY RESULT Human Clinical

"presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and azoospermia in P2"

Directly documents bilateral cryptorchidism.

Clitoral hypertrophy HP:0008665

Show evidence (1 reference)

PMID:28504475 SUPPORT PRIMARY RESULT Human Clinical

"resulting in clitoral hypertrophy with otherwise typical female external genitalia"

Directly documents clitoral hypertrophy in partial disease.

Presence of uterus in 46,XY individual HP:0034546

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"| Presence of uterus | 100% (n = 96/96) | 51.0% (n = 52/102) | 31.3% (n = 30/96) | PGDf vs PGDm .0062 |"

Table 2 columns are CGD, PGDf, PGDm; retains anatomy-specific denominators.

Micropenis HP:0000054

Show evidence (1 reference)

PMID:37240737 SUPPORT PRIMARY RESULT Human Clinical

"The patient had a male sex assignment, with a 1.0 cm phallus, normal male urethral opening without hypospadias, and both gonads palpable in the inguinal canal (Prader 5; EMS 8.0; EGS 8.5)."

Direct infant clinical observation in the p.Arg308Gln partial-disease case.

Decreased testicular size HP:0008734

Show evidence (1 reference)

PMID:33296094 SUPPORT PRIMARY RESULT Human Clinical

"presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and azoospermia in P2"

Directly documents reduced testicular volume.

Azoospermia HP:0000027

Show evidence (1 reference)

PMID:33296094 SUPPORT PRIMARY RESULT Human Clinical

"presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and azoospermia in P2"

Directly documents azoospermia.

Male infertility HP:0003251

Show evidence (1 reference)

PMID:33296094 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"low bitesticular volume and azoospermia in P2"

Azoospermia with low testicular volume supports impaired fertility by inference; the report does not itself use the word infertility.

Gonadoblastoma HP:0000150

Show evidence (2 references)

PMID:25927242 SUPPORT PRIMARY RESULT Human Clinical

"At another site a gonadoblastoma with Call Exner bodies was seen."

Direct gonadal pathology in the DHH partial-dysgenesis case.

PMID:25613702 SUPPORT PRIMARY RESULT Human Clinical

"Gonadectomy was performed at the age of 1 month and the microscopy was thought to be suggestive for a gonadoblastoma."

Microscopy was suggestive of gonadoblastoma; this is not presented as a confirmed neonatal lesion.

Dysgerminoma HP:0100621

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

Table 6 groups are CGD, PGDf and PGDm; the PGDf column provides direct partial-disease evidence.

Steroid-resistant nephrotic syndrome HP:0012588

Show evidence (1 reference)

PMID:32352694 SUPPORT REVIEW SYNTHESIS Other

"WT1 disorder is characterized by congenital/infantile or childhood onset of steroid-resistant nephrotic syndrome (SRNS), a progressive glomerulopathy that does not respond to standard steroid therapy."

Directly documents SRNS as the defining renal feature of WT1 disorder.

Nephroblastoma HP:0002667

Show evidence (1 reference)

PMID:25613702 SUPPORT PRIMARY RESULT Human Clinical

"At the age of 9 months, the patient presented with a bilateral Wilms tumor."

Directly documents Wilms tumor in WT1-related partial gonadal dysgenesis.

Primary amenorrhea HP:0000786

No single incoming edge is assigned because amenorrhea can reflect different combinations of Müllerian anatomy and postnatal gonadal hormone function. The existing fetal hormone nodes do not measure those later physiological causes in the cited individual.

Show evidence (1 reference)

PMID:37240737 SUPPORT PRIMARY RESULT Human Clinical

"At the age of 17, patient 2 presented with primary amenorrhea, spontaneous pubarche and no thelarche."

Patient 2 provides a direct partial-disease presentation.

Oligozoospermia HP:0000798

Show evidence (1 reference)

PMID:25580123 SUPPORT PRIMARY RESULT Human Clinical

"Three patients had a sperm count; all had severe oligozoospermia and low motility, and two had also abnormal semen viscosity."

Three tested participants; no extrapolation to the full cohort.

Integument 1

Hirsutism HP:0001007

Show evidence (1 reference)

PMID:38206718 SUPPORT PRIMARY RESULT Human Clinical

"admitted to the hospital due to hirsutism and a deep voice"

Directly documents hirsutism from pubertal virilization.

Nervous System 2

Peripheral neuropathy HP:0009830

Show evidence (1 reference)

PMID:11017805 SUPPORT PRIMARY RESULT Human Clinical

"We describe a patient with 46,XY partial gonadal dysgenesis (PGD) who presented with polyneuropathy."

Directly documents polyneuropathy in the DHH subtype.

Deep voice Abnormally low-pitched voice HP:0010300

The observation concerns pubertal virilization. It is not a consequence of the existing reduced fetal androgen activity node; an incoming edge would require a separately supported postnatal androgen-production mechanism.

Show evidence (1 reference)

PMID:38206718 SUPPORT PRIMARY RESULT Human Clinical

"admitted to the hospital due to hirsutism and a deep voice"

Direct case observation.

🧬

Genetic Associations

NR5A1 (Heterozygous pathogenic variants causing variable partial gonadal dysgenesis)

Gene: NR5A1 hgnc:7983 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:27463801 SUPPORT PRIMARY RESULT Human Clinical

Directly documents loss-of-function NR5A1 variants in partial disease.

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"with common gene defects in SRY and WT1 in CGD and NR5A1 in PGD."

Establishes NR5A1 as the characteristic partial-disease gene.

url:https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf SUPPORT PRIMARY RESULT Human Clinical

"Segregation analysis across three generations showed incomplete penetrance (<50%) and phenotypic variability among the carriers of NR5A1 c.991-1G>C."

Family-specific penetrance, not a general NR5A1 penetrance estimate.

OTX2 (Proposed, unconfirmed modifier of NR5A1-associated phenotype)

Gene: OTX2 hgnc:8522 gene page relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (1 reference)

url:https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf SUPPORT PRIMARY RESULT Human Clinical

"The variant pathogenicity was possibly modulated by rare heterozygous variants inherited from the other parent, OTX2 p.P134R (P1) or PROP1 c.301_302delAG (P2)."

The source itself calls the modifier effect possible; family observation.

PROP1 (Proposed, unconfirmed modifier of NR5A1-associated phenotype)

Gene: PROP1 hgnc:9455 gene page relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (1 reference)

url:https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf SUPPORT PRIMARY RESULT Human Clinical

"The variant pathogenicity was possibly modulated by rare heterozygous variants inherited from the other parent, OTX2 p.P134R (P1) or PROP1 c.301_302delAG (P2)."

The source itself calls the modifier effect possible; family observation.

MAP3K1 (Causal heterozygous sex-limited gain-of-function variant)

Gene: MAP3K1 hgnc:6848 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:35290982 SUPPORT REVIEW SYNTHESIS Other

"Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis"

Directly includes partial disease in the MAP3K1 spectrum.

PMID:21129722 SUPPORT PRIMARY RESULT Human Clinical

"mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination."

Directly names partial gonadal dysgenesis as a MAP3K1 outcome.

WT1 (Causal heterozygous variant producing syndromic gonadal dysgenesis with steroid-resistant nephrotic syndrome and Wilms tumor predisposition)

Gene: WT1 hgnc:12796 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:25613702 SUPPORT PRIMARY RESULT Human Clinical

"We found a heterozygous WT1 whole-gene deletion but no other gene defects."

Directly documents a causal heterozygous WT1 lesion in partial disease.

PMID:25613702 SUPPORT PRIMARY RESULT Human Clinical

"This case description illustrates that a WT1 deletion might be associated with a more severe phenotype than previously thought."

Clinical counterexample to a simple deletion-equals-mild rule, supporting variability rather than refuting the gene association.

DHX37 (Heterozygous variants associated with partial gonadal dysgenesis and testicular regression, including recurrent p.Arg308Gln)

Gene: DHX37 hgnc:17210 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:37240737 SUPPORT PRIMARY RESULT Human Clinical

"In DHX37, the variant p.(Arg308Gln), recurrent associated with DSD, was identified in one patient"

Directly documents the recurrent DHX37 allele in a partial-disease cohort.

PMID:37240737 SUPPORT PRIMARY RESULT Human Clinical

"Secondly, patient 3 also carries a loss-of-function variant in NR5A1, which could fully explain the PGD phenotype, making the p.Val999Met variant a chance finding."

Authors explicitly acknowledge NR5A1 sufficiency and a possible chance DHX37 finding.

PMID:37240737 SUPPORT PRIMARY RESULT Human Clinical

"| 2 | DHX37 | c.1399C>G/ p.Leu467Val | rs149331610 | 0.0002952 1 /38 | VUS | 22.2 | Disease causing | Probably damaging | Deleterious | Maternal |"

Table 2 classification is uncertain despite damaging prediction scores.

+ 1 more reference

DHH (Biallelic variants associated with partial or complete gonadal dysgenesis and possible peripheral neuropathy)

Gene: DHH hgnc:2865 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:11017805 SUPPORT PRIMARY RESULT Human Clinical

"a homozygous missense mutation (ATG-->ACG) at the initiating codon in exon 1 of the desert hedgehog (DHH) gene, which predicts a failure of translation of the gene."

Directly documents a causal biallelic DHH lesion in partial disease.

PMID:25927242 SUPPORT PRIMARY RESULT Human Clinical

Direct partial phenotype and Leydig-cell finding.

ZFPM2 (Candidate association requiring variant-specific reassessment)

Gene: ZFPM2 hgnc:16700 gene page relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (2 references)

PMID:24549039 SUPPORT PRIMARY RESULT In Vitro

"the failure of testis development in these cases could be explained by the impaired ability of the mutant FOG2 proteins to interact with a known regulator of early testis development, GATA4."

The original small-case functional result supports candidate involvement. The later paper identifies which original alleles belonged to the partial case and weakens the interpretation of p.Met544Ile.

PMID:31962012 SUPPORT PRIMARY RESULT Computational

"Reclassification of the ten ZFPM2 variants revealed six missense were considered benign or likely benign (p.E30G, p.D98N, p.S210T, p.L335V, p.M544I, p.M703L)."

Later variant-specific functional reassessment.

💊

Medical Actions

Individualized gonadal management (retention versus gonadectomy)

Category: Therapeutic Action: orchiectomy Ontology label: Orchiectomy NCIT:C15288

Platform: Surgery

Discuss gonadal function, genotype, tissue location, available pathology, age, fertility potential and the individual's goals with an experienced DSD team. Nonfunctional high-risk dysgenetic gonads may warrant removal; potentially functional gonads may be retained after individualized discussion. Sex assignment and a preserved hCG response are not stand-alone indications for removal or retention. Surveillance options exist, but no strategy reliably excludes neoplasia; the registry percentages are selected histology prevalences rather than prospective risks for retained gonads.

Mechanism Target:

INHIBITS Gonadoblastoma — Removal of nonfunctional at-risk gonads may prevent gonadoblastoma; decisions remain individualized.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"Streak gonads and dysgenetic gonads are at increased risk for the development of gonadoblastoma and should be surgically removed if nonfunctional."

Broader DSD guidance scopes removal to nonfunctional at-risk gonads.

Target Phenotypes: Gonadoblastoma HP:0000150

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"Streak gonads and dysgenetic gonads are at increased risk for the development of gonadoblastoma and should be surgically removed if nonfunctional."

Broader DSD guidance scopes removal to nonfunctional at-risk gonads.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"Depending on the specific diagnosis, potentially functional gonads may be retained with appropriate surveillance for tumor development."

Broader DSD guidance supports individualized retention.

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"However, there was significant variation in monitoring practice amongst centers and only one third (n = 34/92) of individuals with PGDm had histology assessment."

Limits tumor-risk inference and supports specialist follow-up.

Individualized sex-steroid replacement

Category: Therapeutic Action: Hormone Replacement Therapy NCIT:C15599

Agent: 17beta-estradiol CHEBI:16469 testosterone CHEBI:17347

Replace sex steroids when gonadal production is insufficient or after gonadectomy, according to the individual's desired pubertal development and clinical needs. Testosterone or 17-beta-estradiol is introduced gradually with monitoring; an endometrium-bearing uterus requires addition of progestogen after appropriate estrogen priming. Spontaneous pubertal onset does not guarantee completion. Endo-ERN guidance supports individualized induction around age 11 for girls with confirmed hypogonadism and around age 12 for boys at high risk without pubertal onset. These recommendations cover broader congenital hypogonadism; the guideline found no eligible comparative puberty-treatment studies specifically in males with PGD.

Mechanism Target:

BYPASSES Hypergonadotropic hypogonadism — Sex-steroid replacement addresses inadequate hormone production; it does not reverse the developmental lesion.

Show evidence (2 references)

PMID:35353710 SUPPORT REVIEW SYNTHESIS Other

"We recommend to use 17β-oestradiol for puberty induction or to sustain puberty in girls"

General congenital hypogonadism recommendation, applied with individualized DSD assessment.

PMID:35353710 SUPPORT REVIEW SYNTHESIS Other

"We recommend that pubertal induction in boys with hypogonadism should be performed with testosterone"

General hypogonadism recommendation rather than a PGD-specific trial.

Target Phenotypes: Delayed puberty HP:0000823 Hypergonadotropic hypogonadism HP:0000815

Show evidence (4 references)

PMID:35353710 SUPPORT REVIEW SYNTHESIS Other

"We recommend to use 17β-oestradiol for puberty induction or to sustain puberty in girls"

General congenital hypogonadism recommendation, applied with individualized DSD assessment.

PMID:35353710 SUPPORT REVIEW SYNTHESIS Other

"We recommend that pubertal induction in boys with hypogonadism should be performed with testosterone"

General hypogonadism recommendation rather than a PGD-specific trial.

PMID:35353710 SUPPORT REVIEW SYNTHESIS Other

"If a uterus is present, progesterone must be added at some point because of the risk of endometrial cancer associated with long-term unopposed oestrogen"

Explains the uterus-dependent progestogen component.

+ 1 more reference

Genital reconstructive surgery

Category: Therapeutic Action: orchiopexy Ontology label: Orchiopexy NCIT:C111066

Platform: Surgery

Consider hypospadias repair, orchiopexy or other genital procedures for individualized functional goals after multidisciplinary discussion with the patient and family. Decisions should consider timing, potential adverse effects, fertility and future autonomy. Moving a functional gonad into the scrotum can facilitate examination; it has not been shown here to eliminate tumor risk. GeneReviews notes no controlled comparisons of surgical techniques and no consensus on timing.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"surgical options may include hypospadias repair, orchiopexy, scrotoplasty, and phalloplasty."

Lists options in broader testicular-development disorders rather than mandatory procedures.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"There is no consensus on the appropriate timing of the surgical procedures listed."

Defines the limitation on timing recommendations.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"If a dysgenetic gonad is located in the inguinal canal, it may be placed into the scrotum if results indicate some testicular function."

Function-dependent option; surveillance remains necessary.

Renal surveillance and Wilms tumor monitoring

Category: Monitoring Action: supportive care Ontology label: Supportive Care NCIT:C15747

For pathogenic WT1-related disease, follow GeneReviews surveillance for proteinuria every six months until age ten and annually thereafter, and abdominal ultrasound for Wilms tumor every three months until age seven. Follow established renal disease with nephrology. Consider renin-angiotensin system inhibition for proteinuria; immunosuppression is ineffective and potentially toxic in WT1-associated glomerulopathy. Gonadal management and pubertal monitoring remain coordinated with the DSD team.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK556455/ SUPPORT REVIEW SYNTHESIS Other

"Monitor for first appearance of the following: proteinuria every six months until age ten years, yearly thereafter; Wilms tumor every three months until age seven years; early gonadal insufficiency yearly after puberty."

Genotype-specific surveillance from the complete GeneReviews chapter.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK556455/ SUPPORT REVIEW SYNTHESIS Other

"Avoid immunosuppressants, which are ineffective & potentially toxic."

Applies specifically to WT1-associated glomerulopathy.

Long-term endocrine, growth, and developmental follow-up

Category: Monitoring Action: supportive care Ontology label: Supportive Care NCIT:C15747

Continue endocrine review through puberty and adulthood, including clinical pubertal progression and age-appropriate gonadotropins and sex steroids. During induction, guideline follow-up is generally every three to six months, with assessment of growth, skeletal maturation, treatment response and adverse effects. Spontaneous onset or normal growth in a small series does not guarantee lasting gonadal function. Address learning or developmental concerns when present without treating a small-cohort observation as a universal PGD feature.

Show evidence (2 references)

PMID:35353710 SUPPORT REVIEW SYNTHESIS Other

"Regular clinical follow-up is generally performed every 3–6 months to assess the effectiveness of testosterone therapy by assessing pubertal and skeletal maturation and height velocity."

General induction monitoring, not a PGD-specific trial.

PMID:37240737 SUPPORT PRIMARY RESULT Human Clinical

"The patient developed normal puberty at 12 years old but presented with low testosterone levels at 17 years old."

Direct evidence that endocrine needs may change after spontaneous onset.

Gene-specific genetic counseling

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Use the established molecular diagnosis and parental testing for recurrence counseling. Autosomal dominant allele transmission is distinct from phenotypic penetrance; the <50% estimate in one NR5A1 family must not be generalized. Counsel NR5A1 relatives about variable gonadal function and primary ovarian insufficiency in some 46,XX carriers, WT1 relatives about renal/tumor surveillance, and DHH families about recessive inheritance and possible neuropathy. DHX37/NR5A1 dual findings that include a VUS or likely-benign allele do not establish digenic recurrence risk. Prenatal or preimplantation testing may be discussed when a familial pathogenic variant is known.

Show evidence (3 references)

url:https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf SUPPORT PRIMARY RESULT Human Clinical

"Segregation analysis across three generations showed incomplete penetrance (<50%) and phenotypic variability among the carriers of NR5A1 c.991-1G>C."

Supports family-specific variable penetrance.

PMID:37240737 SUPPORT PRIMARY RESULT Human Clinical

"Secondly, patient 3 also carries a loss-of-function variant in NR5A1, which could fully explain the PGD phenotype, making the p.Val999Met variant a chance finding."

Explains why uncertain dual findings cannot define a recurrence model.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"Once the genetic cause of a nonsyndromic disorder of testicular development has been identified in an affected family member, prenatal and ... for a pregnancy at increased risk are possible."

GeneReviews counseling options for a known molecular diagnosis.

Psychosocial support and shared decision-making

Category: Counseling / Informational Action: supportive care Ontology label: Supportive Care NCIT:C15747

Provide developmentally appropriate disclosure, psychological and peer support, sexual-health information and fertility counseling. Assigned sex may not match gender identity as it develops. Patients and families should participate in decisions, with increasing patient autonomy and careful consideration before irreversible interventions. Fertility assessment may include semen testing when appropriate; pregnancy options depend on anatomy, gonadal function and the individual's goals.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"Open communication with affected individuals and families, including their active participation in the decision-making process, is critical."

Central shared-decision recommendation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"Assigned sex of rearing may not be congruent with gender identity, which is determined by the individual over time."

Supports individualized, revisitable goals of care.

Puberty suppression when endogenous puberty conflicts with individual goals

Action: Hormone Therapy NCIT:C15445

For selected individuals with functioning retained gonads, hormonal suppression with the desired sex-steroid replacement may defer gonadectomy while decisions mature. Two virilizing PGDf individuals in the registry received a GnRH analogue, without comparative outcome evidence. Estrogen alone should not be described as proven suppression of endogenous androgen effects.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"If contrasexual puberty occurs, hormonal suppression with replacement of the desired sex hormone can be used to avoid gonadectomy until the individual is of age of consent."

Broader DSD care option; terminology quoted verbatim from the chapter.

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Two individuals with virilization were treated with a GnRH analogue."

Documents use in partial disease without proving comparative efficacy.

🔬

Biochemical Markers

Follicle-stimulating hormone (INCREASED)

Context: FSH elevation may indicate impaired Sertoli/tubular feedback despite preserved testosterone. Interpretation depends on developmental stage and the assay. The registry reported elevated FSH at age 0-6 months in 19/28 PGDf and 22/34 PGDm; normal values also occurred.

Pathograph Readouts

Readout Of Incomplete testicular differentiation Positive Diagnostic

Elevated FSH may reflect the tubular/Sertoli component of current gonadal dysfunction; it is not a direct measure of androgen deficiency.

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"| FSH elevated: 0-6 mo a | 100% (n = 6/6) | 67.9% (n = 19/28) | 64.7% (n = 22/34) | CGD vs PGDf ns CGD vs PGDm ns PGDf vs PGDm ns |"

Age- and group-specific FSH measurements; not a uniform finding.

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"| FSH elevated: 0-6 mo a | 100% (n = 6/6) | 67.9% (n = 19/28) | 64.7% (n = 22/34) | CGD vs PGDf ns CGD vs PGDm ns PGDf vs PGDm ns |"

Age- and group-specific FSH measurements; not a uniform finding.

Testosterone response to hCG stimulation (ABNORMAL)

Context: The hCG test assesses residual testosterone production. A greater than twofold rise was observed in 15/17 participants with spontaneous puberty versus 1/3 with induced puberty, P=.087, in the small tested registry subset. This nonsignificant association is not a validated prediction rule or treatment threshold. A response does not localize function to one or both gonads.

Pathograph Readouts

Readout Of Incomplete testicular differentiation Negative Diagnostic

A blunted hCG testosterone response may support impaired gonadal function in context; an adequate response does not exclude PGD or validate a puberty forecast.

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"testosterone levels after human chorionic gonadotropin (hCG) stimulation test less than twice the basal value"

One study diagnostic criterion, not a universally validated cutoff.

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Also, a higher proportion of individuals in the spontaneous puberty group had a testosterone response to hCG more than double the basal level (88%; n = 15/17, vs 33%; n = 1/3, P = .087)."

The full-text counts and P=.087 qualify the stronger abstract wording; not validated prediction.

Anti-Müllerian hormone (DECREASED)

Context: AMH provides an age- and assay-dependent assessment of current Sertoli-cell function. It was low in 12/25 PGDf and 18/31 PGDm in the registry, with normal values in the remaining measured individuals. Postnatal serum AMH does not directly measure fetal exposure and is not a stand-alone partial-versus-complete discriminator.

Show evidence (2 references)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"| Low | 95.7% (n = 22/23) | 48.0% (n = 12/25) | 58.1% (n = 18/31) | CGD vs PGDf .0003 CGD vs PGDm .002 PGDf vs PGDm ns |"

AMH row in Table 3: CGD, PGDf, PGDm; age-specific reference ranges and small tested subsets.

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"For AMH analysis, each institution used either ELISA or chemiluminescence immunoassay and the age-specific male reference was used for assessment (Beckman Coulter Cat# A73818, RRID:AB_3674123; Beckman Coulter Cat# B13127, RRID:AB_2892998; Roche Cat# 06331076, RRID:AB_2895131)."

Specifies assay and age-dependent interpretation.

Inhibin B (DECREASED)

Context: Inhibin B was low in 8/12 PGDf and 9/13 PGDm individuals with measurements. It complements AMH and gonadotropins in assessing current testicular function. These data do not establish a disease-specific cutoff or prove that inhibin B separates all DSD categories.

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"| Low | 100% (n = 20/20) | 66.7% (n = 8/12) | 69.2% (n = 9/13) | CGD vs PGDf .014 CGD vs PGDm .016 PGDf vs PGDm ns |"

Inhibin B row in Table 3: CGD, PGDf, PGDm; limited tested subsets.

🔬

Diagnosis

Integrated clinical, endocrine, and karyotypic assessment

Integrate genital anatomy, gonadal palpability, family history, associated renal or neurological findings, karyotype, and age-appropriate endocrine testing. Assess FSH, LH, testosterone, AMH and often inhibin B in clinical context. A blood 46,XY result distinguishes many chromosomal diagnoses but cannot exclude low-level or gonad-confined mosaicism.

clinical assessment NCIT:C124351

Results: Atypical genitalia with a 46,XY karyotype and biochemical evidence of partial gonadal function.

Show evidence (1 reference)

PMID:36424806 SUPPORT REVIEW SYNTHESIS Other

"We recommend formal Karyotyping, even if Y chromosome material has been detected by other methods."

Supports formal karyotyping as part of the 46,XY DSD workup.

hCG stimulation test for residual Leydig-cell function

hCG stimulation assesses residual testicular testosterone production and can complement the steroid profile. It is not a validated stand-alone predictor of spontaneous puberty: the small registry subgroup association had P=.087. Endocrine testing cannot identify which gonad functions or determine whether both do.

diagnostic procedure NCIT:C18020

Results: A preserved testosterone rise indicates functionally significant residual testicular tissue.

Show evidence (2 references)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Also, a higher proportion of individuals in the spontaneous puberty group had a testosterone response to hCG more than double the basal level (88%; n = 15/17, vs 33%; n = 1/3, P = .087)."

The full-text counts and P=.087 qualify the stronger abstract wording; not validated prediction.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"Hormonal evaluation cannot distinguish between one versus two functioning gonads."

Anatomical limitation of systemic hormone measurements.

Abdominopelvic imaging for gonadal position and Müllerian anatomy

Ultrasound and, when needed, MRI characterize Müllerian anatomy and gonadal position. A small unestrogenized uterus can be missed; discordant imaging requires clinical interpretation. In the cited NR5A1 case, ultrasound suggested a primordial uterus while MRI reported absence, so this case does not establish definite uterine retention.

Ultrasound NCIT:C17230

Show evidence (3 references)

PMID:38206718 SUPPORT PRIMARY RESULT Human Clinical

"Pelvic magnetic resonance imaging showed absence of uterus and ovaries."

In this partial case MRI reported no uterus while ultrasound in the same workup reported a probable primordial uterus, so modalities can disagree on small Müllerian remnants and a single negative study should not be read as proof of regression.

PMID:38206718 SUPPORT PRIMARY RESULT Human Clinical

"hypoechoic mass (considered primordial uterus) in posterior bladder"

Ultrasound suggested a primordial uterus, while MRI in the same case reported absence. This is suspected, discordant anatomy rather than confirmed uterine retention.

PMID:35353710 SUPPORT REVIEW SYNTHESIS Other

"Ultrasound or MRI should be performed to identify a uterus or Müllerian structures; however, a small uterus before oestrogen exposure may be missed by imagery."

Guideline limitation relevant to anatomy assessment.

Broad molecular testing including WT1

Select molecular testing according to phenotype and family history, using chromosome/CNV assessment, a DSD panel, or exome/genome analysis as appropriate. Include clinically relevant genes such as NR5A1, MAP3K1, WT1, DHH and DHX37. A pathogenic WT1 finding changes renal and tumor surveillance. A negative test does not exclude PGD, and a VUS does not establish a molecular diagnosis. Historical registry yield varied by testing method and subgroup.

genetic testing NCIT:C15709

Show evidence (4 references)

PMID:25613702 SUPPORT PRIMARY RESULT Human Clinical

"even in the absence of renal abnormality, it is recommended to test promptly for WT1 defects in 46,XY gonadal dysgenesis."

Directly supports prompt WT1 testing regardless of renal findings.

PMID:36424806 SUPPORT REVIEW SYNTHESIS Other

"Genetic studies, which include copy number variation (CNV) or molecular testing of a candidate gene or next generation sequencing then should be ordered in a stepwise manner"

Supports the stepwise molecular strategy.

PMID:32352694 SUPPORT REVIEW SYNTHESIS Other

"The diagnosis of WT1 disorder is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in WT1 identified by molecular genetic testing."

Supplies the GeneReviews diagnostic criterion for the WT1 subtype: molecular confirmation, not clinical impression, establishes it.

+ 1 more reference

Selective gonadal histopathology and neoplasia assessment

When gonadal tissue is obtained for a justified clinical indication, expert pathology can characterize dysgenesis, germ-cell maturation and neoplasia. Biopsy is subject to sampling error and potential harm. Gonadectomy or whole-gonad histology is not required in every patient solely to establish the partial phenotype.

diagnostic procedure NCIT:C18020

Show evidence (2 references)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

Direct expert histological review of the registry material.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT REVIEW SYNTHESIS Other

"Results may be inaccurate because of biopsy sampling error; gonadal biopsy may harm the future growth and development of the gonad."

Broader testicular-development guidance warns about sampling and potential harm.

🩻

Imaging Findings

Variable or absent Müllerian structures

Mri

Show evidence (3 references)

PMID:38206718 SUPPORT PRIMARY RESULT Human Clinical

"Pelvic magnetic resonance imaging showed absence of uterus and ovaries."

PMID:38206718 SUPPORT PRIMARY RESULT Human Clinical

"hypoechoic mass (considered primordial uterus) in posterior bladder"

Ultrasound suggested a primordial uterus, while MRI in the same case reported absence. This is suspected, discordant anatomy rather than confirmed uterine retention.

PMID:35353710 SUPPORT REVIEW SYNTHESIS Other

"Ultrasound or MRI should be performed to identify a uterus or Müllerian structures; however, a small uterus before oestrogen exposure may be missed by imagery."

Guideline limitation relevant to anatomy assessment.

Inguinal or intra-abdominal dysgenetic gonads

Gonads may be inguinal or intra-abdominal. Localization informs clinical and surgical planning, but imaging alone does not establish functional capacity or exclude neoplasia. The registry association between labioscrotal location and spontaneous puberty does not demonstrate that repositioning prevents tumors.

Ultrasound

Show evidence (1 reference)

PMID:38206718 SUPPORT PRIMARY RESULT Human Clinical

"The abdominopelvic ultrasound revealed bilateral testicle in bilateral groin."

Directly documents inguinal gonads on ultrasound.

📈

Progression

Fetal partial testis-determination phase

Age: embryonic and fetal development

The developmental disturbance begins during gonadal differentiation. Variable Sertoli- and Leydig-cell function can leave different internal and external genital configurations. Hormonal explanations of fetal anatomy are developmental inferences, not direct measurements of fetal hormone levels in the cited patients.

Show evidence (1 reference)

PMID:28504475 SUPPORT PRIMARY RESULT Human Clinical

"partial gonadal dysgenesis, characterized by incomplete testicular development"

Directly supports incomplete (rather than absent) fetal testis development.

Neonatal and infantile atypical-genitalia recognition phase

Age: birth to infancy

Atypical genitalia frequently prompt recognition in infancy, but female external genitalia or later presentation with delayed puberty also occur. In the registry, atypical genitalia were the presenting feature in all PGDm and 62.1% of PGDf; these are ascertainment data, not a population phenotype frequency.

Show evidence (1 reference)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"46,XY gonadal dysgenesis is classified as complete (CGD) or partial (PGD) subtypes. ... Patients with 46,XY GD were identified from the I-DSD Registry and data on phenotype, genetics, biochemistry, gonadal histology, and pubertal development were collated in 3 categories; CGD (n = 100), PGD..."

Identifies 46,XY partial gonadal dysgenesis and its usual infant presentation, while retaining the delayed-puberty and virilization exceptions in affected individuals raised female.

Variable pubertal phase

Age: adolescence

Among 45 registry participants assigned male at age 13 years or older with at least one retained gonad, including nine reassigned from female before age 13, 36 had spontaneous pubertal onset. Ten of 33 with relevant treatment data later received testosterone; 16 of 27 with final-stage data reached Tanner G5 without hormone treatment. Among 26 assigned female at age 13 years or older with gonads and data, 11 developed virilization; four of these 11 also had gonadal tumors. These selected subsets do not predict an individual course.

Show evidence (6 references)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Information on puberty was available in 45 individuals with PGD who assigned male at age ≥13 years, including 9 individuals reassigned from female to male before age 13 years, with at least 1 retained gonad (bilateral gonads n = 37, unilateral n = 8)."

Defines the retained-gonad puberty denominator and reassigned participants.

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Spontaneous onset of puberty (Tanner stage G2 or testis volume ≥4 mL) occurred in 80.0% (n = 36/45)"

Supplies observed spontaneous onset.

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Of these, 30.3% (n = 10/33) were treated with testosterone to complete puberty"

Documents later supplementation despite spontaneous onset.

+ 3 more references

Long-term gonadal-tumor and fertility phase

Age: childhood through adulthood

Gonadal neoplasia can occur from childhood into adulthood. In the I-DSD histology-assessed subsets, combined malignancy or premalignancy occurred in 13/66 PGDf and 3/34 PGDm, compared with 28/83 CGD. The combined endpoint includes several tumor types and is neither a gonadoblastoma-specific frequency nor lifetime risk. Earlier gonadectomy, selection for histology and inconsistent surveillance limit comparisons. Semen testing in small partial-disease series found severe oligozoospermia or azoospermia even when androgen production was retained.

Show evidence (3 references)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Gonadal malignancy or premalignancy (germ cell neoplasia in situ) was reported in 33.7% (n = 28/83; 18.1% unilateral, 15.7% bilateral) in CGD, 19.7% (n = 13/66; 4.5% unilateral, 15.2% bilateral) in PGDf, and 8.8% (n = 3/34; 5.9% unilateral, 2.9% bilateral) in PGDm (CGD vs PGDf, P = .066; CGD vs..."

Observed histology-subset denominators and combined endpoint.

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"However, there was significant variation in monitoring practice amongst centers and only one third (n = 34/92) of individuals with PGDm had histology assessment."

Limits interpretation of low observed PGDm tumor prevalence.

PMID:25580123 SUPPORT PRIMARY RESULT Human Clinical

"Three patients had a sperm count; all had severe oligozoospermia and low motility, and two had also abnormal semen viscosity."

Direct limited-cohort semen findings.

Adult gonadal-reserve decline phase

Age: adulthood

Endocrine function may decline after spontaneous puberty. In one ten-patient series, FSH was high or high-normal in 3/6 before puberty and 8/10 at final evaluation, while LH was high or high-normal in 5/10 at final assessment. Differing denominators prevent treating this as a uniform within-person decline. A p.Arg308Gln DHX37 case entered puberty spontaneously but required testosterone from age 17. Ongoing endocrine review is appropriate.

Show evidence (2 references)

PMID:25580123 SUPPORT PRIMARY RESULT Human Clinical

"At the end of the prepubertal period, FSH was high or high-normal in 3/6 patients; LH was normal in all. At the last evaluation, FSH was high or high-normal in 8/10; LH was high or high-normal in 5/10"

Consistent with rising gonadotropins over follow-up, but limited by n=10 single-centre, and the 3/6 and 8/10 fractions have different denominators, so this is not a within-patient longitudinal comparison.

PMID:37240737 SUPPORT PRIMARY RESULT Human Clinical

"The patient developed normal puberty at 12 years old but presented with low testosterone levels at 17 years old."

Individual longitudinal observation of later testosterone deficiency.

📊

Prevalence

Worldwide

Unknown Unknown

A population prevalence specific to 46,XY partial gonadal dysgenesis is not established by these sources. The registry includes 210 selected partial cases. The Danish estimate of 1.5 per 100,000 live-born females concerns female-phenotype 46,XY gonadal dysgenesis across subtypes; it cannot be applied as a rate or lower bound for all partial disease.

Show evidence (2 references)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Patients with 46,XY GD were identified from the I-DSD Registry"

Documents referral-registry ascertainment, which does not estimate population prevalence.

PMID:27603905 SUPPORT PRIMARY RESULT Human Clinical

"The prevalence of 46,XY females was 6.4 per 100 000 live born females, and for AIS and gonadal dysgenesis, it was 4.1 and 1.5 per 100 000, respectively."

Female-phenotype gonadal dysgenesis estimate across subtypes; explicitly not adopted as the partial-disease prevalence.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from 46,XY partial gonadal dysgenesis:

46,XY complete gonadal dysgenesis MONDO:0010765

Overlapping Features Typical complete gonadal dysgenesis presents with female external genitalia, Müllerian structures and gonadal failure. Streak gonads are common, but dysgenetic testicular tissue can also occur. Partial disease shows more variable anatomy and residual function. Classification integrates phenotype, hormones, histology and genetics; tumors can themselves produce sex steroids in either group.

Show evidence (2 references)

PMID:40208111 SUPPORT PRIMARY RESULT Human Clinical

"Gonadal pre-/malignancy was found in 33.8% in CGD, 19.7% in PGDf, and 8.8% in PGDm."

A single cohort scoring both entities documents the tumor-risk gradient that separates them.

PMID:28504475 SUPPORT PRIMARY RESULT Human Clinical

"Three of these individuals presented with complete gonadal dysgenesis, characterized by bilateral streak gonads with typical internal and external female genitalia, while the other three presented with partial gonadal dysgenesis, characterized by incomplete testicular development"

Directly contrasts the two phenotypes within one gene's spectrum — the cleanest available statement of the distinction.

45,X/46,XY mixed gonadal dysgenesis

Overlapping Features 45,X/46,XY mosaicism can resemble 46,XY partial gonadal dysgenesis. Gonadal asymmetry does not distinguish them, because a dysgenetic testis and contralateral streak tissue can also occur in 46,XY PGD. Adequate chromosome assessment is required, while low-level or tissue-confined mosaicism may escape a blood test.

Show evidence (1 reference)

PMID:34070473 SUPPORT REVIEW SYNTHESIS Other

"sex chromosome DSD (Klinefelter or Turner Syndrome, chimerism), XX-DSD, and 46 XY-DSD"

Supports separation of sex-chromosome DSD from 46,XY DSD; the asymmetric gonadal detail is clinical synthesis.

Partial androgen insensitivity syndrome

Overlapping Features Androgen insensitivity can produce overlapping external genital findings despite testicular differentiation and androgen production. AMH, testosterone and hCG responses may overlap with other DSD diagnoses, so no single normal hormone result excludes PGD or proves PAIS. Molecular findings and the overall anatomical/endocrine pattern guide differentiation.

Show evidence (1 reference)

PMID:31745530 SUPPORT PRIMARY RESULT Human Clinical

"partially virilized 46,XY DSD (pvDSD) (n = 25), a group that included partial gonadal dysgenesis and those with a broad "partial androgen insensitivity syndrome" label."

Directly documents the clinical conflation of partial gonadal dysgenesis with PAIS, motivating molecular resolution.

46,XY androgen synthesis disorders

Overlapping Features Steroid synthesis or metabolism defects, including 17-beta-hydroxysteroid dehydrogenase 3 and 5-alpha-reductase 2 deficiencies, can impair virilization despite testicular differentiation. Steroid profiles, selected stimulation testing and molecular results help distinguish these from gonadal dysgenesis; preserved AMH alone is not a definitive discriminator.

Show evidence (1 reference)

PMID:34070473 SUPPORT REVIEW SYNTHESIS Other

"46 XY-DSD (disorders of testicular development and disorders of androgen synthesis or action)"

Supports the mechanistic distinction within 46,XY DSD.

Ovotesticular disorder of sex development

Overlapping Features Ovotesticular DSD is defined by ovarian follicular and testicular tissue in the same individual. Histology can identify these components when tissue is clinically obtained, but sampling can miss heterogeneous tissue. This distinction does not justify routine whole-gonad removal solely for diagnosis.

Show evidence (1 reference)

PMID:38206718 SUPPORT PRIMARY RESULT Human Clinical

"primary ovarian insufficiency and ovotesticular DSD in 46, XX individuals."

Establishes ovotesticular DSD as a distinct entity within the same gene's phenotypic spectrum; the histological criterion is clinical synthesis.

Testicular regression syndrome

Overlapping Features Testicular regression reflects loss of previously differentiated testicular tissue rather than failure to differentiate it. The distinction can be genuinely difficult, and DHX37 variants are found in both cohorts, so the two are best regarded as adjacent points on a spectrum of testis-development failure.

Show evidence (1 reference)

PMID:37240737 SUPPORT PRIMARY RESULT Human Clinical

"including complete and partial GD (PGD) and testicular regression syndrome (TRS)"

Places testicular regression syndrome alongside partial dysgenesis in the same disease group with shared genetic causes.

🧫

Experimental Models

MAP3K1 patient lymphoblastoid phosphorylation assays CELL_LINE

Patient lymphoblastoid cell lines carrying selected MAP3K1 alleles were compared with wild-type lines after serum starvation and refeeding.

Publication

PMID:21129722

Pathograph links

Enhanced MAP3K1-RHOA association recapitulates

Show evidence (1 reference)

PMID:21129722 SUPPORT PRIMARY RESULT In Vitro

"these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex."

Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association; p38 effects differed among alleles.

Increased ERK1/2 phosphorylation recapitulates

Show evidence (1 reference)

PMID:21129722 SUPPORT PRIMARY RESULT In Vitro

"these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex."

Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association; p38 effects differed among alleles.

Increased p38 phosphorylation recapitulates

Show evidence (1 reference)

PMID:21129722 SUPPORT PRIMARY RESULT In Vitro

"these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex."

Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association; p38 effects differed among alleles.

The model reproduces biochemical readouts outside the fetal gonadal lineage. The p38 response was not uniform across variants; gene expression and splicing findings were allele-specific.

Show evidence (1 reference)

PMID:21129722 SUPPORT PRIMARY RESULT In Vitro

"these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex."

Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association; p38 effects differed among alleles.

MAP3K1 p.Arg186Gly overexpression assays CELL_LINE

HEK293T protein-interaction and TCF/LEF reporter assays, with NT2/D1 and KGN phosphorylation/protein-expression assays, compared wild type, p.Arg186Gly and relevant empty-vector controls.

Publication

PMID:35309143

Pathograph links

Enhanced MAP3K1-RHOA association recapitulates

Show evidence (1 reference)

PMID:35309143 SUPPORT PRIMARY RESULT In Vitro

Selected p.Arg186Gly variant in HEK293T cells; binding and ubiquitination measurements, not gonadal epistasis.

Reduced MAP3K1 ubiquitination recapitulates

Show evidence (1 reference)

PMID:35309143 SUPPORT PRIMARY RESULT In Vitro

Selected p.Arg186Gly variant in HEK293T cells; binding and ubiquitination measurements, not gonadal epistasis.

Increased MAP3K1 protein abundance recapitulates

Show evidence (1 reference)

PMID:35309143 SUPPORT PRIMARY RESULT In Vitro

"The protein expression of the MAP3K1R186G variant was 6.4 and 2.0 times higher than that of the wild type in the KGN and NT2/D1 cells, respectively (Figures 6A–D)."

Measured abundance in KGN and NT2/D1 overexpression models; not a direct half-life measurement.

Increased p38 phosphorylation recapitulates

Show evidence (1 reference)

PMID:35309143 SUPPORT PRIMARY RESULT In Vitro

Measured phosphorylation responses in an overexpression model.

Increased beta-catenin-dependent transcription recapitulates

Show evidence (1 reference)

PMID:35309143 SUPPORT PRIMARY RESULT In Vitro

"The data showed that at 48 h after transfection, the relative activity of TCF/LEF in the mutant group reached its peak, which was 9.78 ± 0.57 times that of the wild-type group (Figures 6E,F)."

TCF/LEF reporter assay measures beta-catenin-dependent transcription in HEK293T cells.

Transfected tumor-derived or kidney-derived cells do not reproduce a fetal gonad. The paper did not demonstrate necessary mediation between every measured intermediate, directly measure protein half-life, or establish the partial phenotype for the studied family.

Show evidence (4 references)

PMID:35309143 SUPPORT PRIMARY RESULT In Vitro

Selected p.Arg186Gly variant in HEK293T cells; binding and ubiquitination measurements, not gonadal epistasis.

PMID:35309143 SUPPORT PRIMARY RESULT In Vitro

"The protein expression of the MAP3K1R186G variant was 6.4 and 2.0 times higher than that of the wild type in the KGN and NT2/D1 cells, respectively (Figures 6A–D)."

Measured abundance in KGN and NT2/D1 overexpression models; not a direct half-life measurement.

PMID:35309143 SUPPORT PRIMARY RESULT In Vitro

Measured phosphorylation responses in an overexpression model.

+ 1 more reference

NR5A1 variant promoter-reporter assays CELL_LINE

Wild-type and p.Gly22Asp or p.Leu420Pro SF-1 constructs were tested on a Cyp11a1 promoter reporter in tsa201 human kidney-derived cells.

Publication

PMID:31745530

Pathograph links

Reduced SF-1 transcriptional activity recapitulates

Show evidence (1 reference)

PMID:31745530 SUPPORT PRIMARY RESULT In Vitro

"Transient transfection assays showing activation of a Cyp11a1 promoter by WT SF-1 and impaired transcriptional activity by the p.G22D and p.L420P mutants."

Cyp11a1 reporter in tsa201 kidney-derived cells; the clinical cohort used a broader partially virilized DSD category.

The clinical subgroup was partially virilized 46,XY DSD, not a uniformly histology-confirmed PGD cohort. This assay does not measure every developmental SF-1 target.

Show evidence (1 reference)

PMID:31745530 SUPPORT PRIMARY RESULT In Vitro

"Transient transfection assays showing activation of a Cyp11a1 promoter by WT SF-1 and impaired transcriptional activity by the p.G22D and p.L420P mutants."

Cyp11a1 reporter in tsa201 kidney-derived cells; the clinical cohort used a broader partially virilized DSD category.

DHX37 variant expression and localization assays CELL_LINE

The p.Arg308Gln and p.Arg671Thr constructs were assessed for protein abundance in HEK293T cells; localization was studied in COS7 cells.

Publication

PMID:38769888

Pathograph links

Reduced DHX37 protein abundance recapitulates

Show evidence (1 reference)

PMID:38769888 SUPPORT PRIMARY RESULT In Vitro

"The results indicated that mutant DHX37 decreased the protein levels of DHX37."

Selected-variant overexpression assay; not an ATPase or ribosome-biogenesis assay.

Localization was unchanged. The study prose calls p.Arg671Thr pathogenic, but its table lists VUS; the classification is kept uncertain. No variant-specific ATPase or ribosome-output assay was performed.

Show evidence (1 reference)

PMID:38769888 SUPPORT PRIMARY RESULT In Vitro

"The results indicated that mutant DHX37 decreased the protein levels of DHX37."

Selected-variant overexpression assay; not an ATPase or ribosome-biogenesis assay.

DHX37 p.Ser408Leu human Sertoli-cell overexpression CELL_LINE

A commercial human Sertoli-cell line was transfected with wild-type, p.Ser408Leu or empty-vector constructs. Transcript/protein abundance, localization, beta-catenin, p53, apoptosis and proliferation were assessed.

Publication

PMID:37065748

Pathograph links

Reduced DHX37 protein abundance recapitulates

Show evidence (1 reference)

PMID:37065748 SUPPORT PRIMARY RESULT In Vitro

"compared with the cells transfected with pcDNA3.1-WT, those with pcDNA3.1-S408L displayed decreased DHX37 expression both at the mRNA and protein levels."

Variant overexpression effect in a human Sertoli-cell line, with uncertain clinical classification.

Notes

The variant had the same localization as wild type. Beta-catenin was higher than in wild-type-transfected cells because wild type suppressed it. p53 was unchanged; apoptosis was not increased relative to wild-type overexpression, although both constructs increased apoptosis relative to empty vector. Neither helicase activity nor ribosome biogenesis was assayed. Clinical pathogenicity remains uncertain.

Show evidence (2 references)

PMID:37065748 SUPPORT PRIMARY RESULT In Vitro

"compared with the cells transfected with pcDNA3.1-WT, those with pcDNA3.1-S408L displayed decreased DHX37 expression both at the mRNA and protein levels."

Variant overexpression effect in a human Sertoli-cell line, with uncertain clinical classification.

PMID:37065748 SUPPORT PRIMARY RESULT In Vitro

"there is no difference in p53 expression among cells transfected with empty expressing vector, wt-DHX37, or mutant DHX37."

Negative measured result constrains a proposed nucleolar-stress mechanism.

🐁

Animal Models

Sox9-Cre conditional Nr5a1 knockout mice

Conditional Nr5a1 loss in the Sox9 lineage reduced AMH-positive cells, impaired Sertoli differentiation and permitted ectopic FOXL2-positive cells. The reported postnatal spectrum included partial and complete gonadal sex reversal.

Species

Mouse

Genotype

Sox9-Cre;Nr5a1flox/flox and Sox9-Cre;Nr5a1flox/-

Publication

PMID:33627800

Pathograph links

Incomplete testicular differentiation recapitulates fidelity: moderate

Limitations: Lineage-specific engineered biallelic loss is not the same as a human heterozygous NR5A1 allele. Leydig-marker reduction differed between the two knockout genotypes. Only the abstract is cached.

Show evidence (1 reference)

PMID:33627800 SUPPORT PRIMARY RESULT Model Organism

"These data suggested that the loss of Nr5a1 abrogates the testicular pathway and induces the ectopic ovarian pathway, resulting in postnatal partial/complete male-to-female gonadal sex reversal."

Conditional mouse knockout establishes a developmental effect in that model; not a human penetrance estimate.

Show evidence (1 reference)

PMID:33627800 SUPPORT PRIMARY RESULT Model Organism

"These data suggested that the loss of Nr5a1 abrogates the testicular pathway and induces the ectopic ovarian pathway, resulting in postnatal partial/complete male-to-female gonadal sex reversal."

Conditional mouse knockout establishes a developmental effect in that model; not a human penetrance estimate.

{ }

Source YAML

click to show

name: 46,XY partial gonadal dysgenesis
creation_date: '2026-08-01T00:00:00Z'
category: Mendelian
description: >-
  46,XY partial gonadal dysgenesis (PGD) is a genetically heterogeneous disorder of testicular development
  with variable dysgenetic gonadal tissue and testicular hormone production. External genitalia range
  from female appearance to varying degrees of masculinization; Müllerian structures may be present or
  absent. Presentation may occur with atypical genitalia in infancy, pubertal delay or virilization, or
  impaired fertility. Some retained gonads support spontaneous puberty, but later hormone replacement
  may still be needed. Dysgenetic gonads can contain gonadoblastoma, germ cell neoplasia in situ, or invasive
  tumors. Genotype, gonadal function and anatomy, age, and the individual's goals inform care.
disease_term:
  preferred_term: 46,XY partial gonadal dysgenesis
  term:
    id: MONDO:0016674
    label: 46,XY partial gonadal dysgenesis
synonyms:
- 46,XY PGD
- 46,XY partial testicular dysgenesis
- partial gonadal dysgenesis
parents:
- Disorder of sex development
- Gonadal development disorder
definitions:
- name: 46,XY partial gonadal dysgenesis case definition
  definition_type: CASE_DEFINITION
  description: >-
    A 46,XY karyotype with evidence of incomplete or disordered testicular development, assessed through
    the genital phenotype, endocrine function, histology when available, and molecular findings. Atypical
    external genitalia are common but are not obligatory: the I-DSD study also included individuals with
    female external genitalia, absent uterus, and evidence of gonadal dysfunction. No single hormone value
    or histological pattern separates every partial and complete presentation.
  scope: >-
    This entry covers partial gonadal dysgenesis, including gene-specific syndromic forms. Complete gonadal
    dysgenesis, 45,X/46,XY mosaicism, ovotesticular DSD, testicular regression, androgen insensitivity,
    and steroid synthesis defects require distinction. A blood 46,XY result does not exclude low-level
    or tissue-confined sex-chromosome mosaicism.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      A small group of patients (n = 10) had typical female genitalia but without a uterus and evidence
      of gonadal dysfunction from biochemical, genetic, or histological investigations.
    explanation: The registry explicitly included this exception to an atypical-genitalia definition.
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      As 46,XY PGD is a heterogeneous disorder without clearly defined diagnostic criteria, we used the
      diagnostic criteria from a previous study which requires evidence of testicular dysgenesis, either
      in a biochemical test (e.g., low testosterone response after hCG stimulation, low AMH or inhibin
      B), histology findings, or a genetic defect associated with GD (8).
    explanation: >-
      Documents the study-specific combination of clinical, biochemical, histological and genetic criteria.
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Furthermore, standard karyotyping techniques may miss mosaicism such as 46,XY/45,X.
    explanation: >-
      The registry authors explicitly identify a limitation of conventional karyotyping; a blood result
      does not exclude every mosaic cell line.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0016674
      label: 46,XY partial gonadal dysgenesis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0016674 is the exact disease anchor and carries the corresponding Orphanet:251510 cross-reference.
has_subtypes:
- name: NR5A1-related PGD
  display_name: NR5A1/SF-1-related 46,XY partial gonadal dysgenesis
  classification: gene
  genes:
  - preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:33296094
      reference_title: >-
        NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete
        penetrance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Segregation analysis across three generations showed incomplete penetrance (<50%) and phenotypic
        variability among the carriers of NR5A1 c.991-1G > C.
      explanation: Multigenerational heterozygous segregation supports dominant transmission with reduced penetrance.
      quote_role: PRIMARY_RESULT
  description: >-
    Heterozygous NR5A1 variants, including truncating, missense and splice-site alleles, cause variable
    partial gonadal dysgenesis. NR5A1 was the most frequent molecular finding in the partial groups of
    the I-DSD registry. Spontaneous puberty and unaffected transmitting relatives are reported, but neither
    gonadal function nor fertility is guaranteed. Adrenal insufficiency is uncommon in the broader NR5A1-related
    DSD spectrum and should be evaluated when clinically indicated.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A genetic etiology was identified in 42% of the cohort, with common gene defects in SRY and WT1
      in CGD and NR5A1 in PGD.
    explanation: >-
      Directly identifies NR5A1 as the gene most characteristically implicated in the partial form, in
      contrast to SRY/WT1 in complete disease.
    quote_role: PRIMARY_RESULT
  - reference: PMID:27463801
    reference_title: >-
      NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three
      Novel Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 3 novel NR5A1 mutations were identified in 3 patients with 46,XY partial gonadal dysgenesis
    explanation: Directly documents NR5A1 variants in molecularly defined partial disease.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: may need to be managed for adrenal insufficiency.
    explanation: Broader NR5A1-related DSD guidance, not a measured frequency in partial disease.
- name: MAP3K1-related PGD
  display_name: MAP3K1-related 46,XY partial gonadal dysgenesis
  classification: gene
  genes:
  - preferred_term: MAP3K1
    term:
      id: hgnc:6848
      label: MAP3K1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:35290982
      reference_title: 'Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance
        in 46,XY individuals.
      explanation: Directly supports sex-limited dominant inheritance for this subtype.
      quote_role: REVIEW_SYNTHESIS
  description: >-
    Heterozygous MAP3K1 variants cause a sex-limited spectrum of partial and complete gonadal dysgenesis.
    A three-patient partial subgroup had clitoral hypertrophy with otherwise female external genitalia;
    other families include more masculinized partial presentations. Functional effects have been demonstrated
    for selected variants and should not be assumed for every rare missense allele. The review estimate
    of at least 4% concerns combined nonsyndromic partial and complete GD, not partial disease alone.
  evidence:
  - reference: PMID:28504475
    reference_title: 'MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the other three presented with partial gonadal dysgenesis, characterized by incomplete testicular
      development, resulting in clitoral hypertrophy with otherwise typical female external genitalia
    explanation: Directly documents the MAP3K1 partial phenotype and its genital pattern.
    quote_role: PRIMARY_RESULT
  - reference: PMID:35290982
    reference_title: 'Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and
      complete gonadal dysgenesis, accounting for at least 4% of cases.
    explanation: Quantifies the MAP3K1 contribution across the partial-to-complete spectrum.
    quote_role: REVIEW_SYNTHESIS
- name: WT1-related PGD
  display_name: WT1-related 46,XY partial gonadal dysgenesis (Denys-Drash/Frasier continuum)
  classification: gene
  genes:
  - preferred_term: WT1
    term:
      id: hgnc:12796
      label: WT1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:32352694
      reference_title: WT1 Disorder.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: WT1 disorder is inherited in an autosomal dominant manner.
      explanation: Directly supports the inheritance mode for WT1-related disease.
      quote_role: REVIEW_SYNTHESIS
  description: >-
    WT1-related testicular-development disorders may accompany glomerulopathy, steroid-resistant nephrotic
    syndrome and Wilms tumor predisposition, with variable combinations and timing. GeneReviews treats
    the historical Denys-Drash and Frasier labels as a phenotypic continuum. A reported whole-gene deletion
    caused severe partial dysgenesis and bilateral Wilms tumor; gonadal histology in infancy was described
    as suggestive of gonadoblastoma. Surveillance follows the molecular WT1 diagnosis even when renal
    findings are initially absent.
  evidence:
  - reference: PMID:25613702
    reference_title: >-
      WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe a newborn with 46,XY severe partial gonadal dysgenesis
    explanation: Directly documents WT1-associated partial gonadal dysgenesis.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK556455/
    reference_title: WT1 Disorder - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      WT1 disorder is characterized by congenital /infantile or childhood onset of steroid-resistant nephrotic
      syndrome (SRNS), a progressive glomerulopathy that does not respond to standard steroid therapy.
    explanation: Current full GeneReviews clinical baseline for WT1-associated manifestations.
- name: DHH-related PGD
  display_name: DHH-related 46,XY partial gonadal dysgenesis with minifascicular neuropathy
  classification: gene
  genes:
  - preferred_term: DHH
    term:
      id: hgnc:2865
      label: DHH
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:11017805
      reference_title: >-
        A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied
        by minifascicular neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We found, in the patient, a homozygous missense mutation (ATG-->ACG) at the initiating codon in
        exon 1 of the desert hedgehog (DHH) gene
      explanation: Homozygosity with a heterozygous carrier father supports recessive inheritance.
      quote_role: PRIMARY_RESULT
  description: >-
    Biallelic DHH variants can cause partial or complete gonadal dysgenesis. Reported partial cases include
    a dysgenetic testis with streak regions, abnormal Leydig-cell differentiation, and gonadal neoplasia.
    Peripheral neuropathy may accompany the gonadal disorder and can become apparent in adulthood; its
    absence in childhood does not exclude DHH-related disease.
  evidence:
  - reference: PMID:11017805
    reference_title: >-
      A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied
      by minifascicular neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: mutation of the DHH gene may cause 46, XY PGD associated with minifascicular neuropathy.
    explanation: Directly links biallelic DHH defects to partial disease with neuropathy.
    quote_role: PRIMARY_RESULT
  - reference: PMID:25927242
    reference_title: >-
      46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome
      Sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a novel homozygous R124Q mutation in the desert hedgehog gene (DHH)
    explanation: An independent consanguineous family, so the subtype no longer rests on a single 2000 case report.
    quote_role: PRIMARY_RESULT
  - reference: PMID:25927242
    reference_title: >-
      46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome
      Sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in DHH play a role in 46,XY gonadal dysgenesis and are associated with seminoma formation
      and a neuropathy with minifascicle formation.
    explanation: Confirms the gonad-plus-neuropathy pairing and adds seminoma risk to this subtype's profile.
    quote_role: PRIMARY_RESULT
- name: DHX37-related PGD
  display_name: DHX37-related 46,XY partial gonadal dysgenesis
  classification: gene
  genes:
  - preferred_term: DHX37
    term:
      id: hgnc:17210
      label: DHX37
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:37240737
      reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In DHX37, the variant p.(Arg308Gln), recurrent associated with DSD, was identified in one patient
      explanation: >-
        Documents a heterozygous recurrent DHX37 allele in partial disease. The unrelated dual-variant
        cases do not establish digenic inheritance.
      quote_role: PRIMARY_RESULT
  description: >-
    Heterozygous DHX37 variants, notably recurrent p.Arg308Gln, are associated with partial gonadal dysgenesis
    and testicular regression. Some variants arise de novo and some are maternally inherited. Structural
    predictions and selected overexpression assays suggest altered protein function, but variant-dependent
    ATPase failure, defective ribosome production and the pathway to human gonadal dysgenesis have not
    been established. Co-occurring NR5A1 variants do not by themselves establish digenic inheritance.
  evidence:
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recent studies have identified variants in DHX37, a gene encoding a putative RNA helicase essential
      in ribosome biogenesis and previously associated with neurodevelopmental disorders, as a cause of
      PGD and TRS.
    explanation: Directly establishes DHX37 as a cause of partial gonadal dysgenesis.
    quote_role: PRIMARY_RESULT
  - reference: PMID:31337883
    reference_title: >-
      Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis
      and 46,XY testicular regression syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including
      gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum.
    explanation: >-
      The primary discovery cohort establishes autosomal dominant inheritance and places gonadal dysgenesis
      and testicular regression on one spectrum.
    quote_role: PRIMARY_RESULT
- name: Molecularly unresolved PGD
  display_name: Molecularly unresolved 46,XY partial gonadal dysgenesis
  classification: molecular
  description: >-
    A clinical diagnosis may remain without molecular confirmation. In the historical I-DSD registry,
    a likely gene or chromosome alteration was reported in 59.0% of screened PGDf individuals and 50.0%
    of screened PGDm individuals. Testing methods and variant classification varied; these selected-cohort
    results are not a fixed yield for current panels or genome sequencing.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Of those who underwent screening, 48.3% of individuals with CGD, 59.0% with PGDf, and 50.0% with
      PGDm had a gene or chromosome alteration identified.
    explanation: Reports tested-subgroup yields; not a plateau or all-patient diagnostic sensitivity.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    A population prevalence specific to 46,XY partial gonadal dysgenesis is not established by these sources.
    The registry includes 210 selected partial cases. The Danish estimate of 1.5 per 100,000 live-born
    females concerns female-phenotype 46,XY gonadal dysgenesis across subtypes; it cannot be applied as
    a rate or lower bound for all partial disease.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients with 46,XY GD were identified from the I-DSD Registry
    explanation: Documents referral-registry ascertainment, which does not estimate population prevalence.
    quote_role: PRIMARY_RESULT
  - reference: PMID:27603905
    reference_title: >-
      Incidence, Prevalence, Diagnostic Delay, and Clinical Presentation of Female 46,XY Disorders of
      Sex Development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of 46,XY females was 6.4 per 100 000 live born females, and for AIS and gonadal dysgenesis,
      it was 4.1 and 1.5 per 100 000, respectively.
    explanation: >-
      Female-phenotype gonadal dysgenesis estimate across subtypes; explicitly not adopted as the partial-disease
      prevalence.
    quote_role: PRIMARY_RESULT
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Established heterozygous causes include NR5A1, MAP3K1, WT1 and DHX37. Transmission, penetrance and
    associated features are gene- and variant-dependent. An unaffected carrier parent can transmit a pathogenic
    allele; 50% transmission risk for an autosomal dominant allele is not equivalent to 50% risk of the
    same gonadal phenotype.
  evidence:
  - reference: PMID:33296094
    reference_title: >-
      NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete
      penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Segregation analysis across three generations showed incomplete penetrance (<50%) and phenotypic
      variability among the carriers of NR5A1 c.991-1G > C.
    explanation: Directly documents dominant transmission with reduced penetrance in partial disease.
    quote_role: PRIMARY_RESULT
  - reference: PMID:35290982
    reference_title: 'Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance
      in 46,XY individuals.
    explanation: Supports sex-limited dominant inheritance with gene-specific penetrance for MAP3K1.
    quote_role: REVIEW_SYNTHESIS
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic DHH variants underlie a recessive form with sex-chromosome-dependent gonadal manifestations
    and possible peripheral neuropathy.
  evidence:
  - reference: PMID:11017805
    reference_title: >-
      A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied
      by minifascicular neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a homozygous missense mutation (ATG-->ACG) at the initiating codon in exon 1 of the desert hedgehog
      (DHH) gene
    explanation: Homozygosity in the proband supports recessive inheritance.
    quote_role: PRIMARY_RESULT
progression:
- phase: Fetal partial testis-determination phase
  age_range: embryonic and fetal development
  notes: >-
    The developmental disturbance begins during gonadal differentiation. Variable Sertoli- and Leydig-cell
    function can leave different internal and external genital configurations. Hormonal explanations of
    fetal anatomy are developmental inferences, not direct measurements of fetal hormone levels in the
    cited patients.
  evidence:
  - reference: PMID:28504475
    reference_title: 'MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: partial gonadal dysgenesis, characterized by incomplete testicular development
    explanation: Directly supports incomplete (rather than absent) fetal testis development.
    quote_role: PRIMARY_RESULT
- phase: Neonatal and infantile atypical-genitalia recognition phase
  age_range: birth to infancy
  notes: >-
    Atypical genitalia frequently prompt recognition in infancy, but female external genitalia or later
    presentation with delayed puberty also occur. In the registry, atypical genitalia were the presenting
    feature in all PGDm and 62.1% of PGDf; these are ascertainment data, not a population phenotype frequency.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      46,XY gonadal dysgenesis is classified as complete (CGD) or partial (PGD) subtypes. ...
      Patients with 46,XY GD were identified from the I-DSD Registry and data on phenotype,
      genetics, biochemistry, gonadal histology, and pubertal development were collated in 3
      categories; CGD (n = 100), PGD assigned female (PGDf, n = 107), and male (PGDm, n = 103) at
      birth. ... Most individuals with PGD presented with atypical genitalia in infancy, though, 18%
      of PGDf presented with delayed puberty and 8% with virilization. ... due to atypical genitalia
      in all patients with PGDm and 62.1% in PGDf. Delayed puberty was the presenting feature in
      17.9% of PGDf patients and in 8.4%, it was associated with virilization.
    explanation: >-
      Identifies 46,XY partial gonadal dysgenesis and its usual infant presentation, while retaining
      the delayed-puberty and virilization exceptions in affected individuals raised female.
- phase: Variable pubertal phase
  age_range: adolescence
  notes: >-
    Among 45 registry participants assigned male at age 13 years or older with at least one retained gonad,
    including nine reassigned from female before age 13, 36 had spontaneous pubertal onset. Ten of 33
    with relevant treatment data later received testosterone; 16 of 27 with final-stage data reached Tanner
    G5 without hormone treatment. Among 26 assigned female at age 13 years or older with gonads and data,
    11 developed virilization; four of these 11 also had gonadal tumors. These selected subsets do not
    predict an individual course.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Information on puberty was available in 45 individuals with PGD who assigned male at age ≥13 years,
      including 9 individuals reassigned from female to male before age 13 years, with at least 1 retained
      gonad (bilateral gonads n = 37, unilateral n = 8).
    explanation: Defines the retained-gonad puberty denominator and reassigned participants.
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Spontaneous onset of puberty (Tanner stage G2 or testis volume ≥4 mL) occurred in 80.0% (n = 36/45)
    explanation: Supplies observed spontaneous onset.
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Of these, 30.3% (n = 10/33) were treated with testosterone to complete puberty
    explanation: Documents later supplementation despite spontaneous onset.
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: In puberty completion assessment, 59.3% (n = 16/27) achieved Tanner G5 without hormone treatment
    explanation: Defines the completion denominator.
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Of individuals with PGD assigned female at age ≥13 years with at least 1 gonad (n = 18/22 individuals
      with intra-abdominal or impalpable gonad, n = 4/22 uni-/bilateral inguinal gonad) 42.3% (n = 11/26)
      developed features of virilization (hirsutism n = 5, clitoral enlargement n = 7) (Table 5)
    explanation: Reports the female-assigned retained-gonad subgroup, not all PGDf.
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 36.4% (n = 4/11) of virilization associated with tumor (gonadoblastoma, dysgerminoma, seminoma)
    explanation: Table 5 shows tumor association in four of the eleven virilizing PGDf individuals.
- phase: Long-term gonadal-tumor and fertility phase
  age_range: childhood through adulthood
  notes: >-
    Gonadal neoplasia can occur from childhood into adulthood. In the I-DSD histology-assessed subsets,
    combined malignancy or premalignancy occurred in 13/66 PGDf and 3/34 PGDm, compared with 28/83 CGD.
    The combined endpoint includes several tumor types and is neither a gonadoblastoma-specific frequency
    nor lifetime risk. Earlier gonadectomy, selection for histology and inconsistent surveillance limit
    comparisons. Semen testing in small partial-disease series found severe oligozoospermia or azoospermia
    even when androgen production was retained.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Gonadal malignancy or premalignancy (germ cell neoplasia in situ) was reported in 33.7% (n = 28/83;
      18.1% unilateral, 15.7% bilateral) in CGD, 19.7% (n = 13/66; 4.5% unilateral, 15.2% bilateral) in
      PGDf, and 8.8% (n = 3/34; 5.9% unilateral, 2.9% bilateral) in PGDm (CGD vs PGDf, P = .066; CGD vs
      PGDm, P = .005).
    explanation: Observed histology-subset denominators and combined endpoint.
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      However, there was significant variation in monitoring practice amongst centers and only one third
      (n = 34/92) of individuals with PGDm had histology assessment.
    explanation: Limits interpretation of low observed PGDm tumor prevalence.
  - reference: PMID:25580123
    reference_title: Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Three patients had a sperm count; all had severe oligozoospermia and low motility, and two had also
      abnormal semen viscosity.
    explanation: Direct limited-cohort semen findings.
- phase: Adult gonadal-reserve decline phase
  age_range: adulthood
  notes: >-
    Endocrine function may decline after spontaneous puberty. In one ten-patient series, FSH was high
    or high-normal in 3/6 before puberty and 8/10 at final evaluation, while LH was high or high-normal
    in 5/10 at final assessment. Differing denominators prevent treating this as a uniform within-person
    decline. A p.Arg308Gln DHX37 case entered puberty spontaneously but required testosterone from age
    17. Ongoing endocrine review is appropriate.
  evidence:
  - reference: PMID:25580123
    reference_title: Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the end of the prepubertal period, FSH was high or high-normal in 3/6 patients; LH was normal
      in all. At the last evaluation, FSH was high or high-normal in 8/10; LH was high or high-normal
      in 5/10
    explanation: >-
      Consistent with rising gonadotropins over follow-up, but limited by n=10 single-centre, and the
      3/6 and 8/10 fractions have different denominators, so this is not a within-patient longitudinal
      comparison.
    quote_role: PRIMARY_RESULT
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The patient developed normal puberty at 12 years old but presented with low testosterone levels
      at 17 years old.
    explanation: Individual longitudinal observation of later testosterone deficiency.
pathophysiology:
- name: NR5A1 sequence alteration
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Heterozygous pathogenic NR5A1 variants occur in partial gonadal dysgenesis. Early truncating alleles
    are predicted to reduce functional SF-1; other alleles have variant-specific effects. Nonsense-mediated
    decay and splice changes in the cited partial cases were predicted rather than directly measured.
  evidence:
  - reference: PMID:27463801
    reference_title: >-
      NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three
      Novel Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3 novel NR5A1 mutations were identified in 3 patients with 46,XY partial gonadal dysgenesis: p.Lys38*
      and p.Leu80Trpfs*8 lead to premature translation termination codons within the SF1 DNA-binding domain
    explanation: Directly documents loss-of-function NR5A1 variants in partial disease.
    quote_role: PRIMARY_RESULT
  genes:
  - preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  downstream:
  - target: Reduced SF-1 transcriptional activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Selected NR5A1 missense variants reduce a steroidogenic-promoter reporter in transfected cells;
      this does not establish the effect of every allele.
    evidence:
    - reference: PMID:31745530
      reference_title: >-
        Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults
        With 46,XY DSD.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Transient transfection assays showing activation of a Cyp11a1 promoter by WT SF-1 and impaired
        transcriptional activity by the p.G22D and p.L420P mutants.
      explanation: >-
        Cyp11a1 reporter in tsa201 kidney-derived cells; the clinical cohort used a broader partially
        virilized DSD category.
  - target: Incomplete testicular differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The genetic association establishes a developmental effect, but the causal fetal targets and thresholds
      vary and are not resolved for each allele.
    evidence:
    - reference: PMID:27463801
      reference_title: >-
        NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of
        Three Novel Mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        3 novel NR5A1 mutations were identified in 3 patients with 46,XY partial gonadal dysgenesis: p.Lys38*
        and p.Leu80Trpfs*8 lead to premature translation termination codons within the SF1 DNA-binding
        domain
      explanation: Directly documents loss-of-function NR5A1 variants in partial disease.
      quote_role: PRIMARY_RESULT
- name: Reduced SF-1 transcriptional activity
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    p.Gly22Asp and p.Leu420Pro reduced Cyp11a1 promoter activation in kidney-derived tsa201 cells. This
    is an experimental readout of variant-dependent transcriptional function; it does not directly measure
    fetal Sertoli differentiation or all SF-1 target genes.
  evidence:
  - reference: PMID:31745530
    reference_title: >-
      Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults
      With 46,XY DSD.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Transient transfection assays showing activation of a Cyp11a1 promoter by WT SF-1 and impaired transcriptional
      activity by the p.G22D and p.L420P mutants.
    explanation: >-
      Cyp11a1 reporter in tsa201 kidney-derived cells; the clinical cohort used a broader partially virilized
      DSD category.
  genes:
  - preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
- name: MAP3K1 sequence alteration
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Heterozygous MAP3K1 variants are associated with partial and complete gonadal dysgenesis. Functional
    consequences below are allele- and assay-specific. The p.Arg186Gly family had severe 46,XY DSD with
    streak gonads or tumors; its cellular results inform a broader gene mechanism rather than prove the
    mechanism of every partial presentation.
  evidence:
  - reference: PMID:21129722
    reference_title: >-
      Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
      pathway in human testis determination.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate
      this pathway in normal human sex determination.
    explanation: Directly names partial gonadal dysgenesis as a MAP3K1 outcome.
    quote_role: PRIMARY_RESULT
  genes:
  - preferred_term: MAP3K1
    term:
      id: hgnc:6848
      label: MAP3K1
  downstream:
  - target: Enhanced MAP3K1-RHOA association
    causal_link_type: DIRECT
    description: Patient-derived and transfected-cell assays identify increased association for selected variants.
    evidence:
    - reference: PMID:21129722
      reference_title: >-
        Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
        pathway in human testis determination.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced
        binding of RHOA to the MAP3K1 complex.
      explanation: >-
        Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association;
        p38 effects differed among alleles.
    - reference: PMID:35309143
      reference_title: >-
        MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY
        Disorders/Differences of Sex Development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Our Co-IP assay confirmed that the binding capacity of MAP3K1R186G to RhoA was 2.57 times that
        of the wild-type protein (Figures 5A,A'), and the ubiquitination degree of the wild-type MAP3K1
        protein was 3.6-fold that of the MAP3K1R186G variant (Figures 5B,B').
      explanation: >-
        Selected p.Arg186Gly variant in HEK293T cells; binding and ubiquitination measurements, not gonadal
        epistasis.
  - target: Reduced MAP3K1 ubiquitination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The p.Arg186Gly construct shows reduced ubiquitination in HEK293T cells; mediation by increased
      RHOA binding remains an interpretation.
    evidence:
    - reference: PMID:35309143
      reference_title: >-
        MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY
        Disorders/Differences of Sex Development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Our Co-IP assay confirmed that the binding capacity of MAP3K1R186G to RhoA was 2.57 times that
        of the wild-type protein (Figures 5A,A'), and the ubiquitination degree of the wild-type MAP3K1
        protein was 3.6-fold that of the MAP3K1R186G variant (Figures 5B,B').
      explanation: >-
        Selected p.Arg186Gly variant in HEK293T cells; binding and ubiquitination measurements, not gonadal
        epistasis.
  - target: Increased MAP3K1 protein abundance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The p.Arg186Gly construct produces more MAP3K1 protein in NT2/D1 and KGN cells.
    evidence:
    - reference: PMID:35309143
      reference_title: >-
        MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY
        Disorders/Differences of Sex Development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        The protein expression of the MAP3K1R186G variant was 6.4 and 2.0 times higher than that of the
        wild type in the KGN and NT2/D1 cells, respectively (Figures 6A–D).
      explanation: Measured abundance in KGN and NT2/D1 overexpression models; not a direct half-life measurement.
  - target: Increased ERK1/2 phosphorylation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Selected patient lymphoblastoid lines show altered ERK phosphorylation after serum refeeding.
    evidence:
    - reference: PMID:21129722
      reference_title: >-
        Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
        pathway in human testis determination.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced
        binding of RHOA to the MAP3K1 complex.
      explanation: >-
        Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association;
        p38 effects differed among alleles.
  - target: Increased p38 phosphorylation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The response occurs in selected patient lines and p.Arg186Gly overexpression models, with allele-dependent
      differences.
    evidence:
    - reference: PMID:21129722
      reference_title: >-
        Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
        pathway in human testis determination.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced
        binding of RHOA to the MAP3K1 complex.
      explanation: >-
        Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association;
        p38 effects differed among alleles.
    - reference: PMID:35309143
      reference_title: >-
        MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY
        Disorders/Differences of Sex Development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Similarly, in the NT2/D1 testicular cells, phosphorylated p38 and GSK3β proteins were significantly
        elevated in the mutant group, which were 2.3 and 2.2 times higher than those in the wild-type
        group, respectively.
      explanation: Measured phosphorylation responses in an overexpression model.
  - target: Increased beta-catenin-dependent transcription
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The p.Arg186Gly construct increases TCF/LEF reporter activity; intervening signaling was not dissected
      by epistasis.
    evidence:
    - reference: PMID:35309143
      reference_title: >-
        MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY
        Disorders/Differences of Sex Development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        The data showed that at 48 h after transfection, the relative activity of TCF/LEF in the mutant
        group reached its peak, which was 9.78 ± 0.57 times that of the wild-type group (Figures 6E,F).
      explanation: TCF/LEF reporter assay measures beta-catenin-dependent transcription in HEK293T cells.
  - target: Incomplete testicular differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Human pedigrees and cases support MAP3K1-related partial dysgenesis. The observed signaling changes
      propose, but do not experimentally reconstruct, the human fetal developmental route.
    evidence:
    - reference: PMID:21129722
      reference_title: >-
        Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
        pathway in human testis determination.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate
        this pathway in normal human sex determination.
      explanation: Directly names partial gonadal dysgenesis as a MAP3K1 outcome.
      quote_role: PRIMARY_RESULT
- name: Enhanced MAP3K1-RHOA association
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    Selected MAP3K1 variants increase RHOA association in protein-interaction assays. The p.Arg186Gly
    study used both NanoBiT and co-immunoprecipitation. Stronger association alone does not prove that
    RHOA mediates all downstream signaling changes.
  evidence:
  - reference: PMID:21129722
    reference_title: >-
      Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
      pathway in human testis determination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced
      binding of RHOA to the MAP3K1 complex.
    explanation: >-
      Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association; p38
      effects differed among alleles.
  - reference: PMID:35309143
    reference_title: >-
      MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences
      of Sex Development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Our Co-IP assay confirmed that the binding capacity of MAP3K1R186G to RhoA was 2.57 times that of
      the wild-type protein (Figures 5A,A'), and the ubiquitination degree of the wild-type MAP3K1 protein
      was 3.6-fold that of the MAP3K1R186G variant (Figures 5B,B').
    explanation: >-
      Selected p.Arg186Gly variant in HEK293T cells; binding and ubiquitination measurements, not gonadal
      epistasis.
  genes:
  - preferred_term: MAP3K1
    term:
      id: hgnc:6848
      label: MAP3K1
- name: Reduced MAP3K1 ubiquitination
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    The p.Arg186Gly MAP3K1 protein showed less ubiquitination than wild type in transfected HEK293T cells.
    Reduced turnover is a proposed explanation for greater abundance, but protein half-life and dependence
    on RHOA competition were not directly established.
  evidence:
  - reference: PMID:35309143
    reference_title: >-
      MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences
      of Sex Development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Our Co-IP assay confirmed that the binding capacity of MAP3K1R186G to RhoA was 2.57 times that of
      the wild-type protein (Figures 5A,A'), and the ubiquitination degree of the wild-type MAP3K1 protein
      was 3.6-fold that of the MAP3K1R186G variant (Figures 5B,B').
    explanation: >-
      Selected p.Arg186Gly variant in HEK293T cells; binding and ubiquitination measurements, not gonadal
      epistasis.
  genes:
  - preferred_term: MAP3K1
    term:
      id: hgnc:6848
      label: MAP3K1
- name: Increased MAP3K1 protein abundance
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    MAP3K1 p.Arg186Gly protein abundance was increased 6.4-fold in KGN and 2.0-fold in NT2/D1 cells relative
    to wild type. This measured steady-state difference is separated from the unmeasured degradation-rate
    explanation.
  evidence:
  - reference: PMID:35309143
    reference_title: >-
      MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences
      of Sex Development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      The protein expression of the MAP3K1R186G variant was 6.4 and 2.0 times higher than that of the
      wild type in the KGN and NT2/D1 cells, respectively (Figures 6A–D).
    explanation: Measured abundance in KGN and NT2/D1 overexpression models; not a direct half-life measurement.
  genes:
  - preferred_term: MAP3K1
    term:
      id: hgnc:6848
      label: MAP3K1
- name: Increased ERK1/2 phosphorylation
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    Serum-refed patient-derived lymphoblastoid cells carrying selected MAP3K1 variants showed increased
    ERK1/2 phosphorylation. These cells are not fetal gonadal cells, and phosphorylation does not by itself
    identify the developmental fate change.
  evidence:
  - reference: PMID:21129722
    reference_title: >-
      Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
      pathway in human testis determination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced
      binding of RHOA to the MAP3K1 complex.
    explanation: >-
      Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association; p38
      effects differed among alleles.
  genes:
  - preferred_term: MAP3K1
    term:
      id: hgnc:6848
      label: MAP3K1
- name: Increased p38 phosphorylation
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    p38 phosphorylation increased in selected MAP3K1 variant assays, including p.Arg186Gly-transfected
    NT2/D1 and KGN cells. The original lymphoblastoid study did not find the same p38 response for every
    tested allele.
  evidence:
  - reference: PMID:21129722
    reference_title: >-
      Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
      pathway in human testis determination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced
      binding of RHOA to the MAP3K1 complex.
    explanation: >-
      Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association; p38
      effects differed among alleles.
  - reference: PMID:35309143
    reference_title: >-
      MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences
      of Sex Development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Similarly, in the NT2/D1 testicular cells, phosphorylated p38 and GSK3β proteins were significantly
      elevated in the mutant group, which were 2.3 and 2.2 times higher than those in the wild-type group,
      respectively.
    explanation: Measured phosphorylation responses in an overexpression model.
  genes:
  - preferred_term: MAP3K1
    term:
      id: hgnc:6848
      label: MAP3K1
- name: Increased beta-catenin-dependent transcription
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    MAP3K1 p.Arg186Gly increased TCF/LEF reporter activity in HEK293T cells. The same study observed GSK3beta
    phosphorylation, greater WNT4/beta-catenin protein and altered sex-development gene expression. Those
    parallel measurements suggest an ovarian-signaling bias, but do not establish a necessary linear cascade
    or ovarian tissue formation in partial human disease.
  evidence:
  - reference: PMID:35309143
    reference_title: >-
      MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences
      of Sex Development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      The data showed that at 48 h after transfection, the relative activity of TCF/LEF in the mutant
      group reached its peak, which was 9.78 ± 0.57 times that of the wild-type group (Figures 6E,F).
    explanation: TCF/LEF reporter assay measures beta-catenin-dependent transcription in HEK293T cells.
  genes:
  - preferred_term: MAP3K1
    term:
      id: hgnc:6848
      label: MAP3K1
- name: Biallelic DHH sequence alteration
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Biallelic DHH variants are associated with gonadal dysgenesis and, in some patients, peripheral neuropathy.
    Initiating-codon translation failure and altered p.Arg124Gln ligand interactions were predicted; a
    universal complete loss of hedgehog signaling was not directly demonstrated in these cases.
  evidence:
  - reference: PMID:11017805
    reference_title: >-
      A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied
      by minifascicular neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a homozygous missense mutation (ATG-->ACG) at the initiating codon in exon 1 of the desert hedgehog
      (DHH) gene, which predicts a failure of translation of the gene.
    explanation: Directly documents a causal biallelic DHH lesion in partial disease.
    quote_role: PRIMARY_RESULT
  - reference: PMID:25927242
    reference_title: >-
      46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome
      Sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The gonads of one patient showed partial gonadal dysgenesis with loss of Leydig cells in tubular
      areas with seminoma in situ and a hyperplasia of Leydig cell-like cells expressing CYP17A1 in more
      dysgenetic parts of the gonad.
    explanation: >-
      Human gonadal pathology with biallelic DHH p.Arg124Gln; the molecular signaling defect was not directly
      assayed.
  genes:
  - preferred_term: DHH
    term:
      id: hgnc:2865
      label: DHH
  downstream:
  - target: Incomplete testicular differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Human biallelic DHH cases include histologically confirmed partial dysgenesis.
    evidence:
    - reference: PMID:25927242
      reference_title: >-
        46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome
        Sequencing.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        The gonads of one patient showed partial gonadal dysgenesis with loss of Leydig cells in tubular
        areas with seminoma in situ and a hyperplasia of Leydig cell-like cells expressing CYP17A1 in
        more dysgenetic parts of the gonad.
      explanation: >-
        Human gonadal pathology with biallelic DHH p.Arg124Gln; the molecular signaling defect was not
        directly assayed.
  - target: Impaired Leydig-cell maturation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of mature Leydig-cell staining in one partial gonad supports a developmental differentiation
      abnormality; the intervening paracrine mechanism remains inferred.
    evidence:
    - reference: PMID:25927242
      reference_title: >-
        46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome
        Sequencing.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        The gonads of one patient showed partial gonadal dysgenesis with loss of Leydig cells in tubular
        areas with seminoma in situ and a hyperplasia of Leydig cell-like cells expressing CYP17A1 in
        more dysgenetic parts of the gonad.
      explanation: >-
        Human gonadal pathology with biallelic DHH p.Arg124Gln; the molecular signaling defect was not
        directly assayed.
  - target: Peripheral neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The original molecularly characterized patient had minifascicular nerve pathology; the intermediate
      human developmental signaling was not measured.
    evidence:
    - reference: PMID:11017805
      reference_title: >-
        A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied
        by minifascicular neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We describe a patient with 46,XY partial gonadal dysgenesis (PGD) who presented with polyneuropathy.
      explanation: Directly documents polyneuropathy in the DHH subtype.
      quote_role: PRIMARY_RESULT
- name: Impaired Leydig-cell maturation
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    In one DHH p.Arg124Gln partial-dysgenesis gonad, CYP17A1-positive Leydig-like nodules were present
    but mature INSL3-positive Leydig cells were absent from tubular interstitium. This supports abnormal
    differentiation rather than absence of every steroidogenic cell. The finding is postnatal histology,
    not a direct fetal hormone measurement.
  evidence:
  - reference: PMID:25927242
    reference_title: >-
      46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome
      Sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The gonads of one patient showed partial gonadal dysgenesis with loss of Leydig cells in tubular
      areas with seminoma in situ and a hyperplasia of Leydig cell-like cells expressing CYP17A1 in more
      dysgenetic parts of the gonad.
    explanation: >-
      Human gonadal pathology with biallelic DHH p.Arg124Gln; the molecular signaling defect was not directly
      assayed.
  genes:
  - preferred_term: DHH
    term:
      id: hgnc:2865
      label: DHH
  cell_types:
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
- name: DHX37 sequence alteration
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Recurrent heterozygous DHX37 variants, including p.Arg308Gln, occur in partial gonadal dysgenesis
    and testicular regression. Genetic association is established more strongly than the biochemical route.
    The proposed ribosomopathy mechanism must be distinguished from measured protein abundance and from
    uncertain variants.
  evidence:
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In DHX37, the variant p.(Arg308Gln), recurrent associated with DSD, was identified in one patient
    explanation: Directly documents the recurrent DHX37 allele in a partial-disease cohort.
    quote_role: PRIMARY_RESULT
  genes:
  - preferred_term: DHX37
    term:
      id: hgnc:17210
      label: DHX37
  downstream:
  - target: Reduced DHX37 protein abundance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Overexpression experiments found lower protein abundance for p.Arg308Gln and selected other variants.
      The effect is assay-specific and does not prove reduced helicase activity.
    evidence:
    - reference: PMID:38769888
      reference_title: >-
        Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY
        disorders of sex development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: The results indicated that mutant DHX37 decreased the protein levels of DHX37.
      explanation: Selected-variant overexpression assay; not an ATPase or ribosome-biogenesis assay.
  - target: Incomplete testicular differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The p.Arg308Gln patient had biopsy-documented bilateral dysgenetic testes. Intermediates between
      the variant and fetal gonadal development remain unknown.
    evidence:
    - reference: PMID:37240737
      reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In DHX37, the variant p.(Arg308Gln), recurrent associated with DSD, was identified in one patient
      explanation: Directly documents the recurrent DHX37 allele in a partial-disease cohort.
      quote_role: PRIMARY_RESULT
    - reference: PMID:37240737
      reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        A diagnosis of 46,XY PGD was established based on bilateral dysgenetic testis revealed from a
        gonadal biopsy.
      explanation: Histology in patient 1 connects the established recurrent allele to partial disease.
- name: Reduced DHX37 protein abundance
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    In transfected HEK293T cells, p.Arg308Gln and p.Arg671Thr showed lower DHX37 protein expression than
    wild type. A separate p.Ser408Leu Sertoli-cell assay also found lower transcript and protein abundance.
    p.Arg671Thr and p.Ser408Leu were listed as VUS in the later study table. These assays do not demonstrate
    variant-dependent ATPase failure, defective 18S rRNA maturation, or a causal connection from protein
    reduction to human gonadal dysgenesis.
  evidence:
  - reference: PMID:38769888
    reference_title: >-
      Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders
      of sex development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: The results indicated that mutant DHX37 decreased the protein levels of DHX37.
    explanation: Selected-variant overexpression assay; not an ATPase or ribosome-biogenesis assay.
  - reference: PMID:37065748
    reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      compared with the cells transfected with pcDNA3.1-WT, those with pcDNA3.1-S408L displayed decreased
      DHX37 expression both at the mRNA and protein levels.
    explanation: Variant overexpression effect in a human Sertoli-cell line, with uncertain clinical classification.
  genes:
  - preferred_term: DHX37
    term:
      id: hgnc:17210
      label: DHX37
- name: WT1 sequence alteration
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Pathogenic heterozygous WT1 variants can cause partial testicular dysgenesis within a variable renal
    and tumor-predisposition disorder. Effects differ between zinc-finger missense, splice, truncating
    and deletion alleles; a single generic haploinsufficiency mechanism cannot represent all of them.
  evidence:
  - reference: PMID:25613702
    reference_title: >-
      WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We found a heterozygous WT1 whole-gene deletion but no other gene defects.
    explanation: Directly documents a causal heterozygous WT1 lesion in partial disease.
    quote_role: PRIMARY_RESULT
  genes:
  - preferred_term: WT1
    term:
      id: hgnc:12796
      label: WT1
  downstream:
  - target: Incomplete testicular differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The whole-gene deletion case directly documents severe partial dysgenesis; the disrupted fetal transcriptional
      program was not assayed.
    evidence:
    - reference: PMID:25613702
      reference_title: >-
        WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case
        report.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We describe a newborn with 46,XY severe partial gonadal dysgenesis
      explanation: Directly documents WT1-associated partial gonadal dysgenesis.
      quote_role: PRIMARY_RESULT
  - target: Steroid-resistant nephrotic syndrome
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Pathogenic WT1 variants predispose to glomerular disease within WT1 disorder. This is restricted
      to the WT1-related subtype; intervening renal cellular mechanisms are not modeled here.
    evidence:
    - reference: PMID:32352694
      reference_title: WT1 Disorder.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        WT1 disorder is characterized by congenital/infantile or childhood onset of steroid-resistant
        nephrotic syndrome (SRNS), a progressive glomerulopathy that does not respond to standard steroid
        therapy.
      explanation: Directly documents SRNS as the defining renal feature of WT1 disorder.
      quote_role: REVIEW_SYNTHESIS
  - target: Nephroblastoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Wilms tumor occurred in the child with a WT1 whole-gene deletion and partial gonadal dysgenesis.
      This genotype-qualified link does not imply that every variant or affected person develops a tumor,
      or that the somatic initiating events were measured.
    evidence:
    - reference: PMID:25613702
      reference_title: >-
        WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case
        report.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We found a heterozygous WT1 whole-gene deletion but no other gene defects.
      explanation: Directly documents a causal heterozygous WT1 lesion in partial disease.
      quote_role: PRIMARY_RESULT
    - reference: PMID:25613702
      reference_title: >-
        WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case
        report.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: At the age of 9 months, the patient presented with a bilateral Wilms tumor.
      explanation: Directly documents Wilms tumor in WT1-related partial gonadal dysgenesis.
      quote_role: PRIMARY_RESULT
- name: Incomplete testicular differentiation
  role: central_effector
  biological_scale: TISSUE
  description: >-
    The gonads can contain hypoplastic or disorganized testicular tissue, streak tissue and regressed
    regions in varying combinations. Sertoli, Leydig and germ-cell compartments need not be affected equally.
    Preserved testosterone, AMH or spontaneous puberty is compatible with partial dysgenesis and does
    not demonstrate normal fertility or absence of neoplasia.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Features of dysgenetic testis noted were reduced tubular diameter, thickened basal membrane, increased
      interstitial stroma, intracapsular growth, irregular shaped tubules, Leydig cell micronodules or
      hyperplasia, Sertoli cell only tubules, reduced germ cell number, absent spermatogenesis, and tubular
      atrophy (Fig.
    explanation: Expert histological review documents the heterogeneous tissue-level lesion.
  biological_processes:
  - preferred_term: male gonad development
    term:
      id: GO:0008584
      label: male gonad development
    modifier: ABNORMAL
  downstream:
  - target: Gonadal dysgenesis
    causal_link_type: DIRECT
    description: Histology is a direct readout of abnormal tissue differentiation.
    evidence:
    - reference: PMID:40208111
      reference_title: >-
        Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Features of dysgenetic testis noted were reduced tubular diameter, thickened basal membrane, increased
        interstitial stroma, intracapsular growth, irregular shaped tubules, Leydig cell micronodules
        or hyperplasia, Sertoli cell only tubules, reduced germ cell number, absent spermatogenesis, and
        tubular atrophy (Fig.
      explanation: Expert histological review documents the heterogeneous tissue-level lesion.
  - target: Reduced fetal AMH activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Müllerian retention in a subset is consistent with insufficient fetal AMH action; this is a developmental
      inference, not a fetal serum measurement.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
      reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        In a 46,XY individual, absence of virilization and presence of m&#x000fc;llerian structures implies
        that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and
        anti-m&#x000fc;llerian hormone, during fetal life and are unlikely to do so during postnatal life.
      explanation: >-
        General developmental interpretation in GeneReviews; applied only to the deficient-hormone presentations,
        not every PGD case.
  - target: Reduced fetal androgen activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Undervirilized external genital development is consistent with inadequate fetal testicular androgen
      activity; timing and output are inferred rather than measured.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
      reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        In a 46,XY individual, absence of virilization and presence of m&#x000fc;llerian structures implies
        that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and
        anti-m&#x000fc;llerian hormone, during fetal life and are unlikely to do so during postnatal life.
      explanation: >-
        General developmental interpretation in GeneReviews; applied only to the deficient-hormone presentations,
        not every PGD case.
  - target: Impaired spermatogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal tubular and germ-cell architecture plausibly contributes to the semen abnormalities observed
      in clinical follow-up; patient-specific mediation is not experimentally demonstrated.
    evidence:
    - reference: PMID:40208111
      reference_title: >-
        Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Features of dysgenetic testis noted were reduced tubular diameter, thickened basal membrane, increased
        interstitial stroma, intracapsular growth, irregular shaped tubules, Leydig cell micronodules
        or hyperplasia, Sertoli cell only tubules, reduced germ cell number, absent spermatogenesis, and
        tubular atrophy (Fig.
      explanation: Expert histological review documents the heterogeneous tissue-level lesion.
    - reference: PMID:25580123
      reference_title: Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Three patients had a sperm count; all had severe oligozoospermia and low motility, and two had
        also abnormal semen viscosity.
      explanation: Semen outcomes in the three tested participants.
  - target: Delayed gonadal germ-cell maturation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      OCT3/4-positive luminal cells in a MAP3K1-associated partial gonad demonstrate delayed maturation
      within dysgenetic tissue.
    evidence:
    - reference: PMID:40208111
      reference_title: >-
        Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        OCT3/4 staining (B.2) shows peripheral preneoplastic cells (gray arrow) and luminal OCT3/4-positive
        delayed maturation in white arrow.
      explanation: Figure 4 distinguishes delayed maturation from peripheral preneoplastic cells.
  - target: Decreased testicular size
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Underdeveloped testicular tissue is consistent with reduced volume in the reported NR5A1 case. The
      contribution of each histological compartment was not quantified.
    evidence:
    - reference: PMID:33296094
      reference_title: >-
        NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete
        penetrance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and
        azoospermia in P2
      explanation: Directly documents reduced testicular volume.
      quote_role: PRIMARY_RESULT
  - target: Hypergonadotropic hypogonadism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Primary gonadal dysfunction can reduce sex-steroid output and feedback, producing elevated gonadotropins
      with low testosterone in a subset; preserved androgen production in other partial cases remains
      compatible with dysgenesis.
    evidence:
    - reference: PMID:37240737
      reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Hormonal evaluation indicated high levels of FSH (72.1 IU/L) and LH (13.9 IU/L), and low levels
        of total testosterone (70 ng/dL).
      explanation: >-
        Patient 2 had elevated gonadotropins and low testosterone; directly supports the combined endocrine
        phenotype.
- name: Reduced fetal AMH activity
  role: intermediate
  biological_scale: TISSUE
  description: >-
    Insufficient anti-Müllerian hormone activity during the fetal differentiation window is a physiological
    interpretation of Müllerian retention in some partial cases. Other patients lack Müllerian structures,
    indicating that fetal AMH action may have been sufficient despite later gonadal dysfunction. Postnatal
    AMH measurements cannot retrospectively quantify the fetal exposure.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In a 46,XY individual, absence of virilization and presence of m&#x000fc;llerian structures implies
      that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and
      anti-m&#x000fc;llerian hormone, during fetal life and are unlikely to do so during postnatal life.
    explanation: >-
      General developmental interpretation in GeneReviews; applied only to the deficient-hormone presentations,
      not every PGD case.
  downstream:
  - target: Presence of uterus in 46,XY individual
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Insufficient fetal AMH action permits Müllerian structures to persist; regression failure is the
      omitted developmental intermediate.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
      reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        In a 46,XY individual, absence of virilization and presence of m&#x000fc;llerian structures implies
        that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and
        anti-m&#x000fc;llerian hormone, during fetal life and are unlikely to do so during postnatal life.
      explanation: >-
        General developmental interpretation in GeneReviews; applied only to the deficient-hormone presentations,
        not every PGD case.
    intermediate_mechanisms:
    - incomplete Müllerian duct regression
- name: Reduced fetal androgen activity
  role: intermediate
  biological_scale: TISSUE
  description: >-
    Inadequate testicular androgen action during genital differentiation can produce undervirilized external
    genital anatomy. The degree and timing vary, and a female external phenotype is possible. Fetal steroid
    levels were not measured in the cited clinical cohorts.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In a 46,XY individual, absence of virilization and presence of m&#x000fc;llerian structures implies
      that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and
      anti-m&#x000fc;llerian hormone, during fetal life and are unlikely to do so during postnatal life.
    explanation: >-
      General developmental interpretation in GeneReviews; applied only to the deficient-hormone presentations,
      not every PGD case.
  downstream:
  - target: Ambiguous genitalia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Incomplete androgen-dependent external genital differentiation is the physiological interpretation
      of the partial phenotype.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
      reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        In a 46,XY individual, absence of virilization and presence of m&#x000fc;llerian structures implies
        that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and
        anti-m&#x000fc;llerian hormone, during fetal life and are unlikely to do so during postnatal life.
      explanation: >-
        General developmental interpretation in GeneReviews; applied only to the deficient-hormone presentations,
        not every PGD case.
    intermediate_mechanisms:
    - incomplete androgen-dependent external genital differentiation
  - target: Penoscrotal hypospadias
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Incomplete androgen-dependent urethral development is an inferred developmental explanation for
      this observed feature.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
      reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        In a 46,XY individual, absence of virilization and presence of m&#x000fc;llerian structures implies
        that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and
        anti-m&#x000fc;llerian hormone, during fetal life and are unlikely to do so during postnatal life.
      explanation: >-
        General developmental interpretation in GeneReviews; applied only to the deficient-hormone presentations,
        not every PGD case.
    - reference: PMID:33296094
      reference_title: >-
        NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete
        penetrance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and
        azoospermia in P2
      explanation: Directly documents penoscrotal hypospadias in molecularly confirmed partial disease.
      quote_role: PRIMARY_RESULT
  - target: Micropenis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Insufficient androgen-dependent phallic growth provides the developmental interpretation of reduced
      phallic size.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
      reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        In a 46,XY individual, absence of virilization and presence of m&#x000fc;llerian structures implies
        that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and
        anti-m&#x000fc;llerian hormone, during fetal life and are unlikely to do so during postnatal life.
      explanation: >-
        General developmental interpretation in GeneReviews; applied only to the deficient-hormone presentations,
        not every PGD case.
    - reference: PMID:37240737
      reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        The patient had a male sex assignment, with a 1.0 cm phallus, normal male urethral opening without
        hypospadias, and both gonads palpable in the inguinal canal (Prader 5; EMS 8.0; EGS 8.5).
      explanation: Direct infant clinical observation in the p.Arg308Gln partial-disease case.
- name: Impaired spermatogenesis
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    Sperm production may be severely reduced or absent despite retained androgen production. Severe oligozoospermia
    and low motility occurred in the three semen-tested participants of one ten-patient follow-up cohort;
    azoospermia is documented in individual molecularly characterized partial cases.
  evidence:
  - reference: PMID:25580123
    reference_title: Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Three patients had a sperm count; all had severe oligozoospermia and low motility, and two had also
      abnormal semen viscosity.
    explanation: All three tested patients had severe oligozoospermia and low motility; denominator is not all ten.
  - reference: PMID:33296094
    reference_title: >-
      NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete
      penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and
      azoospermia in P2
    explanation: Directly documents azoospermia.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Azoospermia
    causal_link_type: DIRECT
    description: >-
      Severe failure of sperm production can result in an azoospermic ejaculate; observed in individual
      cases, not all PGD.
    evidence:
    - reference: PMID:33296094
      reference_title: >-
        NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete
        penetrance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and
        azoospermia in P2
      explanation: Directly documents azoospermia.
      quote_role: PRIMARY_RESULT
  - target: Male infertility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired sperm production can limit fertility; individual reproductive potential is not determined
      by androgen production alone.
    evidence:
    - reference: PMID:25580123
      reference_title: Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Three patients had a sperm count; all had severe oligozoospermia and low motility, and two had
        also abnormal semen viscosity.
      explanation: Direct semen impairment in the selected tested subgroup.
  - target: Oligozoospermia
    causal_link_type: DIRECT
    description: >-
      Reduced sperm production is reflected by the severe oligozoospermia observed in the three semen-tested
      participants.
    evidence:
    - reference: PMID:25580123
      reference_title: Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Three patients had a sperm count; all had severe oligozoospermia and low motility, and two had
        also abnormal semen viscosity.
      explanation: Three tested participants; no extrapolation to the full cohort.
- name: Delayed gonadal germ-cell maturation
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    In a partial gonad with a MAP3K1 defect, luminal OCT3/4-positive cells were interpreted as delayed
    maturation and peripheral cells as preneoplastic. Delayed maturation is not itself synonymous with
    neoplasia. The molecular steps linking a dysgenetic Y-bearing gonadal environment to a tumor remain
    incompletely defined.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      OCT3/4 staining (B.2) shows peripheral preneoplastic cells (gray arrow) and luminal OCT3/4-positive
      delayed maturation in white arrow.
    explanation: Human histology differentiates maturation delay from preneoplastic location.
  notes: >-
    No maturation-delay-to-neoplasia edge is asserted. The cited cross-sectional histology distinguishes
    luminal delayed maturation from peripheral preneoplastic cells; it does not demonstrate progression
    of the former population to gonadoblastoma or GCNIS.
phenotypes:
- name: Ambiguous genitalia
  category: Reproductive
  description: >-
    Atypical external genitalia are a common presenting feature, but some individuals have female external
    genitalia and absent Müllerian structures. The registry presentation proportions are not population
    frequency estimates.
  phenotype_term:
    preferred_term: Ambiguous genitalia
    term:
      id: HP:0000062
      label: Ambiguous genitalia
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most individuals with PGD presented with atypical genitalia in infancy
    explanation: >-
      Documents the common infant presentation; no pooled arithmetic or population frequency is inferred
      from the abstract.
    quote_role: PRIMARY_RESULT
- name: Gonadal dysgenesis
  category: Reproductive
  description: >-
    Dysgenetic testicular tissue can show hypoplastic tubules, Sertoli-cell-only areas, reduced germ cells,
    interstitial fibrosis or Leydig-cell micronodules. Streak or regressed gonadal tissue may coexist;
    histology alone is not an invariant partial-versus-complete classifier.
  phenotype_term:
    preferred_term: Gonadal dysgenesis
    term:
      id: HP:0000133
      label: Gonadal dysgenesis
  evidence:
  - reference: PMID:38206718
    reference_title: 'NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pathology show testes dysgenesis, composed mainly of hypoplastic seminiferous tubules
    explanation: Directly documents dysgenetic testicular histology.
    quote_role: PRIMARY_RESULT
- name: Penoscrotal hypospadias
  category: Reproductive
  description: Severe proximal hypospadias reflecting incomplete androgen-dependent urethral fusion.
  phenotype_term:
    preferred_term: Penoscrotal hypospadias
    term:
      id: HP:0000808
      label: Penoscrotal hypospadias
  evidence:
  - reference: PMID:33296094
    reference_title: >-
      NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete
      penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and
      azoospermia in P2
    explanation: Directly documents penoscrotal hypospadias in molecularly confirmed partial disease.
    quote_role: PRIMARY_RESULT
- name: Cryptorchidism
  category: Reproductive
  description: >-
    Testes may be inguinal or abdominal. Bilateral cryptorchidism occurred in the NR5A1 family reported
    here; no disease-wide frequency is inferred.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:33296094
    reference_title: >-
      NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete
      penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and
      azoospermia in P2
    explanation: Directly documents bilateral cryptorchidism.
    quote_role: PRIMARY_RESULT
- name: Clitoral hypertrophy
  category: Reproductive
  description: >-
    Partial androgen exposure enlarges the phallic structure in individuals whose external genitalia are
    otherwise female in configuration.
  phenotype_term:
    preferred_term: Clitoral hypertrophy
    term:
      id: HP:0008665
      label: Clitoral hypertrophy
  evidence:
  - reference: PMID:28504475
    reference_title: 'MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: resulting in clitoral hypertrophy with otherwise typical female external genitalia
    explanation: Directly documents clitoral hypertrophy in partial disease.
    quote_role: PRIMARY_RESULT
- name: Presence of uterus in 46,XY individual
  category: Reproductive
  description: >-
    A uterus was reported in 52/102 PGDf and 30/96 PGDm individuals with anatomy data in the I-DSD registry.
    Müllerian remnants may be present or absent. These are selected clinical groups rather than a general
    population frequency.
  phenotype_term:
    preferred_term: Presence of uterus in 46,XY individual
    term:
      id: HP:0034546
      label: Presence of uterus in 46,XY individual
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Presence of uterus | 100% (n = 96/96) | 51.0% (n = 52/102) | 31.3% (n = 30/96) | PGDf vs PGDm
      .0062 |
    explanation: Table 2 columns are CGD, PGDf, PGDm; retains anatomy-specific denominators.
- name: Micropenis
  category: Reproductive
  description: >-
    Reduced phallic size is documented in partial disease, including the p.Arg308Gln DHX37 patient evaluated
    in infancy.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  evidence:
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The patient had a male sex assignment, with a 1.0 cm phallus, normal male urethral opening without
      hypospadias, and both gonads palpable in the inguinal canal (Prader 5; EMS 8.0; EGS 8.5).
    explanation: Direct infant clinical observation in the p.Arg308Gln partial-disease case.
- name: Decreased circulating anti-Mullerian hormone concentration
  category: Endocrine
  description: >-
    AMH was below the age-specific male reference range in 12/25 PGDf and 18/31 PGDm individuals with
    measurements in the registry. Normal AMH also occurred; this finding is neither obligatory nor a direct
    measure of fetal AMH secretion.
  phenotype_term:
    preferred_term: Decreased circulating antimullerian hormone circulation
    term:
      id: HP:0031103
      label: Decreased circulating antimullerian hormone circulation
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Low | 95.7% (n = 22/23) | 48.0% (n = 12/25) | 58.1% (n = 18/31) | CGD vs PGDf .0003 CGD vs PGDm
      .002 PGDf vs PGDm ns |
    explanation: 'AMH row in Table 3: CGD, PGDf, PGDm; age-specific reference ranges and small tested subsets.'
  notes: >-
    No edge or readout link to Reduced fetal AMH activity is assigned: the cited postnatal measurement
    cannot reconstruct fetal AMH secretion or action.
- name: Decreased testicular size
  category: Reproductive
  description: Reduced testicular volume reflecting the hypoplastic tubular compartment.
  phenotype_term:
    preferred_term: Decreased testicular size
    term:
      id: HP:0008734
      label: Decreased testicular size
  evidence:
  - reference: PMID:33296094
    reference_title: >-
      NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete
      penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and
      azoospermia in P2
    explanation: Directly documents reduced testicular volume.
    quote_role: PRIMARY_RESULT
- name: Azoospermia
  category: Reproductive
  description: >-
    Azoospermia occurred in an NR5A1 family member and in a p.Arg308Gln DHX37 case. Other partial-disease
    patients had severe oligozoospermia, so absent sperm production is not assumed for every affected
    individual.
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  evidence:
  - reference: PMID:33296094
    reference_title: >-
      NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete
      penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and
      azoospermia in P2
    explanation: Directly documents azoospermia.
    quote_role: PRIMARY_RESULT
- name: Male infertility
  category: Reproductive
  description: >-
    Spermatogenic impairment can occur despite spontaneous virilization. Small cohorts document severe
    oligozoospermia and individual cases document azoospermia; individual fertility potential requires
    assessment.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:33296094
    reference_title: >-
      NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete
      penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: low bitesticular volume and azoospermia in P2
    explanation: >-
      Azoospermia with low testicular volume supports impaired fertility by inference; the report does
      not itself use the word infertility.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
- name: Hypergonadotropic hypogonadism
  category: Endocrine
  description: >-
    Elevated gonadotropins with inadequate sex-steroid production occur in some individuals. Isolated
    FSH elevation with preserved testosterone instead indicates a different pattern of gonadal dysfunction
    and should not be equated with global androgen deficiency.
  phenotype_term:
    preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  evidence:
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Hormonal evaluation indicated high levels of FSH (72.1 IU/L) and LH (13.9 IU/L), and low levels
      of total testosterone (70 ng/dL).
    explanation: >-
      Patient 2 had elevated gonadotropins and low testosterone; directly supports the combined endocrine
      phenotype.
- name: Delayed puberty
  category: Reproductive
  description: >-
    Delayed or incomplete puberty may be a presenting feature or emerge during follow-up. The proportion
    presenting with delay is not the lifetime frequency of delayed puberty.
  phenotype_term:
    preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 18% of PGDf presented with delayed puberty and 8% with virilization.
    explanation: >-
      Reports the proportion presenting with delayed puberty in the selected PGDf group, not lifetime
      prevalence.
    quote_role: PRIMARY_RESULT
- name: Hirsutism
  category: Integumentary
  description: >-
    Androgenic hair growth can accompany pubertal virilization. Its significance and management depend
    on the individual's goals; gonadal tumors are an additional possible source of hormone production.
  phenotype_term:
    preferred_term: Hirsutism
    term:
      id: HP:0001007
      label: Hirsutism
  evidence:
  - reference: PMID:38206718
    reference_title: 'NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: admitted to the hospital due to hirsutism and a deep voice
    explanation: Directly documents hirsutism from pubertal virilization.
    quote_role: PRIMARY_RESULT
- name: Gonadoblastoma
  category: Neoplasm
  description: >-
    Gonadoblastoma is documented in dysgenetic gonads, including DHH-related partial disease. In the WT1-deletion
    infant, microscopy at one month was described as suggestive rather than definitive. Combined registry
    neoplasia percentages are not a gonadoblastoma-specific frequency.
  phenotype_term:
    preferred_term: Gonadoblastoma
    term:
      id: HP:0000150
      label: Gonadoblastoma
  evidence:
  - reference: PMID:25927242
    reference_title: >-
      46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome
      Sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: At another site a gonadoblastoma with Call Exner bodies was seen.
    explanation: Direct gonadal pathology in the DHH partial-dysgenesis case.
  - reference: PMID:25613702
    reference_title: >-
      WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gonadectomy was performed at the age of 1 month and the microscopy was thought to be suggestive
      for a gonadoblastoma.
    explanation: Microscopy was suggestive of gonadoblastoma; this is not presented as a confirmed neonatal lesion.
    quote_role: PRIMARY_RESULT
- name: Dysgerminoma
  category: Neoplasm
  description: >-
    Seminomatous germ-cell tumors occur in partial gonadal dysgenesis. The registry reported dysgerminoma/seminoma
    in five affected PGDf gonads; this is a lesion count among histologically assessed neoplastic gonads,
    not disease-wide penetrance.
  phenotype_term:
    preferred_term: Dysgerminoma
    term:
      id: HP:0100621
      label: Dysgerminoma
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: '| | Germinoma + GB 1 (2.4%) | Dysgerminoma/seminoma 5 (21.7%) | Gonadoblastoma 1 (33%) | |'
    explanation: Table 6 groups are CGD, PGDf and PGDm; the PGDf column provides direct partial-disease evidence.
- name: Steroid-resistant nephrotic syndrome
  category: Renal
  subtype: WT1-related PGD
  description: >-
    A major manifestation of WT1 disorder. In a patient with partial gonadal dysgenesis, a pathogenic
    WT1 variant warrants renal evaluation and surveillance even before proteinuria appears.
  phenotype_term:
    preferred_term: Steroid-resistant nephrotic syndrome
    term:
      id: HP:0012588
      label: Steroid-resistant nephrotic syndrome
  evidence:
  - reference: PMID:32352694
    reference_title: WT1 Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      WT1 disorder is characterized by congenital/infantile or childhood onset of steroid-resistant nephrotic
      syndrome (SRNS), a progressive glomerulopathy that does not respond to standard steroid therapy.
    explanation: Directly documents SRNS as the defining renal feature of WT1 disorder.
    quote_role: REVIEW_SYNTHESIS
- name: Nephroblastoma
  category: Neoplasm
  subtype: WT1-related PGD
  description: >-
    Wilms tumor is a genotype-qualified risk in WT1-related disease. Bilateral Wilms tumor at nine months
    was reported in a child with WT1 deletion and severe partial gonadal dysgenesis.
  phenotype_term:
    preferred_term: Nephroblastoma
    term:
      id: HP:0002667
      label: Nephroblastoma
  evidence:
  - reference: PMID:25613702
    reference_title: >-
      WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the age of 9 months, the patient presented with a bilateral Wilms tumor.
    explanation: Directly documents Wilms tumor in WT1-related partial gonadal dysgenesis.
    quote_role: PRIMARY_RESULT
- name: Peripheral neuropathy
  category: Neurologic
  subtype: DHH-related PGD
  description: >-
    Peripheral neuropathy is reported with biallelic DHH-related disease. Minifascicular nerve pathology
    was demonstrated in the original case; two later p.Arg124Gln cases developed a mixed axonal and demyelinating
    neuropathy, including adult-onset symptoms.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:11017805
    reference_title: >-
      A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied
      by minifascicular neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe a patient with 46,XY partial gonadal dysgenesis (PGD) who presented with polyneuropathy.
    explanation: Directly documents polyneuropathy in the DHH subtype.
    quote_role: PRIMARY_RESULT
- name: Primary amenorrhea
  category: Reproductive
  phenotype_term:
    preferred_term: Primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  description: >-
    Primary amenorrhea can lead to adolescent recognition of partial gonadal dysgenesis, including a patient
    with a pathogenic NR5A1 truncation and a co-occurring uncertain DHX37 variant.
  evidence:
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      At the age of 17, patient 2 presented with primary amenorrhea, spontaneous pubarche and no thelarche.
    explanation: Patient 2 provides a direct partial-disease presentation.
  notes: >-
    No single incoming edge is assigned because amenorrhea can reflect different combinations of Müllerian
    anatomy and postnatal gonadal hormone function. The existing fetal hormone nodes do not measure those
    later physiological causes in the cited individual.
- name: Deep voice
  category: Head and neck
  phenotype_term:
    preferred_term: Abnormally low-pitched voice
    term:
      id: HP:0010300
      label: Abnormally low-pitched voice
  description: Voice deepening accompanied pubertal virilization in the reported NR5A1 partial-dysgenesis case.
  evidence:
  - reference: PMID:38206718
    reference_title: 'NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: admitted to the hospital due to hirsutism and a deep voice
    explanation: Direct case observation.
  notes: >-
    The observation concerns pubertal virilization. It is not a consequence of the existing reduced fetal
    androgen activity node; an incoming edge would require a separately supported postnatal androgen-production
    mechanism.
- name: Oligozoospermia
  category: Reproductive
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  description: >-
    All three participants who underwent semen testing in a ten-patient long-term PGD series had severe
    oligozoospermia and low motility. The tested subset does not establish population frequency.
  evidence:
  - reference: PMID:25580123
    reference_title: Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Three patients had a sperm count; all had severe oligozoospermia and low motility, and two had also
      abnormal semen viscosity.
    explanation: Three tested participants; no extrapolation to the full cohort.
biochemical:
- name: Follicle-stimulating hormone
  presence: INCREASED
  context: >-
    FSH elevation may indicate impaired Sertoli/tubular feedback despite preserved testosterone. Interpretation
    depends on developmental stage and the assay. The registry reported elevated FSH at age 0-6 months
    in 19/28 PGDf and 22/34 PGDm; normal values also occurred.
  biomarker_term:
    preferred_term: Follicle stimulating hormone
    term:
      id: CHEBI:81569
      label: Follicle stimulating hormone
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | FSH elevated: 0-6 mo a | 100% (n = 6/6) | 67.9% (n = 19/28) | 64.7% (n = 22/34) | CGD vs PGDf
      ns CGD vs PGDm ns PGDf vs PGDm ns |
    explanation: Age- and group-specific FSH measurements; not a uniform finding.
  readouts:
  - target: Incomplete testicular differentiation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated FSH may reflect the tubular/Sertoli component of current gonadal dysfunction; it is not
      a direct measure of androgen deficiency.
    evidence:
    - reference: PMID:40208111
      reference_title: >-
        Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        | FSH elevated: 0-6 mo a | 100% (n = 6/6) | 67.9% (n = 19/28) | 64.7% (n = 22/34) | CGD vs PGDf
        ns CGD vs PGDm ns PGDf vs PGDm ns |
      explanation: Age- and group-specific FSH measurements; not a uniform finding.
- name: Testosterone response to hCG stimulation
  presence: ABNORMAL
  context: >-
    The hCG test assesses residual testosterone production. A greater than twofold rise was observed in
    15/17 participants with spontaneous puberty versus 1/3 with induced puberty, P=.087, in the small
    tested registry subset. This nonsignificant association is not a validated prediction rule or treatment
    threshold. A response does not localize function to one or both gonads.
  biomarker_term:
    preferred_term: testosterone
    term:
      id: CHEBI:17347
      label: testosterone
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Also, a higher proportion of individuals in the spontaneous puberty group had a testosterone response
      to hCG more than double the basal level (88%; n = 15/17, vs 33%; n = 1/3, P = .087).
    explanation: The full-text counts and P=.087 qualify the stronger abstract wording; not validated prediction.
  readouts:
  - target: Incomplete testicular differentiation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A blunted hCG testosterone response may support impaired gonadal function in context; an adequate
      response does not exclude PGD or validate a puberty forecast.
    evidence:
    - reference: PMID:40208111
      reference_title: >-
        Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        testosterone levels after human chorionic gonadotropin (hCG) stimulation test less than twice
        the basal value
      explanation: One study diagnostic criterion, not a universally validated cutoff.
- name: Anti-Müllerian hormone
  presence: DECREASED
  context: >-
    AMH provides an age- and assay-dependent assessment of current Sertoli-cell function. It was low in
    12/25 PGDf and 18/31 PGDm in the registry, with normal values in the remaining measured individuals.
    Postnatal serum AMH does not directly measure fetal exposure and is not a stand-alone partial-versus-complete
    discriminator.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Low | 95.7% (n = 22/23) | 48.0% (n = 12/25) | 58.1% (n = 18/31) | CGD vs PGDf .0003 CGD vs PGDm
      .002 PGDf vs PGDm ns |
    explanation: 'AMH row in Table 3: CGD, PGDf, PGDm; age-specific reference ranges and small tested subsets.'
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      For AMH analysis, each institution used either ELISA or chemiluminescence immunoassay and the age-specific
      male reference was used for assessment (Beckman Coulter Cat# A73818, RRID:AB_3674123; Beckman Coulter
      Cat# B13127, RRID:AB_2892998; Roche Cat# 06331076, RRID:AB_2895131).
    explanation: Specifies assay and age-dependent interpretation.
- name: Inhibin B
  presence: DECREASED
  context: >-
    Inhibin B was low in 8/12 PGDf and 9/13 PGDm individuals with measurements. It complements AMH and
    gonadotropins in assessing current testicular function. These data do not establish a disease-specific
    cutoff or prove that inhibin B separates all DSD categories.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Low | 100% (n = 20/20) | 66.7% (n = 8/12) | 69.2% (n = 9/13) | CGD vs PGDf .014 CGD vs PGDm .016
      PGDf vs PGDm ns |
    explanation: 'Inhibin B row in Table 3: CGD, PGDf, PGDm; limited tested subsets.'
genetic:
- name: NR5A1
  gene_term:
    preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  association: Heterozygous pathogenic variants causing variable partial gonadal dysgenesis
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:27463801
    reference_title: >-
      NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three
      Novel Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3 novel NR5A1 mutations were identified in 3 patients with 46,XY partial gonadal dysgenesis: p.Lys38*
      and p.Leu80Trpfs*8 lead to premature translation termination codons within the SF1 DNA-binding domain
    explanation: Directly documents loss-of-function NR5A1 variants in partial disease.
    quote_role: PRIMARY_RESULT
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: with common gene defects in SRY and WT1 in CGD and NR5A1 in PGD.
    explanation: Establishes NR5A1 as the characteristic partial-disease gene.
    quote_role: PRIMARY_RESULT
  - reference: url:https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf
    reference_title: https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Segregation analysis across three generations showed incomplete penetrance (<50%) and phenotypic
      variability among the carriers of NR5A1 c.991-1G>C.
    explanation: Family-specific penetrance, not a general NR5A1 penetrance estimate.
  notes: >-
    Reported variants include early truncations p.Lys38* and p.Leu80Trpfs*8, missense alleles and c.991-1G>C.
    The latter segregated with incomplete penetrance in one extended family; the reported <50% is family-
    and allele-specific, not a general counseling estimate. Its splice effect was predicted, not measured
    in patient RNA. NR5A1-related DSD may rarely accompany adrenal insufficiency; relatives with a 46,XX
    complement can have primary ovarian insufficiency.
- name: OTX2
  gene_term:
    preferred_term: OTX2
    term:
      id: hgnc:8522
      label: OTX2
  association: Proposed, unconfirmed modifier of NR5A1-associated phenotype
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  notes: >-
    Co-inheritance and computational oligogenic predictions support a hypothesis, not a demonstrated modifier
    effect. These observations do not establish digenic causation or a recurrence rule.
  evidence:
  - reference: url:https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf
    reference_title: https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The variant pathogenicity was possibly modulated by rare heterozygous variants inherited from the
      other parent, OTX2 p.P134R (P1) or PROP1 c.301_302delAG (P2).
    explanation: The source itself calls the modifier effect possible; family observation.
- name: PROP1
  gene_term:
    preferred_term: PROP1
    term:
      id: hgnc:9455
      label: PROP1
  association: Proposed, unconfirmed modifier of NR5A1-associated phenotype
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  notes: >-
    Co-inheritance and computational oligogenic predictions support a hypothesis, not a demonstrated modifier
    effect. These observations do not establish digenic causation or a recurrence rule.
  evidence:
  - reference: url:https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf
    reference_title: https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The variant pathogenicity was possibly modulated by rare heterozygous variants inherited from the
      other parent, OTX2 p.P134R (P1) or PROP1 c.301_302delAG (P2).
    explanation: The source itself calls the modifier effect possible; family observation.
- name: MAP3K1
  gene_term:
    preferred_term: MAP3K1
    term:
      id: hgnc:6848
      label: MAP3K1
  association: Causal heterozygous sex-limited gain-of-function variant
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:35290982
    reference_title: 'Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and
      complete gonadal dysgenesis
    explanation: Directly includes partial disease in the MAP3K1 spectrum.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21129722
    reference_title: >-
      Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
      pathway in human testis determination.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate
      this pathway in normal human sex determination.
    explanation: Directly names partial gonadal dysgenesis as a MAP3K1 outcome.
    quote_role: PRIMARY_RESULT
- name: WT1
  gene_term:
    preferred_term: WT1
    term:
      id: hgnc:12796
      label: WT1
  association: >-
    Causal heterozygous variant producing syndromic gonadal dysgenesis with steroid-resistant nephrotic
    syndrome and Wilms tumor predisposition
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Variant type affects the distribution and timing of renal, gonadal and tumor findings, but a deletion
    does not guarantee mild disease. The deletion infant had severe partial dysgenesis; gonadal microscopy
    was suggestive of gonadoblastoma and bilateral Wilms tumor was diagnosed at nine months.
  evidence:
  - reference: PMID:25613702
    reference_title: >-
      WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We found a heterozygous WT1 whole-gene deletion but no other gene defects.
    explanation: Directly documents a causal heterozygous WT1 lesion in partial disease.
    quote_role: PRIMARY_RESULT
  - reference: PMID:25613702
    reference_title: >-
      WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      This case description illustrates that a WT1 deletion might be associated with a more severe phenotype
      than previously thought.
    explanation: >-
      Clinical counterexample to a simple deletion-equals-mild rule, supporting variability rather than
      refuting the gene association.
- name: DHX37
  gene_term:
    preferred_term: DHX37
    term:
      id: hgnc:17210
      label: DHX37
  association: >-
    Heterozygous variants associated with partial gonadal dysgenesis and testicular regression, including
    recurrent p.Arg308Gln
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In DHX37, the variant p.(Arg308Gln), recurrent associated with DSD, was identified in one patient
    explanation: Directly documents the recurrent DHX37 allele in a partial-disease cohort.
    quote_role: PRIMARY_RESULT
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Secondly, patient 3 also carries a loss-of-function variant in NR5A1, which could fully explain
      the PGD phenotype, making the p.Val999Met variant a chance finding.
    explanation: Authors explicitly acknowledge NR5A1 sufficiency and a possible chance DHX37 finding.
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | 2 | DHX37 | c.1399C>G/ p.Leu467Val | rs149331610 | 0.0002952 1 /38 | VUS | 22.2 | Disease causing
      | Probably damaging | Deleterious | Maternal |
    explanation: Table 2 classification is uncertain despite damaging prediction scores.
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | 3 | DHX37 | c.2995G>A/ p.Val999Met | rs148710712 | 0.002316 2 /54 | Likely Benign | 24.8 | Disease
      causing | Probably damaging | Deleterious | Paternal |
    explanation: >-
      Table 2 classifies Val999Met as likely benign; do not convert in-silico predictions into proven
      causality.
  notes: >-
    The 2023 dual-variant cases carried pathogenic NR5A1 variants with DHX37 p.Leu467Val classified as
    VUS or p.Val999Met classified as likely benign in Table 2. NR5A1 could explain their phenotypes; digenic
    causation remains unproven. For p.Arg308Gln, the original structural study predicted altered RNA interaction
    rather than measuring ATPase activity. Later overexpression assays found reduced protein abundance
    for selected variants, without demonstrating defective ribosome output.
- name: DHH
  gene_term:
    preferred_term: DHH
    term:
      id: hgnc:2865
      label: DHH
  association: >-
    Biallelic variants associated with partial or complete gonadal dysgenesis and possible peripheral
    neuropathy
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:11017805
    reference_title: >-
      A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied
      by minifascicular neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a homozygous missense mutation (ATG-->ACG) at the initiating codon in exon 1 of the desert hedgehog
      (DHH) gene, which predicts a failure of translation of the gene.
    explanation: Directly documents a causal biallelic DHH lesion in partial disease.
    quote_role: PRIMARY_RESULT
  - reference: PMID:25927242
    reference_title: >-
      46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome
      Sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The gonads of one patient showed partial gonadal dysgenesis with loss of Leydig cells in tubular
      areas with seminoma in situ and a hyperplasia of Leydig cell-like cells expressing CYP17A1 in more
      dysgenetic parts of the gonad.
    explanation: Direct partial phenotype and Leydig-cell finding.
  notes: >-
    The initiating-codon variant was predicted to impair translation. Homozygous p.Arg124Gln was identified
    in two affected sisters; structural modeling predicted altered interaction with several signaling
    partners, without a direct ligand-function assay. In one sister, partial dysgenesis with loss of mature
    Leydig-cell staining was documented.
- name: ZFPM2
  gene_term:
    preferred_term: ZFPM2
    term:
      id: hgnc:16700
      label: ZFPM2
  association: Candidate association requiring variant-specific reassessment
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  notes: >-
    The initial report included a partial-dysgenesis patient with p.Met544Ile homozygosity and heterozygous
    p.Arg260Gln, and a complete-dysgenesis patient with p.Ser402Arg. Later work classified p.Met544Ile
    as benign and found normal activity for the tested ZFPM2 variants. This does not refute all possible
    ZFPM2 involvement, but does not justify a confirmed causal PGD subtype.
  evidence:
  - reference: PMID:24549039
    reference_title: Mutations in the FOG2/ZFPM2 gene are associated with anomalies of human testis determination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the failure of testis development in these cases could be explained by the impaired ability of the
      mutant FOG2 proteins to interact with a known regulator of early testis development, GATA4.
    explanation: >-
      The original small-case functional result supports candidate involvement. The later paper identifies
      which original alleles belonged to the partial case and weakens the interpretation of p.Met544Ile.
    quote_role: PRIMARY_RESULT
  - reference: PMID:31962012
    reference_title: >-
      Analysis of variants in GATA4 and FOG2/ZFPM2 demonstrates benign contribution to 46,XY disorders
      of sex development.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Reclassification of the ten ZFPM2 variants revealed six missense were considered benign or likely
      benign (p.E30G, p.D98N, p.S210T, p.L335V, p.M544I, p.M703L).
    explanation: Later variant-specific functional reassessment.
environmental: []
histopathology:
- name: Dysgenetic testis with hypoplastic seminiferous tubules
  description: >-
    Partial disease can include dysgenetic testes, streak tissue or regressed gonads. Observed testicular
    abnormalities include reduced tubular diameter, thick basement membranes, irregular tubules, interstitial
    fibrosis, Sertoli-cell-only tubules and reduced germ cells. Histology contributes to diagnosis and
    neoplasia assessment but does not by itself classify every partial versus complete case; small biopsies
    can miss heterogeneous tissue.
  diagnostic: true
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Features of dysgenetic testis noted were reduced tubular diameter, thickened basal membrane, increased
      interstitial stroma, intracapsular growth, irregular shaped tubules, Leydig cell micronodules or
      hyperplasia, Sertoli cell only tubules, reduced germ cell number, absent spermatogenesis, and tubular
      atrophy (Fig.
    explanation: Direct expert histological review of the registry material.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Results may be inaccurate because of biopsy sampling error; gonadal biopsy may harm the future growth
      and development of the gonad.
    explanation: Broader testicular-development guidance warns about sampling and potential harm.
- name: Gonadoblastoma and germ cell neoplasia in situ in dysgenetic gonads
  description: >-
    Gonadoblastoma and germ cell neoplasia in situ are distinct lesions reported in partial gonadal dysgenesis.
    DHH-related partial disease included GCNIS with incipient stromal invasion and gonadoblastoma. These
    are pathological findings, not an obligatory sequential progression in every gonad.
  diagnostic: false
  evidence:
  - reference: PMID:25927242
    reference_title: >-
      46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome
      Sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: At another site a gonadoblastoma with Call Exner bodies was seen.
    explanation: Direct DHH-case pathology.
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The common types of tumors in all 3 groups were gonadoblastoma (47.8%, n = 32/67), dysgerminoma/seminoma
      (28.4%, n = 19/67), and germ cell neoplasia in situ (11.9%, n = 8/67).
    explanation: Lists the lesion classes across the GD cohort; subgroup counts are in Table 6.
imaging_findings:
- name: Variable or absent Müllerian structures
  modality: MRI
  diagnostic: false
  description: >-
    Ultrasound and, when needed, MRI characterize Müllerian anatomy and gonadal position. A small unestrogenized
    uterus can be missed; discordant imaging requires clinical interpretation. In the cited NR5A1 case,
    ultrasound suggested a primordial uterus while MRI reported absence, so this case does not establish
    definite uterine retention.
  evidence:
  - reference: PMID:38206718
    reference_title: 'NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pelvic magnetic resonance imaging showed absence of uterus and ovaries.
    explanation: >-
      In this partial case MRI reported no uterus while ultrasound in the same workup reported a probable
      primordial uterus, so modalities can disagree on small Müllerian remnants and a single negative
      study should not be read as proof of regression.
    quote_role: PRIMARY_RESULT
  - reference: PMID:38206718
    reference_title: 'NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hypoechoic mass (considered primordial uterus) in posterior bladder
    explanation: >-
      Ultrasound suggested a primordial uterus, while MRI in the same case reported absence. This is suspected,
      discordant anatomy rather than confirmed uterine retention.
    quote_role: PRIMARY_RESULT
  - reference: PMID:35353710
    reference_title: >-
      Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary
      or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Ultrasound or MRI should be performed to identify a uterus or Müllerian structures; however, a small
      uterus before oestrogen exposure may be missed by imagery.
    explanation: Guideline limitation relevant to anatomy assessment.
- name: Inguinal or intra-abdominal dysgenetic gonads
  modality: ULTRASOUND
  diagnostic: false
  description: >-
    Gonads may be inguinal or intra-abdominal. Localization informs clinical and surgical planning, but
    imaging alone does not establish functional capacity or exclude neoplasia. The registry association
    between labioscrotal location and spontaneous puberty does not demonstrate that repositioning prevents
    tumors.
  evidence:
  - reference: PMID:38206718
    reference_title: 'NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The abdominopelvic ultrasound revealed bilateral testicle in bilateral groin.
    explanation: Directly documents inguinal gonads on ultrasound.
    quote_role: PRIMARY_RESULT
diagnosis:
- name: Integrated clinical, endocrine, and karyotypic assessment
  description: >-
    Integrate genital anatomy, gonadal palpability, family history, associated renal or neurological findings,
    karyotype, and age-appropriate endocrine testing. Assess FSH, LH, testosterone, AMH and often inhibin
    B in clinical context. A blood 46,XY result distinguishes many chromosomal diagnoses but cannot exclude
    low-level or gonad-confined mosaicism.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: Atypical genitalia with a 46,XY karyotype and biochemical evidence of partial gonadal function.
  evidence:
  - reference: PMID:36424806
    reference_title: 'Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: We recommend formal Karyotyping, even if Y chromosome material has been detected by other methods.
    explanation: Supports formal karyotyping as part of the 46,XY DSD workup.
    quote_role: REVIEW_SYNTHESIS
- name: hCG stimulation test for residual Leydig-cell function
  description: >-
    hCG stimulation assesses residual testicular testosterone production and can complement the steroid
    profile. It is not a validated stand-alone predictor of spontaneous puberty: the small registry subgroup
    association had P=.087. Endocrine testing cannot identify which gonad functions or determine whether
    both do.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: A preserved testosterone rise indicates functionally significant residual testicular tissue.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Also, a higher proportion of individuals in the spontaneous puberty group had a testosterone response
      to hCG more than double the basal level (88%; n = 15/17, vs 33%; n = 1/3, P = .087).
    explanation: The full-text counts and P=.087 qualify the stronger abstract wording; not validated prediction.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Hormonal evaluation cannot distinguish between one versus two functioning gonads.
    explanation: Anatomical limitation of systemic hormone measurements.
- name: Abdominopelvic imaging for gonadal position and Müllerian anatomy
  description: >-
    Ultrasound and, when needed, MRI characterize Müllerian anatomy and gonadal position. A small unestrogenized
    uterus can be missed; discordant imaging requires clinical interpretation. In the cited NR5A1 case,
    ultrasound suggested a primordial uterus while MRI reported absence, so this case does not establish
    definite uterine retention.
  diagnosis_term:
    preferred_term: Ultrasound
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  evidence:
  - reference: PMID:38206718
    reference_title: 'NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pelvic magnetic resonance imaging showed absence of uterus and ovaries.
    explanation: >-
      In this partial case MRI reported no uterus while ultrasound in the same workup reported a probable
      primordial uterus, so modalities can disagree on small Müllerian remnants and a single negative
      study should not be read as proof of regression.
    quote_role: PRIMARY_RESULT
  - reference: PMID:38206718
    reference_title: 'NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hypoechoic mass (considered primordial uterus) in posterior bladder
    explanation: >-
      Ultrasound suggested a primordial uterus, while MRI in the same case reported absence. This is suspected,
      discordant anatomy rather than confirmed uterine retention.
    quote_role: PRIMARY_RESULT
  - reference: PMID:35353710
    reference_title: >-
      Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary
      or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Ultrasound or MRI should be performed to identify a uterus or Müllerian structures; however, a small
      uterus before oestrogen exposure may be missed by imagery.
    explanation: Guideline limitation relevant to anatomy assessment.
- name: Broad molecular testing including WT1
  description: >-
    Select molecular testing according to phenotype and family history, using chromosome/CNV assessment,
    a DSD panel, or exome/genome analysis as appropriate. Include clinically relevant genes such as NR5A1,
    MAP3K1, WT1, DHH and DHX37. A pathogenic WT1 finding changes renal and tumor surveillance. A negative
    test does not exclude PGD, and a VUS does not establish a molecular diagnosis. Historical registry
    yield varied by testing method and subgroup.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:25613702
    reference_title: >-
      WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      even in the absence of renal abnormality, it is recommended to test promptly for WT1 defects in
      46,XY gonadal dysgenesis.
    explanation: Directly supports prompt WT1 testing regardless of renal findings.
    quote_role: PRIMARY_RESULT
  - reference: PMID:36424806
    reference_title: 'Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genetic studies, which include copy number variation (CNV) or molecular testing of a candidate gene
      or next generation sequencing then should be ordered in a stepwise manner
    explanation: Supports the stepwise molecular strategy.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:32352694
    reference_title: WT1 Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of WT1 disorder is established in a proband with suggestive clinical findings and
      a heterozygous pathogenic variant in WT1 identified by molecular genetic testing.
    explanation: >-
      Supplies the GeneReviews diagnostic criterion for the WT1 subtype: molecular confirmation, not clinical
      impression, establishes it.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Genetic screening was performed in 78.7% of the cohort with various methods; targeted gene screening
      (71%), gene panels (13%), and whole exome sequencing (15%).
    explanation: Documents heterogeneous methods rather than a mandatory sequential algorithm.
- name: Selective gonadal histopathology and neoplasia assessment
  description: >-
    When gonadal tissue is obtained for a justified clinical indication, expert pathology can characterize
    dysgenesis, germ-cell maturation and neoplasia. Biopsy is subject to sampling error and potential
    harm. Gonadectomy or whole-gonad histology is not required in every patient solely to establish the
    partial phenotype.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Features of dysgenetic testis noted were reduced tubular diameter, thickened basal membrane, increased
      interstitial stroma, intracapsular growth, irregular shaped tubules, Leydig cell micronodules or
      hyperplasia, Sertoli cell only tubules, reduced germ cell number, absent spermatogenesis, and tubular
      atrophy (Fig.
    explanation: Direct expert histological review of the registry material.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Results may be inaccurate because of biopsy sampling error; gonadal biopsy may harm the future growth
      and development of the gonad.
    explanation: Broader testicular-development guidance warns about sampling and potential harm.
differential_diagnoses:
- name: 46,XY complete gonadal dysgenesis
  description: >-
    Typical complete gonadal dysgenesis presents with female external genitalia, Müllerian structures
    and gonadal failure. Streak gonads are common, but dysgenetic testicular tissue can also occur. Partial
    disease shows more variable anatomy and residual function. Classification integrates phenotype, hormones,
    histology and genetics; tumors can themselves produce sex steroids in either group.
  disease_term:
    preferred_term: 46,XY complete gonadal dysgenesis
    term:
      id: MONDO:0010765
      label: 46,XY complete gonadal dysgenesis
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Gonadal pre-/malignancy was found in 33.8% in CGD, 19.7% in PGDf, and 8.8% in PGDm.
    explanation: A single cohort scoring both entities documents the tumor-risk gradient that separates them.
    quote_role: PRIMARY_RESULT
  - reference: PMID:28504475
    reference_title: 'MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of these individuals presented with complete gonadal dysgenesis, characterized by bilateral
      streak gonads with typical internal and external female genitalia, while the other three presented
      with partial gonadal dysgenesis, characterized by incomplete testicular development
    explanation: >-
      Directly contrasts the two phenotypes within one gene's spectrum — the cleanest available statement
      of the distinction.
    quote_role: PRIMARY_RESULT
- name: 45,X/46,XY mixed gonadal dysgenesis
  description: >-
    45,X/46,XY mosaicism can resemble 46,XY partial gonadal dysgenesis. Gonadal asymmetry does not distinguish
    them, because a dysgenetic testis and contralateral streak tissue can also occur in 46,XY PGD. Adequate
    chromosome assessment is required, while low-level or tissue-confined mosaicism may escape a blood
    test.
  evidence:
  - reference: PMID:34070473
    reference_title: >-
      Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series
      and Review of the Literature.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: sex chromosome DSD (Klinefelter or Turner Syndrome, chimerism), XX-DSD, and 46 XY-DSD
    explanation: >-
      Supports separation of sex-chromosome DSD from 46,XY DSD; the asymmetric gonadal detail is clinical
      synthesis.
    quote_role: REVIEW_SYNTHESIS
- name: Partial androgen insensitivity syndrome
  description: >-
    Androgen insensitivity can produce overlapping external genital findings despite testicular differentiation
    and androgen production. AMH, testosterone and hCG responses may overlap with other DSD diagnoses,
    so no single normal hormone result excludes PGD or proves PAIS. Molecular findings and the overall
    anatomical/endocrine pattern guide differentiation.
  evidence:
  - reference: PMID:31745530
    reference_title: >-
      Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults
      With 46,XY DSD.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      partially virilized 46,XY DSD (pvDSD) (n = 25), a group that included partial gonadal dysgenesis
      and those with a broad "partial androgen insensitivity syndrome" label.
    explanation: >-
      Directly documents the clinical conflation of partial gonadal dysgenesis with PAIS, motivating molecular
      resolution.
    quote_role: PRIMARY_RESULT
- name: 46,XY androgen synthesis disorders
  description: >-
    Steroid synthesis or metabolism defects, including 17-beta-hydroxysteroid dehydrogenase 3 and 5-alpha-reductase
    2 deficiencies, can impair virilization despite testicular differentiation. Steroid profiles, selected
    stimulation testing and molecular results help distinguish these from gonadal dysgenesis; preserved
    AMH alone is not a definitive discriminator.
  evidence:
  - reference: PMID:34070473
    reference_title: >-
      Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series
      and Review of the Literature.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 46 XY-DSD (disorders of testicular development and disorders of androgen synthesis or action)
    explanation: Supports the mechanistic distinction within 46,XY DSD.
    quote_role: REVIEW_SYNTHESIS
- name: Ovotesticular disorder of sex development
  description: >-
    Ovotesticular DSD is defined by ovarian follicular and testicular tissue in the same individual. Histology
    can identify these components when tissue is clinically obtained, but sampling can miss heterogeneous
    tissue. This distinction does not justify routine whole-gonad removal solely for diagnosis.
  evidence:
  - reference: PMID:38206718
    reference_title: 'NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: primary ovarian insufficiency and ovotesticular DSD in 46, XX individuals.
    explanation: >-
      Establishes ovotesticular DSD as a distinct entity within the same gene's phenotypic spectrum; the
      histological criterion is clinical synthesis.
    quote_role: PRIMARY_RESULT
- name: Testicular regression syndrome
  description: >-
    Testicular regression reflects loss of previously differentiated testicular tissue rather than failure
    to differentiate it. The distinction can be genuinely difficult, and DHX37 variants are found in both
    cohorts, so the two are best regarded as adjacent points on a spectrum of testis-development failure.
  evidence:
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: including complete and partial GD (PGD) and testicular regression syndrome (TRS)
    explanation: >-
      Places testicular regression syndrome alongside partial dysgenesis in the same disease group with
      shared genetic causes.
    quote_role: PRIMARY_RESULT
treatments:
- name: Individualized gonadal management (retention versus gonadectomy)
  action_category: THERAPEUTIC
  description: >-
    Discuss gonadal function, genotype, tissue location, available pathology, age, fertility potential
    and the individual's goals with an experienced DSD team. Nonfunctional high-risk dysgenetic gonads
    may warrant removal; potentially functional gonads may be retained after individualized discussion.
    Sex assignment and a preserved hCG response are not stand-alone indications for removal or retention.
    Surveillance options exist, but no strategy reliably excludes neoplasia; the registry percentages
    are selected histology prevalences rather than prospective risks for retained gonads.
  treatment_term:
    preferred_term: orchiectomy
    term:
      id: NCIT:C15288
      label: Orchiectomy
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Gonadoblastoma
    term:
      id: HP:0000150
      label: Gonadoblastoma
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Streak gonads and dysgenetic gonads are at increased risk for the development of gonadoblastoma
      and should be surgically removed if nonfunctional.
    explanation: Broader DSD guidance scopes removal to nonfunctional at-risk gonads.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Depending on the specific diagnosis, potentially functional gonads may be retained with appropriate
      surveillance for tumor development.
    explanation: Broader DSD guidance supports individualized retention.
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      However, there was significant variation in monitoring practice amongst centers and only one third
      (n = 34/92) of individuals with PGDm had histology assessment.
    explanation: Limits tumor-risk inference and supports specialist follow-up.
  target_mechanisms:
  - target: Gonadoblastoma
    treatment_effect: INHIBITS
    description: Removal of nonfunctional at-risk gonads may prevent gonadoblastoma; decisions remain individualized.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
      reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Streak gonads and dysgenetic gonads are at increased risk for the development of gonadoblastoma
        and should be surgically removed if nonfunctional.
      explanation: Broader DSD guidance scopes removal to nonfunctional at-risk gonads.
- name: Individualized sex-steroid replacement
  action_category: THERAPEUTIC
  description: >-
    Replace sex steroids when gonadal production is insufficient or after gonadectomy, according to the
    individual's desired pubertal development and clinical needs. Testosterone or 17-beta-estradiol is
    introduced gradually with monitoring; an endometrium-bearing uterus requires addition of progestogen
    after appropriate estrogen priming. Spontaneous pubertal onset does not guarantee completion. Endo-ERN
    guidance supports individualized induction around age 11 for girls with confirmed hypogonadism and
    around age 12 for boys at high risk without pubertal onset. These recommendations cover broader congenital
    hypogonadism; the guideline found no eligible comparative puberty-treatment studies specifically in
    males with PGD.
  treatment_term:
    preferred_term: Hormone Replacement Therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: 17beta-estradiol
      term:
        id: CHEBI:16469
        label: 17beta-estradiol
    - preferred_term: testosterone
      term:
        id: CHEBI:17347
        label: testosterone
  target_phenotypes:
  - preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  - preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  evidence:
  - reference: PMID:35353710
    reference_title: >-
      Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary
      or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: We recommend to use 17β-oestradiol for puberty induction or to sustain puberty in girls
    explanation: General congenital hypogonadism recommendation, applied with individualized DSD assessment.
  - reference: PMID:35353710
    reference_title: >-
      Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary
      or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: We recommend that pubertal induction in boys with hypogonadism should be performed with testosterone
    explanation: General hypogonadism recommendation rather than a PGD-specific trial.
  - reference: PMID:35353710
    reference_title: >-
      Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary
      or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      If a uterus is present, progesterone must be added at some point because of the risk of endometrial
      cancer associated with long-term unopposed oestrogen
    explanation: Explains the uterus-dependent progestogen component.
  - reference: PMID:35353710
    reference_title: >-
      Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary
      or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      We found no studies on treatment to induce or sustain puberty in male patients with partial gonadal
      dysgenesis.
    explanation: Explicit evidence limitation from the guideline systematic review.
  target_mechanisms:
  - target: Hypergonadotropic hypogonadism
    treatment_effect: BYPASSES
    description: >-
      Sex-steroid replacement addresses inadequate hormone production; it does not reverse the developmental
      lesion.
    evidence:
    - reference: PMID:35353710
      reference_title: >-
        Pubertal induction and transition to adult sex hormone replacement in patients with congenital
        pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: We recommend to use 17β-oestradiol for puberty induction or to sustain puberty in girls
      explanation: General congenital hypogonadism recommendation, applied with individualized DSD assessment.
    - reference: PMID:35353710
      reference_title: >-
        Pubertal induction and transition to adult sex hormone replacement in patients with congenital
        pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: We recommend that pubertal induction in boys with hypogonadism should be performed with testosterone
      explanation: General hypogonadism recommendation rather than a PGD-specific trial.
- name: Genital reconstructive surgery
  action_category: THERAPEUTIC
  description: >-
    Consider hypospadias repair, orchiopexy or other genital procedures for individualized functional
    goals after multidisciplinary discussion with the patient and family. Decisions should consider timing,
    potential adverse effects, fertility and future autonomy. Moving a functional gonad into the scrotum
    can facilitate examination; it has not been shown here to eliminate tumor risk. GeneReviews notes
    no controlled comparisons of surgical techniques and no consensus on timing.
  treatment_term:
    preferred_term: orchiopexy
    term:
      id: NCIT:C111066
      label: Orchiopexy
  therapeutic_modality: SURGERY
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: surgical options may include hypospadias repair, orchiopexy, scrotoplasty, and phalloplasty.
    explanation: Lists options in broader testicular-development disorders rather than mandatory procedures.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: There is no consensus on the appropriate timing of the surgical procedures listed.
    explanation: Defines the limitation on timing recommendations.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      If a dysgenetic gonad is located in the inguinal canal, it may be placed into the scrotum if results
      indicate some testicular function.
    explanation: Function-dependent option; surveillance remains necessary.
- name: Renal surveillance and Wilms tumor monitoring
  action_category: MONITORING
  description: >-
    For pathogenic WT1-related disease, follow GeneReviews surveillance for proteinuria every six months
    until age ten and annually thereafter, and abdominal ultrasound for Wilms tumor every three months
    until age seven. Follow established renal disease with nephrology. Consider renin-angiotensin system
    inhibition for proteinuria; immunosuppression is ineffective and potentially toxic in WT1-associated
    glomerulopathy. Gonadal management and pubertal monitoring remain coordinated with the DSD team.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK556455/
    reference_title: WT1 Disorder - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Monitor for first appearance of the following: proteinuria every six months until age ten years,
      yearly thereafter; Wilms tumor every three months until age seven years; early gonadal insufficiency
      yearly after puberty.
    explanation: Genotype-specific surveillance from the complete GeneReviews chapter.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK556455/
    reference_title: WT1 Disorder - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Avoid immunosuppressants, which are ineffective &#x00026; potentially toxic.
    explanation: Applies specifically to WT1-associated glomerulopathy.
- name: Long-term endocrine, growth, and developmental follow-up
  action_category: MONITORING
  description: >-
    Continue endocrine review through puberty and adulthood, including clinical pubertal progression and
    age-appropriate gonadotropins and sex steroids. During induction, guideline follow-up is generally
    every three to six months, with assessment of growth, skeletal maturation, treatment response and
    adverse effects. Spontaneous onset or normal growth in a small series does not guarantee lasting gonadal
    function. Address learning or developmental concerns when present without treating a small-cohort
    observation as a universal PGD feature.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:35353710
    reference_title: >-
      Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary
      or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Regular clinical follow-up is generally performed every 3–6 months to assess the effectiveness of
      testosterone therapy by assessing pubertal and skeletal maturation and height velocity.
    explanation: General induction monitoring, not a PGD-specific trial.
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The patient developed normal puberty at 12 years old but presented with low testosterone levels
      at 17 years old.
    explanation: Direct evidence that endocrine needs may change after spontaneous onset.
- name: Gene-specific genetic counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Use the established molecular diagnosis and parental testing for recurrence counseling. Autosomal
    dominant allele transmission is distinct from phenotypic penetrance; the <50% estimate in one NR5A1
    family must not be generalized. Counsel NR5A1 relatives about variable gonadal function and primary
    ovarian insufficiency in some 46,XX carriers, WT1 relatives about renal/tumor surveillance, and DHH
    families about recessive inheritance and possible neuropathy. DHX37/NR5A1 dual findings that include
    a VUS or likely-benign allele do not establish digenic recurrence risk. Prenatal or preimplantation
    testing may be discussed when a familial pathogenic variant is known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf
    reference_title: https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Segregation analysis across three generations showed incomplete penetrance (<50%) and phenotypic
      variability among the carriers of NR5A1 c.991-1G>C.
    explanation: Supports family-specific variable penetrance.
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Secondly, patient 3 also carries a loss-of-function variant in NR5A1, which could fully explain
      the PGD phenotype, making the p.Val999Met variant a chance finding.
    explanation: Explains why uncertain dual findings cannot define a recurrence model.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Once the genetic cause of a nonsyndromic disorder of testicular development has been identified
      in an affected family member, prenatal and ... for a pregnancy at increased risk are possible.
    explanation: GeneReviews counseling options for a known molecular diagnosis.
- name: Psychosocial support and shared decision-making
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Provide developmentally appropriate disclosure, psychological and peer support, sexual-health information
    and fertility counseling. Assigned sex may not match gender identity as it develops. Patients and
    families should participate in decisions, with increasing patient autonomy and careful consideration
    before irreversible interventions. Fertility assessment may include semen testing when appropriate;
    pregnancy options depend on anatomy, gonadal function and the individual's goals.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Open communication with affected individuals and families, including their active participation
      in the decision-making process, is critical.
    explanation: Central shared-decision recommendation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Assigned sex of rearing may not be congruent with gender identity, which is determined by the individual
      over time.
    explanation: Supports individualized, revisitable goals of care.
- name: Puberty suppression when endogenous puberty conflicts with individual goals
  description: >-
    For selected individuals with functioning retained gonads, hormonal suppression with the desired sex-steroid
    replacement may defer gonadectomy while decisions mature. Two virilizing PGDf individuals in the registry
    received a GnRH analogue, without comparative outcome evidence. Estrogen alone should not be described
    as proven suppression of endogenous androgen effects.
  treatment_term:
    preferred_term: Hormone Therapy
    term:
      id: NCIT:C15445
      label: Hormone Therapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      If contrasexual puberty occurs, hormonal suppression with replacement of the desired sex hormone
      can be used to avoid gonadectomy until the individual is of age of consent.
    explanation: Broader DSD care option; terminology quoted verbatim from the chapter.
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Two individuals with virilization were treated with a GnRH analogue.
    explanation: Documents use in partial disease without proving comparative efficacy.
clinical_trials: []
datasets: []
discussions:
- discussion_id: gap_xy_pgd_gonad_retention_risk_benefit
  prompt: >-
    What is the prospective, age-specific neoplasia risk in retained gonads in 46,XY partial gonadal dysgenesis,
    and how reliably can monitoring detect clinically significant lesions?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    Registry estimates arise from selected histology subsets with different gonadectomy ages and inconsistent
    monitoring, not person-time follow-up of all retained gonads. Neither gonadal position nor hCG responsiveness
    is a validated rule for safe retention. Endocrine value and patient goals must be weighed against
    uncertain neoplasia risk.
  attaches_to:
  - treatments#Individualized gonadal management (retention versus gonadectomy)
  proposed_experiments:
  - experiment_id: exp_xy_pgd_retained_gonad_incidence
    name: Prospective registry follow-up of retained gonads in 46,XY partial gonadal dysgenesis
    description: >-
      Follow retained gonads prospectively within a multinational DSD registry using protocolized imaging,
      tumor markers, and (where performed) biopsy, reporting neoplasia incidence per gonad-year stratified
      by gonadal position and hCG-stimulated testosterone response, rather than prevalence at gonadectomy.
  - experiment_id: exp_xy_pgd_ihc_germ_cell_marker_triage
    name: Immunohistochemical germ-cell marker triage of gonadal biopsy material
    description: >-
      Evaluate whether immunohistochemical germ-cell markers (for example OCT3/4, TSPY, SALL4) on gonadal
      biopsy material can stratify premalignant risk well enough to serve as a triage test for gonad retention
      versus removal.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      However, there was significant variation in monitoring practice amongst centers and only one third
      (n = 34/92) of individuals with PGDm had histology assessment.
    explanation: Primary study identifies ascertainment and surveillance limitations.
- discussion_id: gap_xy_pgd_molecular_yield
  prompt: >-
    Which unsolved partial-gonadal-dysgenesis cases are explained by noncoding variants, tissue-confined
    mosaicism, additional genes or true multilocus effects?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    The I-DSD study identified a likely gene or chromosome alteration in 131/310 across complete and partial
    disease, but only 78.7% underwent screening and methods and variant classification varied. This is
    not evidence of a fixed diagnostic-yield plateau. SOX9 regulatory architecture is relevant broader
    DSD biology; the cited enhancer paper does not establish every deletion as partial disease. The NR5A1/DHX37
    dual-variant cases include uncertain or likely-benign DHX37 findings and do not prove a multilocus
    explanation.
  attaches_to:
  - diagnosis#Broad molecular testing including WT1
  proposed_experiments:
  - experiment_id: exp_xy_pgd_enhancer_genome_sequencing
    name: Genome sequencing with targeted gonadal-enhancer interrogation
    description: >-
      Apply genome sequencing to exome-negative partial-dysgenesis cases with explicit interrogation of
      known gonadal enhancer regions, including the testis-specific enhancers upstream of SOX9, to test
      whether non-coding regulatory variation explains part of the diagnostic gap.
  - experiment_id: exp_xy_pgd_gonadal_mosaicism_sequencing
    name: Deep sequencing of gonadal tissue for gonad-confined mosaicism
    description: >-
      Deep-sequence gonadal tissue obtained at gonadectomy alongside matched blood to test whether mosaic
      variants confined to the gonad account for cases undiagnosed on peripheral-blood testing.
  evidence:
  - reference: PMID:40208111
    reference_title: >-
      Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Genetic screening was performed in 78.7% of the cohort with various methods; targeted gene screening
      (71%), gene panels (13%), and whole exome sequencing (15%).
    explanation: Defines testing ascertainment.
  - reference: PMID:37240737
    reference_title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Secondly, patient 3 also carries a loss-of-function variant in NR5A1, which could fully explain
      the PGD phenotype, making the p.Val999Met variant a chance finding.
    explanation: Explicit uncertainty about a dual-variant interpretation.
  - reference: PMID:30552336
    reference_title: Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: Here, we identified four DSD patients with overlapping duplications or deletions upstream of SOX9.
    explanation: >-
      Broader human SOX9 enhancer biology motivates a noncoding hypothesis, without asserting partial-specific
      clinical causation.
- discussion_id: mismatch_xy_pgd_nr5a1_mouse_model_divergence
  prompt: >-
    Do mouse Nr5a1 models faithfully reproduce the human NR5A1 gonadal phenotype, given that the same
    p.R92W substitution induces testicular development in human 46,XX gonads but produces no masculinization
    in XX mice?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  rationale: >-
    The p.Arg92Trp comparison showed species differences, including absence of XX masculinization in mice
    despite human 46,XX testicular development. This is a caution about translating allele-specific sex-development
    models, not a claim that the mouse directly models every human PGD presentation.
  attaches_to:
  - pathophysiology#NR5A1 sequence alteration
  proposed_experiments:
  - experiment_id: exp_xy_pgd_human_gonadal_organoid_nr5a1_dosage
    name: Human gonadal organoid or iPSC titration of NR5A1 dosage
    description: >-
      Titrate NR5A1 dosage and introduce patient-specific alleles in human-derived gonadal somatic cell
      models (iPSC-derived or fetal gonadal organoid) to establish the human-specific dose-response threshold
      that separates partial from complete testis-determination failure, and compare it directly against
      the corresponding murine threshold.
  evidence:
  - reference: PMID:27833742
    reference_title: >-
      The p.R92W variant of NR5A1/Nr5a1 induces testicular development of 46,XX gonads in humans, but
      not in mice: phenotypic comparison of human patients and mutation-induced mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Importantly, mutation-positive XX mice showed no signs of masculinization.
    explanation: >-
      Directly documents the species divergence for the identical allele that masculinizes human 46,XX
      gonads.
    quote_role: PRIMARY_RESULT
- discussion_id: gap_xy_pgd_dhx37_biochemical_mechanism
  prompt: >-
    Do established PGD-associated DHX37 alleles alter RNA-dependent ATPase activity, ribosome maturation,
    or another cell function in developing human gonadal cells?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#DHX37 sequence alteration
  rationale: >-
    The original study used structural modeling and expression/localization analysis. Later overexpression
    experiments measured abundance and selected signaling readouts, with unchanged p53 and no increase
    in apoptosis for p.Ser408Leu. The proposed ribosomopathy mechanism and the route from altered protein
    abundance to gonadal differentiation remain unproven.
  evidence:
  - reference: PMID:31337883
    reference_title: >-
      Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis
      and 46,XY testicular regression syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: This raises the possibility that some forms of DSD may be a ribosomopathy.
    explanation: >-
      The authors propose ribosomopathy as a hypothesis in their conclusion; they do not demonstrate variant-dependent
      ribosome dysfunction.
  - reference: PMID:37065748
    reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Surprisingly, we did not see increases in the p53 protein and cell apoptosis by DHX37 mutation
    explanation: Negative experimental observations constrain the proposed stress mechanism.
references:
- reference: PMID:20301714
  title: Nonsyndromic Disorders of Testicular Development Overview.
  tags:
  - GeneReviews
  findings:
  - statement: >-
      PubMed record is a chapter-purpose abstract. The complete Bookshelf URL chapter supplies substantive
      clinical evidence.
- reference: PMID:32352694
  title: WT1 Disorder.
  tags:
  - GeneReviews
  findings: []
- reference: PMID:40208111
  title: >-
    Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.
  findings: []
- reference: PMID:38206718
  title: 'NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review.'
  findings: []
- reference: PMID:37240737
  title: DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.
  findings: []
- reference: PMID:33296094
  title: >-
    NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete
    penetrance.
  findings:
  - statement: >-
      The PubMed cache contains the abstract and repository metadata. The separately cited institutional
      PDF supplies the full article and supplementary methods; tabular material was not extractable from
      that PDF cache.
- reference: PMID:27463801
  title: >-
    NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three
    Novel Mutations.
  findings: []
- reference: PMID:35290982
  title: 'Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review.'
  findings: []
- reference: PMID:28504475
  title: 'MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature.'
  findings: []
- reference: PMID:21129722
  title: >-
    Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
    pathway in human testis determination.
  findings: []
- reference: PMID:35309143
  title: >-
    MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences
    of Sex Development.
  findings: []
- reference: PMID:11017805
  title: >-
    A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied
    by minifascicular neuropathy.
  findings: []
- reference: PMID:25613702
  title: >-
    WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case report.
  findings: []
- reference: PMID:24549039
  title: Mutations in the FOG2/ZFPM2 gene are associated with anomalies of human testis determination.
  findings: []
- reference: PMID:30552336
  title: Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9.
  findings: []
- reference: PMID:31745530
  title: >-
    Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults
    With 46,XY DSD.
  findings: []
- reference: PMID:32905884
  title: Risk of gonadal neoplasia in patients with disorders/differences of sex development.
  findings:
  - statement: Reviewed as contextual literature; not used as direct claim evidence after source-scope assessment.
- reference: PMID:34070473
  title: >-
    Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series
    and Review of the Literature.
  findings: []
- reference: PMID:39371651
  title: Germ Cell Tumors in 46, XY Gonadal Dysgenesis.
  findings:
  - statement: Reviewed as contextual literature; not used as direct claim evidence after source-scope assessment.
- reference: PMID:36424806
  title: 'Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement.'
  findings: []
- reference: PMID:35353710
  title: >-
    Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary
    or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.
  findings: []
- reference: PMID:23276787
  title: Review and management of 46,XY disorders of sex development.
  findings:
  - statement: Reviewed as contextual literature; not used as direct claim evidence after source-scope assessment.
- reference: PMID:31337883
  title: >-
    Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis
    and 46,XY testicular regression syndrome.
  findings: []
- reference: PMID:35249806
  title: Genetics of 46,XY gonadal dysgenesis.
  findings:
  - statement: Reviewed as contextual literature; not used as direct claim evidence after source-scope assessment.
- reference: PMID:25580123
  title: Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males.
  findings: []
- reference: PMID:27603905
  title: >-
    Incidence, Prevalence, Diagnostic Delay, and Clinical Presentation of Female 46,XY Disorders of Sex
    Development.
  findings: []
- reference: PMID:27833742
  title: >-
    The p.R92W variant of NR5A1/Nr5a1 induces testicular development of 46,XX gonads in humans, but not
    in mice: phenotypic comparison of human patients and mutation-induced mice.
  findings: []
- reference: PMID:25927242
  title: >-
    46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome
    Sequencing.
  findings: []
- reference: PMID:35137906
  title: >-
    Leydig and Sertoli cell function in individuals with genital ambiguity, 46,XY karyotype, palpable
    gonads and normal testosterone secretion: a case-control study.
  findings:
  - statement: Reviewed as contextual literature; not used as direct claim evidence after source-scope assessment.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
  title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
  findings:
  - statement: >-
      Complete cached chapter used for clinical baseline, diagnosis, management and genetic counseling;
      syndrome-specific scope is preserved.
  tags:
  - GeneReviews
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK556455/
  title: WT1 Disorder - GeneReviews® - NCBI Bookshelf
  findings:
  - statement: >-
      Complete cached chapter used for clinical baseline, diagnosis, management and genetic counseling;
      syndrome-specific scope is preserved.
  tags:
  - GeneReviews
- reference: PMID:38769888
  title: >-
    Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders
    of sex development.
  findings: []
- reference: PMID:37065748
  title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
  findings: []
- reference: url:https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf
  title: https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf
  findings: []
- reference: PMID:31962012
  title: >-
    Analysis of variants in GATA4 and FOG2/ZFPM2 demonstrates benign contribution to 46,XY disorders of
    sex development.
  findings: []
- reference: PMID:33627800
  title: >-
    The conditional deletion of steroidogenic factor 1 (Nr5a1) in Sox9-Cre mice compromises testis differentiation.
  findings:
  - statement: >-
      Conditional mouse model supports the developmental role of Nr5a1, with explicit limits on equivalence
      to human heterozygous variants.
notes: "This entry is scoped to the partial phenotype and is deliberately built as the complement of, not a duplicate of, kb/disorders/46_XY_complete_gonadal_dysgenesis.yaml (MONDO:0010765). Where content necessarily overlaps (shared genes, shared tumor substrate), the partial entry emphasizes what is mechanistically different: residual testicular tissue, partial fetal AMH and androgen, ambiguous rather than female genitalia, variable rather than uniform Müllerian retention, potential for spontaneous puberty and for discordant virilization, lower tumor risk, and a genuine gonad-retention trade-off. The gene set overlaps the complete form because most of these genes are dosage-sensitive and produce a spectrum; per-subtype descriptions state which end of the spectrum is being modeled.\nSubtype-scoping decisions, stated explicitly because two of them diverge from the complete-form entry: - NR0B1 and DMRT1 get no subtype here - the partial-specific evidence is thin;\n  they remain in the complete-form entry.\n- SRY and SOX9 get no subtype here, despite being canonical testis-determination\n  genes, because every located citation reports the 46,XY phenotype as complete\n  (sex reversal).\
  \ They are kept as `genetic:` records with that limitation\n  stated. Asserting partial subtypes for them would have meant reusing the\n  complete-form entry's own evidence, which cannot support both.\n- WT1 IS given a subtype here, although the complete-form entry treats syndromic\n  WT1 disease as outside its root. The divergence is deliberate: WT1-related\n  partial dysgenesis is well documented, and the renal/Wilms surveillance and\n  the immunosuppressant warning are management-critical, so the subtype earns\n  its place with its extra-gonadal features scoped to it.\n- ZFPM2 IS given a subtype here, although the complete-form entry declined it on\n  gene-validity grounds. It is retained only as provisional/emerging and is\n  flagged as such in both the subtype and the `genetic:` record; if a\n  gene-validity review rejects ZFPM2, this subtype should go with it.\n\n45,X/46,XY mixed gonadal dysgenesis is out of scope as a sex-chromosome DSD. Frequency bands are given only where a cohort percentage supports them, and the one derived band (ambiguous genitalia) declares its arithmetic.\nKnown gaps for follow-up: no quotable partial-versus-complete AMH or inhibin B comparison was located,\
  \ so those biomarkers are modeled qualitatively rather than with reference values; and an asymmetric streak-plus-testis gonadal pair, though characteristic of this disease, is not curated as a phenotype because no cached source states it quotably. It is not a member of Digenic_and_Oligogenic_Disorders: co-occurring DHX37 and NR5A1 variants and oligogenic predictions do not establish digenic inheritance, so no HP:0010984 inheritance block is bound."
experimental_models:
- name: MAP3K1 patient lymphoblastoid phosphorylation assays
  description: >-
    Patient lymphoblastoid cell lines carrying selected MAP3K1 alleles were compared with wild-type lines
    after serum starvation and refeeding.
  experimental_model_type: CELL_LINE
  publication: PMID:21129722
  modeled_mechanisms:
  - target: Enhanced MAP3K1-RHOA association
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:21129722
      reference_title: >-
        Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
        pathway in human testis determination.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced
        binding of RHOA to the MAP3K1 complex.
      explanation: >-
        Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association;
        p38 effects differed among alleles.
  - target: Increased ERK1/2 phosphorylation
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:21129722
      reference_title: >-
        Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
        pathway in human testis determination.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced
        binding of RHOA to the MAP3K1 complex.
      explanation: >-
        Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association;
        p38 effects differed among alleles.
  - target: Increased p38 phosphorylation
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:21129722
      reference_title: >-
        Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
        pathway in human testis determination.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced
        binding of RHOA to the MAP3K1 complex.
      explanation: >-
        Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association;
        p38 effects differed among alleles.
  evidence:
  - reference: PMID:21129722
    reference_title: >-
      Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction
      pathway in human testis determination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced
      binding of RHOA to the MAP3K1 complex.
    explanation: >-
      Patient lymphoblastoid-cell assays support altered MAPK phosphorylation and RHOA association; p38
      effects differed among alleles.
  notes: >-
    The model reproduces biochemical readouts outside the fetal gonadal lineage. The p38 response was
    not uniform across variants; gene expression and splicing findings were allele-specific.
- name: MAP3K1 p.Arg186Gly overexpression assays
  description: >-
    HEK293T protein-interaction and TCF/LEF reporter assays, with NT2/D1 and KGN phosphorylation/protein-expression
    assays, compared wild type, p.Arg186Gly and relevant empty-vector controls.
  experimental_model_type: CELL_LINE
  publication: PMID:35309143
  modeled_mechanisms:
  - target: Enhanced MAP3K1-RHOA association
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:35309143
      reference_title: >-
        MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY
        Disorders/Differences of Sex Development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Our Co-IP assay confirmed that the binding capacity of MAP3K1R186G to RhoA was 2.57 times that
        of the wild-type protein (Figures 5A,A'), and the ubiquitination degree of the wild-type MAP3K1
        protein was 3.6-fold that of the MAP3K1R186G variant (Figures 5B,B').
      explanation: >-
        Selected p.Arg186Gly variant in HEK293T cells; binding and ubiquitination measurements, not gonadal
        epistasis.
  - target: Reduced MAP3K1 ubiquitination
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:35309143
      reference_title: >-
        MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY
        Disorders/Differences of Sex Development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Our Co-IP assay confirmed that the binding capacity of MAP3K1R186G to RhoA was 2.57 times that
        of the wild-type protein (Figures 5A,A'), and the ubiquitination degree of the wild-type MAP3K1
        protein was 3.6-fold that of the MAP3K1R186G variant (Figures 5B,B').
      explanation: >-
        Selected p.Arg186Gly variant in HEK293T cells; binding and ubiquitination measurements, not gonadal
        epistasis.
  - target: Increased MAP3K1 protein abundance
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:35309143
      reference_title: >-
        MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY
        Disorders/Differences of Sex Development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        The protein expression of the MAP3K1R186G variant was 6.4 and 2.0 times higher than that of the
        wild type in the KGN and NT2/D1 cells, respectively (Figures 6A–D).
      explanation: Measured abundance in KGN and NT2/D1 overexpression models; not a direct half-life measurement.
  - target: Increased p38 phosphorylation
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:35309143
      reference_title: >-
        MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY
        Disorders/Differences of Sex Development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Similarly, in the NT2/D1 testicular cells, phosphorylated p38 and GSK3β proteins were significantly
        elevated in the mutant group, which were 2.3 and 2.2 times higher than those in the wild-type
        group, respectively.
      explanation: Measured phosphorylation responses in an overexpression model.
  - target: Increased beta-catenin-dependent transcription
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:35309143
      reference_title: >-
        MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY
        Disorders/Differences of Sex Development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        The data showed that at 48 h after transfection, the relative activity of TCF/LEF in the mutant
        group reached its peak, which was 9.78 ± 0.57 times that of the wild-type group (Figures 6E,F).
      explanation: TCF/LEF reporter assay measures beta-catenin-dependent transcription in HEK293T cells.
  evidence:
  - reference: PMID:35309143
    reference_title: >-
      MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences
      of Sex Development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Our Co-IP assay confirmed that the binding capacity of MAP3K1R186G to RhoA was 2.57 times that of
      the wild-type protein (Figures 5A,A'), and the ubiquitination degree of the wild-type MAP3K1 protein
      was 3.6-fold that of the MAP3K1R186G variant (Figures 5B,B').
    explanation: >-
      Selected p.Arg186Gly variant in HEK293T cells; binding and ubiquitination measurements, not gonadal
      epistasis.
  - reference: PMID:35309143
    reference_title: >-
      MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences
      of Sex Development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      The protein expression of the MAP3K1R186G variant was 6.4 and 2.0 times higher than that of the
      wild type in the KGN and NT2/D1 cells, respectively (Figures 6A–D).
    explanation: Measured abundance in KGN and NT2/D1 overexpression models; not a direct half-life measurement.
  - reference: PMID:35309143
    reference_title: >-
      MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences
      of Sex Development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Similarly, in the NT2/D1 testicular cells, phosphorylated p38 and GSK3β proteins were significantly
      elevated in the mutant group, which were 2.3 and 2.2 times higher than those in the wild-type group,
      respectively.
    explanation: Measured phosphorylation responses in an overexpression model.
  - reference: PMID:35309143
    reference_title: >-
      MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences
      of Sex Development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      The data showed that at 48 h after transfection, the relative activity of TCF/LEF in the mutant
      group reached its peak, which was 9.78 ± 0.57 times that of the wild-type group (Figures 6E,F).
    explanation: TCF/LEF reporter assay measures beta-catenin-dependent transcription in HEK293T cells.
  notes: >-
    Transfected tumor-derived or kidney-derived cells do not reproduce a fetal gonad. The paper did not
    demonstrate necessary mediation between every measured intermediate, directly measure protein half-life,
    or establish the partial phenotype for the studied family.
- name: NR5A1 variant promoter-reporter assays
  description: >-
    Wild-type and p.Gly22Asp or p.Leu420Pro SF-1 constructs were tested on a Cyp11a1 promoter reporter
    in tsa201 human kidney-derived cells.
  experimental_model_type: CELL_LINE
  publication: PMID:31745530
  modeled_mechanisms:
  - target: Reduced SF-1 transcriptional activity
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:31745530
      reference_title: >-
        Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults
        With 46,XY DSD.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Transient transfection assays showing activation of a Cyp11a1 promoter by WT SF-1 and impaired
        transcriptional activity by the p.G22D and p.L420P mutants.
      explanation: >-
        Cyp11a1 reporter in tsa201 kidney-derived cells; the clinical cohort used a broader partially
        virilized DSD category.
  evidence:
  - reference: PMID:31745530
    reference_title: >-
      Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults
      With 46,XY DSD.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Transient transfection assays showing activation of a Cyp11a1 promoter by WT SF-1 and impaired transcriptional
      activity by the p.G22D and p.L420P mutants.
    explanation: >-
      Cyp11a1 reporter in tsa201 kidney-derived cells; the clinical cohort used a broader partially virilized
      DSD category.
  notes: >-
    The clinical subgroup was partially virilized 46,XY DSD, not a uniformly histology-confirmed PGD cohort.
    This assay does not measure every developmental SF-1 target.
- name: DHX37 variant expression and localization assays
  description: >-
    The p.Arg308Gln and p.Arg671Thr constructs were assessed for protein abundance in HEK293T cells; localization
    was studied in COS7 cells.
  experimental_model_type: CELL_LINE
  publication: PMID:38769888
  modeled_mechanisms:
  - target: Reduced DHX37 protein abundance
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:38769888
      reference_title: >-
        Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY
        disorders of sex development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: The results indicated that mutant DHX37 decreased the protein levels of DHX37.
      explanation: Selected-variant overexpression assay; not an ATPase or ribosome-biogenesis assay.
  evidence:
  - reference: PMID:38769888
    reference_title: >-
      Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders
      of sex development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: The results indicated that mutant DHX37 decreased the protein levels of DHX37.
    explanation: Selected-variant overexpression assay; not an ATPase or ribosome-biogenesis assay.
  notes: >-
    Localization was unchanged. The study prose calls p.Arg671Thr pathogenic, but its table lists VUS;
    the classification is kept uncertain. No variant-specific ATPase or ribosome-output assay was performed.
- name: DHX37 p.Ser408Leu human Sertoli-cell overexpression
  description: >-
    A commercial human Sertoli-cell line was transfected with wild-type, p.Ser408Leu or empty-vector constructs.
    Transcript/protein abundance, localization, beta-catenin, p53, apoptosis and proliferation were assessed.
  experimental_model_type: CELL_LINE
  publication: PMID:37065748
  modeled_mechanisms:
  - target: Reduced DHX37 protein abundance
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:37065748
      reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        compared with the cells transfected with pcDNA3.1-WT, those with pcDNA3.1-S408L displayed decreased
        DHX37 expression both at the mRNA and protein levels.
      explanation: Variant overexpression effect in a human Sertoli-cell line, with uncertain clinical classification.
  evidence:
  - reference: PMID:37065748
    reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      compared with the cells transfected with pcDNA3.1-WT, those with pcDNA3.1-S408L displayed decreased
      DHX37 expression both at the mRNA and protein levels.
    explanation: Variant overexpression effect in a human Sertoli-cell line, with uncertain clinical classification.
  - reference: PMID:37065748
    reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      there is no difference in p53 expression among cells transfected with empty expressing vector, wt-DHX37,
      or mutant DHX37.
    explanation: Negative measured result constrains a proposed nucleolar-stress mechanism.
  notes: >-
    The variant had the same localization as wild type. Beta-catenin was higher than in wild-type-transfected
    cells because wild type suppressed it. p53 was unchanged; apoptosis was not increased relative to
    wild-type overexpression, although both constructs increased apoptosis relative to empty vector. Neither
    helicase activity nor ribosome biogenesis was assayed. Clinical pathogenicity remains uncertain.
animal_models:
- name: Sox9-Cre conditional Nr5a1 knockout mice
  species: Mouse
  genotype: Sox9-Cre;Nr5a1flox/flox and Sox9-Cre;Nr5a1flox/-
  publication: PMID:33627800
  description: >-
    Conditional Nr5a1 loss in the Sox9 lineage reduced AMH-positive cells, impaired Sertoli differentiation
    and permitted ectopic FOXL2-positive cells. The reported postnatal spectrum included partial and complete
    gonadal sex reversal.
  modeled_mechanisms:
  - target: Incomplete testicular differentiation
    relationship: RECAPITULATES
    fidelity: MODERATE
    limitations: >-
      Lineage-specific engineered biallelic loss is not the same as a human heterozygous NR5A1 allele.
      Leydig-marker reduction differed between the two knockout genotypes. Only the abstract is cached.
    evidence:
    - reference: PMID:33627800
      reference_title: >-
        The conditional deletion of steroidogenic factor 1 (Nr5a1) in Sox9-Cre mice compromises testis
        differentiation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        These data suggested that the loss of Nr5a1 abrogates the testicular pathway and induces the ectopic
        ovarian pathway, resulting in postnatal partial/complete male-to-female gonadal sex reversal.
      explanation: >-
        Conditional mouse knockout establishes a developmental effect in that model; not a human penetrance
        estimate.
  evidence:
  - reference: PMID:33627800
    reference_title: >-
      The conditional deletion of steroidogenic factor 1 (Nr5a1) in Sox9-Cre mice compromises testis differentiation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      These data suggested that the loss of Nr5a1 abrogates the testicular pathway and induces the ectopic
      ovarian pathway, resulting in postnatal partial/complete male-to-female gonadal sex reversal.
    explanation: >-
      Conditional mouse knockout establishes a developmental effect in that model; not a human penetrance
      estimate.

📚

References & Deep Research

References

PMID:20301714

Nonsyndromic Disorders of Testicular Development Overview.

1 finding

PubMed record is a chapter-purpose abstract. The complete Bookshelf URL chapter supplies substantive clinical evidence.

PMID:32352694

WT1 Disorder.

No top-level findings curated for this source.

PMID:40208111

Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis.

No top-level findings curated for this source.

PMID:38206718

NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review.

No top-level findings curated for this source.

PMID:37240737

DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.

No top-level findings curated for this source.

PMID:33296094

NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete penetrance.

1 finding

The PubMed cache contains the abstract and repository metadata. The separately cited institutional PDF supplies the full article and supplementary methods; tabular material was not extractable from that PDF cache.

PMID:27463801

NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations.

No top-level findings curated for this source.

PMID:35290982

Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review.

No top-level findings curated for this source.

PMID:28504475

MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature.

No top-level findings curated for this source.

PMID:21129722

Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination.

No top-level findings curated for this source.

PMID:35309143

MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences of Sex Development.

No top-level findings curated for this source.

PMID:11017805

A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied by minifascicular neuropathy.

No top-level findings curated for this source.

PMID:25613702

WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case report.

No top-level findings curated for this source.

PMID:24549039

Mutations in the FOG2/ZFPM2 gene are associated with anomalies of human testis determination.

No top-level findings curated for this source.

PMID:30552336

Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9.

No top-level findings curated for this source.

PMID:31745530

Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults With 46,XY DSD.

No top-level findings curated for this source.

PMID:32905884

Risk of gonadal neoplasia in patients with disorders/differences of sex development.

1 finding

Reviewed as contextual literature; not used as direct claim evidence after source-scope assessment.

PMID:34070473

Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature.

No top-level findings curated for this source.

PMID:39371651

Germ Cell Tumors in 46, XY Gonadal Dysgenesis.

1 finding

Reviewed as contextual literature; not used as direct claim evidence after source-scope assessment.

PMID:36424806

Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement.

No top-level findings curated for this source.

PMID:35353710

Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.

No top-level findings curated for this source.

PMID:23276787

Review and management of 46,XY disorders of sex development.

1 finding

Reviewed as contextual literature; not used as direct claim evidence after source-scope assessment.

PMID:31337883

Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.

No top-level findings curated for this source.

PMID:35249806

Genetics of 46,XY gonadal dysgenesis.

1 finding

Reviewed as contextual literature; not used as direct claim evidence after source-scope assessment.

PMID:25580123

Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males.

No top-level findings curated for this source.

PMID:27603905

Incidence, Prevalence, Diagnostic Delay, and Clinical Presentation of Female 46,XY Disorders of Sex Development.

No top-level findings curated for this source.

PMID:27833742

The p.R92W variant of NR5A1/Nr5a1 induces testicular development of 46,XX gonads in humans, but not in mice: phenotypic comparison of human patients and mutation-induced mice.

No top-level findings curated for this source.

PMID:25927242

46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome Sequencing.

No top-level findings curated for this source.

PMID:35137906

Leydig and Sertoli cell function in individuals with genital ambiguity, 46,XY karyotype, palpable gonads and normal testosterone secretion: a case-control study.

1 finding

Reviewed as contextual literature; not used as direct claim evidence after source-scope assessment.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/

Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf

1 finding

Complete cached chapter used for clinical baseline, diagnosis, management and genetic counseling; syndrome-specific scope is preserved.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK556455/

WT1 Disorder - GeneReviews® - NCBI Bookshelf

1 finding

Complete cached chapter used for clinical baseline, diagnosis, management and genetic counseling; syndrome-specific scope is preserved.

PMID:38769888

Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development.

No top-level findings curated for this source.

PMID:37065748

A novel DEAH-box helicase 37 mutation associated with differences of sex development.

No top-level findings curated for this source.

url:https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf

https://dipot.ulb.ac.be/dspace/bitstream/2013/316657/5/Laan_Maintext_final.pdf

No top-level findings curated for this source.

PMID:31962012

Analysis of variants in GATA4 and FOG2/ZFPM2 demonstrates benign contribution to 46,XY disorders of sex development.

No top-level findings curated for this source.

PMID:33627800

The conditional deletion of steroidogenic factor 1 (Nr5a1) in Sox9-Cre mice compromises testis differentiation.

1 finding

Conditional mouse model supports the developmental role of Nr5a1, with explicit limits on equivalence to human heterozygous variants.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review partial gonadal dysgenesis against full sources; correct clinical denominators and mechanistic overclaims · 2026-09-21T03:49:58Z · View source

Reviewed the complete existing entry and the matching genuine Claude deep-research report. The fresh fully paginated live open-PR search found no overlapping review for this exact disorder, and no prior REVIEW history existed. The disease identity was checked against MONDO/Orphanet before using research leads. Read all 29 originally cited PMID records, distinguishing true main-body text from abstract-only or repository-metadata caches. Regenerated seven PMID caches through just fetch-reference, recovered the Laan primary manuscript and supplementary methods as a canonical repository PDF, and used complete Nonsyndromic Disorders of Testicular Development and WT1 Disorder GeneReviews chapters. Additional primary full texts on ZFPM2 reassessment and two DHX37 functional studies were read, together with the Nr5a1 conditional-mouse abstract. Puberty guideline recommendations were checked in context; an independent peer reviewed the applicable Endo-ERN sections. The Laan PDF cache does not expose its main tables, so no new table-only claim was introduced. Corrected the PGD definition to allow variable external anatomy, Müllerian structures and histology. Removed unjustified phenotype frequency bands and pooled arithmetic. Preserved registry denominators for uterus, AMH, inhibin B, puberty and combined neoplasia. The hCG subgroup association was nonsignificant (P=.087), not a validated forecast. Corrected tumor ascertainment, gonadoblastoma-specific versus composite outcomes, neonatal WT1 pathology uncertainty, azoospermia generalization, and imaging discordance. Added direct primary amenorrhea, deep-voice and severe oligozoospermia observations without population extrapolation. Rebuilt the graph as separate genetic perturbations, measured protein interaction/abundance/phosphorylation/transcription events, tissue dysgenesis, developmental hormone inferences and spermatogenic impairment. Retained allele and experimental-system limits. Removed the asserted DHX37 ATPase/ribosome failure and proven digenic model: the dual-variant cases include DHX37 VUS or likely-benign alleles. Corrected ZFPM2 candidacy and predicted rather than measured NR5A1 splice/NMD effects. Did not add a germ-cell-maturation-to-neoplasia edge without evidence of transformation. Five cell models and a conditional mouse model state what they measure and what they cannot establish. Clinical care now distinguishes guideline recommendations from PGD-specific trial evidence, preserves the option of retained functional gonads, acknowledges surveillance limitations, and centers informed patient participation. Added reversible puberty suppression with desired replacement as an option, corrected estrogen-alone anti-virilization claims, and incorporated genotype-specific WT1 surveillance, fertility and family counseling. Removed obligatory whole-gonad histology and rigid molecular-testing sequences. Completeness cross-check: phenotype coverage, supported gene subtypes, atomic mechanisms, care, variant interpretation, diagnosis/biomarkers, citations and overall research consumption were addressed. Environmental testicular-dysgenesis hypotheses, XX animal sex-reversal reports, and general reproductive toxicology do not establish etiologies of this 46,XY PGD entity. Unsolved genetics and DHX37 biochemical mechanism remain explicit knowledge gaps. Peers audited registry rates, DHX37 source classification, clinical/care prose, fetal hormone inference and model limits; all actionable findings were applied. Validation includes authoritative schema, live ontology and exact-cache snippet validation, background/quote-boundary audits, reference and graph gates, and shared-cache consumer checks. Reference cache files were generated only by the sanctioned fetcher; the frozen dataset-accession cache was never read or touched. The standalone tracked PMC fallback is included so two regenerated HTML caches are reproducible; its twelve targeted tests pass. Final verification results and CI are recorded in the PR.

Create: 46,XY partial gonadal dysgenesis (MONDO:0016674) · 2026-08-01T06:39:18Z · View source

De-novo curation of 46,XY partial gonadal dysgenesis [MONDO:0016674] fulfilling issue #7595, modelled as CURATE_ROOT_WITH_SUBTYPES. Deep research: "just research-disorder claude_code 46_XY_Partial_Gonadal_Dysgenesis" -- provider claude_code, 20 web searches, 58 turns, 43 citations. Falcon was unavailable in this environment because no EDISON_API_KEY / FUTUREHOUSE_API_KEY is set. The DR report was treated as leads only: every PMID was independently fetched with "just fetch-reference" and every snippet was re-derived as an exact substring of the cached abstract rather than copied from the report, which explicitly warned that its own snippets were page-summarisation paraphrases. GeneReviews baseline: PMID:20301714 -- Nonsyndromic Disorders of Testicular Development Overview -- exists but its PubMed abstract is a purpose statement only, so it is tagged in top-level references without inline phenotype evidence. PMID:32352694 -- WT1 Disorder -- is a substantive GeneReviews chapter and supplies the WT1 subtype, the steroid-resistant nephrotic syndrome and Wilms tumour phenotypes, the surveillance schedule, and the agents-to-avoid warning that the glomerulopathy must not be treated with immunosuppressants. Modelling: the entry is deliberately built as the complement of the existing 46_XY_complete_gonadal_dysgenesis.yaml [MONDO:0010765], which was NOT edited. The organising contrast is residual testicular tissue -- hypoplastic seminiferous tubules rather than fibrous streaks, partial fetal AMH and androgen, ambiguous rather than typically female genitalia, variable rather than uniform Mullerian retention, potential for spontaneous puberty in 80 percent of PGDm with a retained gonad and for discordant pubertal virilization in 42 percent of PGDf with gonads, a lower tumour gradient of 33.8 percent CGD versus 19.7 percent PGDf versus 8.8 percent PGDm in one registry, and a genuine gonad-retention risk/benefit trade-off that does not arise in the complete form. Nine subtypes: NR5A1-related as the characteristic partial gene, MAP3K1-related, SRY-related, WT1-related spanning the Denys-Drash/Frasier continuum, DHH-related with minifascicular neuropathy, DHX37-related, SOX9-regulatory, ZFPM2-related, and Molecularly unresolved. A top-level Digenic inheritance block bound to HP:0010984 captures the documented DHX37 plus NR5A1 double heterozygotes. Three discussions: two KNOWLEDGE_GAP entries covering the retained-gonad tumour-incidence denominator problem and the roughly 50 percent molecularly unexplained fraction, plus one HUMAN_MODEL_MISMATCH recording that NR5A1 p.R92W masculinises human 46,XX gonads but not XX mice [PMID:27833742]. Validation: just validate, just validate-terms and just validate-references all pass; 156 of 156 snippets verified against cached references; weighted compliance 97.3 percent. All HP, GO, CL, CHEBI, NCIT, HGNC and MONDO terms verified with OAK.

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-5[1m] 43 citations 2026-08-01T02:21:12.205702

1. Disease Information

1.1 Definition

Orphanet/MONDO definition (verbatim, the source of the MONDO def:):

"46,XY partial gonadal dysgenesis (46,XY PGD) is a disorder of sex development (DSD) associated with anomalies in gonadal development that results in genital ambiguity of variable degree ranging from almost female phenotype to almost male phenotype in a patient carrying a male 46,XY karyotype." — Orphanet:251510 (source of MONDO:0016674 definition)

Operational clinical definition. 46,XY PGD is defined by incomplete (rather than absent) testis determination in a person with a non-mosaic 46,XY karyotype and no syndromic features. Gonads are bilaterally dysgenetic testes, or a dysgenetic testis on one side with a streak gonad on the other, and produce enough fetal testosterone and anti-Müllerian hormone (AMH) to partially virilize the external genitalia and partially regress the Müllerian ducts — hence the hallmark combination of ambiguous genitalia plus variably retained Müllerian structures.

GeneReviews frames the diagnostic boundary as: "normal general physical examination AND absence of clinical findings involving other organ systems" — i.e., 46,XY PGD in the strict sense is a nonsyndromic disorder of testicular development. Syndromic gonadal dysgenesis (WT1-related Denys–Drash/Frasier, campomelic dysplasia/SOX9, 9p deletion, ATRX, DHH with minifascicular neuropathy) are curated as distinct entities, though they overlap mechanistically. (GeneReviews, Nonsyndromic Disorders of Testicular Development Overview, NCBI Bookshelf NBK1547)

The distinction from CGD is quantitative, not qualitative: PGD retains partial testis-determining function, CGD retains essentially none. The 2025 I-DSD registry study makes this explicit — "46,XY gonadal dysgenesis is classified as complete (CGD) or partial (PGD) subtypes. The phenotype of PGD and the long-term outcome is not clearly defined." (Tadokoro-Cuccaro et al., J Clin Endocrinol Metab 2025; PMID:40208111)

1.2 Key identifiers

Resource	Identifier	Notes
MONDO	`MONDO:0016674`	`is_a` MONDO:0020040 (46,XY disorder of sex development)
Orphanet	`ORPHA:251510`	Definition source; subset `ordo_malformation_syndrome`, `ordo_disorder`
UMLS	`C4510744`
MedGen	`1388250`
SNOMED CT	`725045004`
GARD	`GARD:0017211`	rarediseases.info.nih.gov/diseases/17211
MeSH	`D023961` (Gonadal Dysgenesis, 46,XY)	Nearest MeSH; no PGD-specific descriptor
ICD-10	`Q56.3` (Pseudohermaphroditism, unspecified) / `Q99.1` (46,XX true hermaphrodite… — not applicable); most registries use Q56.3 or Q99.8	ICD-10 has no specific PGD code; Orphanet maps the DSD group loosely
ICD-11	`LD2A.Y` / `LD2A.0` — "Sex chromosome structure variations… / 46,XY disorders of sex development"	ICD-11 foundation covers "46,XY DSD"; no PGD-specific stem code
OMIM	No single OMIM number. Gene-specific SRXY series applies — see §4.1	This is important: OMIM models PGD by gene, not as one entity

MONDO structural note (verified locally via OAK):

[Term]
id: MONDO:0016674
name: 46,XY partial gonadal dysgenesis
def: "46,XY partial gonadal dysgenesis (46,XY PGD) is a disorder of sex development (DSD)
      associated with anomalies in gonadal development that results in genital ambiguity of
      variable degree ranging from almost female phenotype to almost male phenotype in a
      patient carrying a male 46,XY karyotype." [Orphanet:251510]
synonym: "46,XY PGD" EXACT
synonym: "46,XY partial testicular dysgenesis" EXACT
is_a: MONDO:0020040 ! 46,XY disorder of sex development

1.3 Synonyms and alternative names

Current/preferred: 46,XY partial gonadal dysgenesis; 46,XY PGD; 46,XY partial testicular dysgenesis; partial testicular dysgenesis; partial XY gonadal dysgenesis.

Historical/deprecated (do NOT use as preferred terms — explicitly retired by the 2006 Chicago Consensus): male pseudohermaphroditism; partial XY sex reversal; dysgenetic male pseudohermaphroditism; intersex. The Chicago Consensus (Hughes IA, Houk C, Ahmed SF, Lee PA; LWPES/ESPE Consensus Groups. Arch Dis Child 2006;91(7):554-63; PMID:16624884) replaced "intersex, pseudohermaphroditism, hermaphroditism, sex reversal, and gender-based diagnostic labels" with the DSD nomenclature. Note HPO still carries the legacy term HP:0000037 "Male pseudohermaphroditism" — flag it, don't use it.

Terminology sensitivity. Many affected adults and advocacy organisations prefer "differences of sex development" or "variations of sex characteristics" over "disorders." Curated description and notes text should use neutral phrasing; the D/DSD abbreviation is broadly accepted.

1.4 Data provenance character

Information for this entity is overwhelmingly aggregated disease-level and case-series derived, not EHR/individual-patient derived:

Registry-derived (highest quality): the I-DSD Registry (international, 34 centres) supplied the only large PGD-specific outcome cohort (n=310 across CGD/PGDf/PGDm; PMID:40208111).
National population registry: Danish nationwide cytogenetic/health registry linkage gives the only true population-based prevalence (PMID:27603905).
Single-centre case series: Brazilian (São Paulo/Campinas), French (Institut Pasteur), UK, Chinese cohorts — the bulk of the genotype literature.
Ontology aggregation: HPO annotations for ORPHA:251510 are curator-derived from Orphanet text, not frequency-counted from patients — treat the "Very frequent"/"Frequent" bands as editorial, not empirical (see §3.1 caveat).
No claims-based/OMOP phenotype algorithm exists for 46,XY PGD; ICD coding is too coarse (Q56.3) to support EHR case-finding without chart review or karyotype linkage.

2. Etiology

2.1 Primary causal factors

46,XY PGD is a monogenic (or oligogenic) developmental disorder of testis determination. The proximate cause is a germline (occasionally mosaic) variant that reduces — but does not abolish — the output of the testis-determining gene regulatory network during the narrow window of gonadal fate commitment (human ~gestational weeks 6–8; mouse E10.5–E12.5).

The unifying model, stated by the definitive genetics review:

"In 46,XY men, testis is determined by a genetic network(s) that both promotes testis formation and represses ovarian development. Disruption of this process results in a lack of testis-determination and affected individuals present with 46,XY gonadal dysgenesis (GD), a part of the spectrum of Disorders/Differences of Sex Development/Determination (DSD). A minority of all cases of GD are associated with pathogenic variants in key players of testis-determination, SRY, SOX9, MAP3K1 and NR5A1. However, most of the cases remain unexplained." — Elzaiat M, McElreavey K, Bashamboo A. Genetics of 46,XY gonadal dysgenesis. Best Pract Res Clin Endocrinol Metab 2022;36(1):101633. PMID:35249806

Key etiological points:

Dosage/threshold biology, not simple loss of function. Testis determination is a bistable switch with a steep dose–response. PGD arises when the pro-testis signal falls into an intermediate band — enough to build some seminiferous tubules and Leydig cells, not enough to build a normal testis. This is why the same variant can produce CGD in one family member and PGD (or even isolated hypospadias/infertility) in another.
Both loss-of-function of pro-testis genes and gain-of-function of pro-ovary signalling cause the same phenotype. MAP3K1 is the canonical gain-of-function example (§6.2).
A large diagnostic gap remains. Approximately 50–60% of 46,XY GD cases are genetically unexplained even after exome sequencing (PMID:35249806; Frontiers in Genetics 2024, DOI:10.3389/fgene.2024.1387598). In the largest PGD-specific cohort, "A genetic cause was identified in 42% overall" (PMID:40208111).
Karyotype must be non-mosaic 46,XY. Hidden low-level 45,X/46,XY mosaicism (peripheral blood may be negative while gonadal tissue is mosaic) is a recognised misclassification route into this entity.

2.2 Genetic risk/causal factors

Causal (high-penetrance) loci — see §4 for full detail. Summary of PGD-relevant genes and approximate contribution (GeneReviews NBK1547; PMID:35249806):

Gene	Locus	Share of nonsyndromic 46,XY testicular DSD	Inheritance	Direction of effect
NR5A1 (SF-1)	9q33.3	10–15% (up to 42% of PGDf in I-DSD)	Sex-limited AD (also de novo; rare AR)	LoF / haploinsufficiency
MAP3K1	5q11.2	10–18% (≥4% of PGD+CGD)	Sex-limited AD, near-complete penetrance in 46,XY	Gain of function
DHX37	12q24.31	~10–20% (enriched in TRS/PGD)	Sex-limited AD	Missense, domain-clustered; likely hypomorph
SRY	Yp11.2	10–15% (predominantly CGD; PGD when mosaic/partial-function)	Y-linked, usually de novo	LoF
DHH	12q13.12	Rare	AR (sex-limited)	LoF
DMRT1 / 9p24 del	9p24.3	Rare	AD / contiguous deletion	Haploinsufficiency
SOX9 / SOX8	17q24.3 / 16p13.3	Rare (incl. enhancer/RevSex CNVs)	AD	LoF or regulatory
NR0B1 (DAX1) dup	Xp21.2	Rare	X-linked dosage	Duplication (anti-testis)
WT1	11p13	Rare in nonsyndromic PGD	AD	LoF / KTS-isoform imbalance
ZFPM2 (FOG2), GATA4	8q23.1 / 8p23.1	Rare	AD	LoF
WNT4 / RSPO1 dup	1p36	Very rare	Dosage	Pro-ovary gain
PPP2R3C, PBX1, HHAT, LHX9, SOS1, MYRF, PPP1R12A, WWOX, TSPYL1, CBX2, ESR2, SART3, AKR1C2/4, ARX, ATRX, MAMLD1	various	Individually rare; collectively meaningful	mixed	mixed

(Gene list compiled from GeneReviews NBK1547; Idris et al., Andrology 2025, PMID:39081229; PMID:35249806)

Y-chromosome microdeletions are NOT a cause of non-mosaic 46,XY PGD. This is a useful negative result: in a Brazilian series of 13 PGD patients, "All STS showed positive amplifications in the PGD group" — no AZF deletions — whereas 6/15 (40%) of the 45,X/46,XY MGD group carried Yq microdeletions (PMC3827999). Curate this as a REFUTE/negative evidence item distinguishing PGD from MGD.

Modifier genes and oligogenicity. A clear genotype–phenotype correlation is absent for NR5A1, which has led to the hypothesis that "genetic modifiers, such as pathogenic variants in other testis/ovarian-determining genes, may contribute to the phenotypic expression." Direct evidence exists: in a 25-patient 46,XY DSD cohort, two patients carried pathogenic variants in both DHX37 and NR5A1, with "the most severe phenotype occurring in the digenic case" — DHX37 p.(Leu467Val) + NR5A1 frameshift, and DHX37 p.(Val999Met) + de novo NR5A1 nonsense (PMC10222664, DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis).

Curation flag for this KB: This is a genuine digenic inheritance finding. Per the CLAUDE.md digenic/oligogenic SOP, it warrants an Inheritance block bound to HP:0010984 (Digenic inheritance) with the DHX37+NR5A1 double-heterozygote citation as its own evidence item, and relationship_type: COOPERATING/MODIFIER on the second locus in the genetic: section.

2.3 Environmental risk factors

For 46,XY PGD specifically: essentially none established. This is a genetically determined developmental disorder; no environmental exposure has been shown to cause bona fide 46,XY partial gonadal dysgenesis with dysgenetic/streak gonads.

Adjacent but distinct — the testicular dysgenesis syndrome (TDS) hypothesis. Skakkebæk and colleagues proposed that cryptorchidism, hypospadias, impaired spermatogenesis and testicular cancer share a common origin in disturbed prenatal testicular development, possibly driven by endocrine-disrupting chemicals (EDCs) — anti-androgenic phthalates in particular (Skakkebaek et al., Best Pract Res Clin Endocrinol Metab 2006; PMID:16522521; see also PMID:29183799, "Is testicular dysgenesis syndrome a genetic, endocrine, or environmental disease…?"). Mechanistically, EDCs "may interfere with the control of testicular descent, which is regulated by two Leydig cell hormones, testosterone, and insulin like peptide 3 (INSL3)," and in utero phthalate exposure in rats suppresses fetal-testis steroidogenic gene expression, inducing multinucleated germ cells, hypospadias and cryptorchidism.

How to curate this: TDS is a mechanistically convergent but etiologically separate entity. It shares the downstream node "fetal Leydig cell dysfunction → androgen insufficiency → undervirilization" with PGD, but the trigger is exogenous and the gonad is not dysgenetic in the PGD sense. Record it as a discussion/KNOWLEDGE_GAP or a mechanistic note, not as a risk factor for MONDO:0016674. Most TDS evidence is MODEL_ORGANISM (rat) or ecological-epidemiological; human fetal testis xenografts were notably resistant to phthalate-induced endocrine disruption (PMC3440087) — a genuine human/model mismatch worth recording as HUMAN_MODEL_MISMATCH.

Other environmental factors: no established role for maternal age, parity, radiation, infection, diet, smoking, or alcohol in 46,XY PGD. Advanced paternal age is a plausible but unquantified contributor to the de novo missense burden (MAP3K1, DHX37, NR5A1) — no PGD-specific study exists. GARD's generic statement that "Environmental factors and viruses may also contribute" is boilerplate text and should not be curated as evidence.

2.4 Protective factors

No genetic or environmental protective factors are established for 46,XY PGD. Two observations that superficially resemble protection but are not:

46,XX carriers of MAP3K1 and MAP3K1/DHX37 variants are unaffected. "46,XX carriers appear to have normal fertility and no developmental abnormalities." (Ostrer H. Sex Dev 2022; PMID:35290982) This is sex-limited expression, not protection — the same allele is fully penetrant in a 46,XY background.
DHH heterozygotes are asymptomatic (autosomal recessive; GeneReviews NBK1547) — standard recessive carrier status.

gnomAD-based inference: because the causal variants are individually ultra-rare and largely de novo or sex-limited, gnomAD constraint metrics (pLI, missense z) support intolerance rather than identifying protective alleles. No protective haplotype has been reported.

2.5 Gene–environment interaction

No validated GxE interaction for 46,XY PGD. The plausible-but-unproven hypothesis is that sub-threshold germline variants in testis-determining genes (a "genetic first hit" producing borderline SOX9/SF-1 output) may be unmasked by in-utero anti-androgenic exposure, pushing the bistable switch across threshold. This is a specific, testable, currently-unsupported claim — appropriate for a discussions entry with kind: KNOWLEDGE_GAP and proposed_experiments (e.g., exposure-stratified genotype analysis in a hypospadias/DSD registry; human fetal-testis organoid dose–response on a sensitized NR5A1^+/− background).

3. Phenotypes

3.1 HPO annotation set (ORPHA:251510, retrieved from JAX HPO API; all IDs and labels verified against `sqlite:obo:hp` via OAK)

Frequency caveat — important for this KB. These frequency bands are Orphanet curator-assigned editorial bands, not counts from a genotyped cohort. Per docs/frequency-evidence-guidelines.md, most of these should be curated without a frequency: value unless a quantitative source is cited. Where a real cohort number exists (I-DSD 2025), I give it separately in §3.2 and that is what should carry the frequency band. The annotation set also clearly pools syndromic causes (nephroblastoma/nephrotic syndrome → WT1; adrenal insufficiency → NR5A1), so the tail annotations describe the gene-defined subgroups, not the core entity.

Genital / genitourinary — core phenotype

HPO ID	Label	Orphanet band	Comment
HP:0000062	Ambiguous genitalia	Very frequent	Cardinal sign
HP:0000133	Gonadal dysgenesis	Very frequent	Cardinal sign
HP:0012244	Abnormal sex determination	Very frequent	Mechanistic-level term
HP:0000047	Hypospadias	Very frequent	Penoscrotal/perineal at severe end
HP:0000054	Micropenis	Very frequent
HP:0008736	Hypoplasia of penis	Very frequent
HP:0008734	Decreased testicular size	Very frequent
HP:0000812	Abnormal internal genitalia	Very frequent	Müllerian remnants ± Wolffian hypoplasia
HP:0008665	Clitoral hypertrophy	Very frequent	Female-assigned presentation
HP:0000058	Abnormal labia morphology	Very frequent	Labioscrotal fusion
HP:0000045	Abnormal scrotum morphology	Very frequent	Bifid scrotum
HP:0100779	Urogenital sinus anomaly	Very frequent
HP:0000142	Abnormal vagina morphology	Very frequent
HP:0008726	Hypoplasia of the vagina	Very frequent
HP:0008730	Female external genitalia in individual with 46,XY karyotype	Very frequent	The near-female end of the spectrum
HP:0010464	Streak ovary	Very frequent	Streak gonad (asymmetric in PGD)
HP:0012870	Vanishing testis	Very frequent	TRS overlap
HP:0000028	Cryptorchidism	Frequent
HP:0000027	Azoospermia	Very frequent
HP:0003251	Male infertility	Very frequent
HP:0000868	Decreased fertility in females	Very frequent
HP:0000786	Primary amenorrhea	Very frequent	Female-assigned, later presentation

Endocrine / laboratory

HPO ID	Label	Band
HP:0000815	Hypergonadotropic hypogonadism	Very frequent
HP:0000837	Increased circulating gonadotropin level	Very frequent
HP:0008232	Elevated circulating follicle stimulating hormone level	Very frequent
HP:0011969	Elevated circulating luteinizing hormone level	Very frequent
HP:0040171	Decreased serum testosterone concentration	Very frequent
HP:0008214	Decreased serum estradiol	Very frequent
HP:0008193	Primary gonadal insufficiency	Occasional
HP:0000823	Delayed puberty	Frequent
HP:0008187	Absence of secondary sex characteristics	Occasional
HP:0000846	Adrenal insufficiency	Occasional

Two additional lab terms not in the Orphanet set but clinically central, verified in HPO and worth curating: - HP:0031103 — Decreased circulating antimullerian hormone circulation (sic — that is the canonical HPO label; do not "correct" it) - HP:0031100 — Decreased circulating inhibin B concentration

Neoplasia

HPO ID	Label	Band
HP:0000150	Gonadoblastoma	Frequent
HP:0000030	Testicular gonadoblastoma	Occasional
HP:0000149	Ovarian gonadoblastoma	Occasional
HP:0002667	Nephroblastoma	Very rare

Other / secondary

HPO ID	Label	Band	Comment
HP:0000771	Gynecomastia	Very frequent
HP:0000939	Osteoporosis	Very frequent	Secondary to untreated hypogonadism — downstream complication, not primary
HP:0002225	Sparse pubic hair	Very frequent
HP:0002215	Sparse axillary hair	Very frequent
HP:0002750	Delayed skeletal maturation	Occasional
HP:0000100	Nephrotic syndrome	Very rare	← WT1 subgroup (Denys–Drash/Frasier)
HP:0030680	Abnormal cardiovascular system morphology	Very rare	Likely contiguous-deletion cases

3.2 PGD-specific quantitative phenotype data — I-DSD Registry 2025 (the best available)

Tadokoro-Cuccaro R, et al. Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis. J Clin Endocrinol Metab 2025. PMID:40208111; DOI:10.1210/clinem/dgaf223. 310 patients, 34 international centres: CGD n=100, PGD assigned female (PGDf) n=107, PGD assigned male (PGDm) n=103.

These are the numbers that should carry frequency: values in the KB.

Measure	PGDf	PGDm	CGD
External genital score (median)	4.0	7.0	—
Uterus present	51%	31.3%	—
Presented with atypical genitalia in infancy	62.1%	~100%	—
Presented with delayed puberty	17.9% (abstract: "18%")	—	—
Presented with virilization	8%	—	—
Genetic cause identified	42.3% overall cohort
NR5A1 the most frequent gene	42.2% of solved PGDf	25.6% of solved PGDm
Low AMH	48%	58.1%
Testosterone ≥2× after hCG stimulation	—	66.0% (31/47)
Spontaneous puberty onset (≥13 y, gonads in situ)	—	80.0% (36/45)
Reached Tanner G5 without hormone treatment	—	59.3% (16/27)
Spontaneous virilization at puberty (clitoromegaly/hirsutism)	42.3% (11/26)	—
Gonadal pre-/malignancy	19.7%	8.8%	33.8%
Sex reassignment after initial assignment	16.1% (15/93) to male	5.3% (5/94) to female

Direct quotation from the abstract: "18% of PGDf presented with delayed puberty and 8% with virilization."

Second PGD-specific longitudinal series — Long-term follow-up of 10 patients with 46,XY PGD reared as males, 13.5–19.7 years follow-up (Int J Endocrinol 2014; PMID:25580123): - "All had spontaneous puberty; only one needed androgen therapy"; 9/10 reached Tanner ≥4. - "There was no case of testicular neoplasia" (small n; does not contradict the 8.8% figure above). - All three semen analyses: severe oligozoospermia. - Final height −1.57 to +0.80 SDS (9 patients) — growth is not primarily affected. - 30% had learning disabilities (mild ×2, moderate ×1); 50% had other conditions (VUR, hypothyroidism, hearing loss, psychiatric). Interpret cautiously — n=10, single centre, ascertainment-biased; this is not evidence that 46,XY PGD is a neurodevelopmental disorder.

3.3 Phenotype characteristics

Age of onset. Congenital / neonatal for the great majority. HPO onset: HP:0003577 Congenital onset / HP:0003623 Neonatal onset. The I-DSD data show a bimodal ascertainment: ~100% of PGDm and 62% of PGDf detected in infancy via atypical genitalia; a minority of PGDf present at adolescence with delayed puberty (18%) or virilization (8%). The Danish national data give median age at diagnosis of 17.0 years for gonadal dysgenesis presenting as phenotypic female (vs 7.5 y for AIS) — a striking diagnostic delay (PMID:27603905).

Severity. Variable by definition — the entity is defined by its spectrum (external genital score 0–12; median 4.0 female-assigned, 7.0 male-assigned). Use severity: variable phrasing rather than an enum band at the disease level.

Progression. The gonadal lesion is non-progressive in its determination defect (a fixed developmental event) but the gonadal function declines progressively — and there is a distinct progressive neoplastic risk with age. Curate two separate progression claims: - Endocrine: clinical_course: PROGRESSIVE on gonadal insufficiency (rising FSH/LH, falling testosterone/inhibin B/AMH across childhood into adulthood). - Oncological: cumulative, age-dependent germ cell neoplasia risk (§11.3). - Countervailing: the retained dysgenetic testis in PGDm often functions well enough for spontaneous puberty (80%), so "progressive gonadal failure" must not be over-stated for the male-assigned end of the spectrum.

Frequency among affected individuals. See §3.2. For the core signs (ambiguous genitalia, gonadal dysgenesis) treat as obligate/near-obligate; for everything else use the I-DSD numbers or omit.

3.4 Quality-of-life impact (per phenotype where possible)

No disease-specific validated QoL instrument exists for 46,XY PGD. The main data source is the European dsd-LIFE cross-sectional study (n=1,040 DSD patients, includes SF-36/WHOQOL and sexual-function measures; the same cohort as PMID:32905884). Per-phenotype impacts, ordered by weight of evidence:

Phenotype	QoL domain affected	Note
Atypical genitalia + genital surgery	Sexual function, body image, genital sensation	The most consequential and most contested domain; adult dissatisfaction with early surgery is well documented
Gender assignment uncertainty / reassignment (16.1% PGDf, 5.3% PGDm)	Psychological, identity, family	The single most distinctive QoL burden of PGD vs CGD
Infertility / severe oligozoospermia	Family planning, partnership, psychological	Near-universal
Unanticipated pubertal virilization in female-assigned (42.3%)	Acute distress, body image, need for urgent intervention	PGD-specific; does not occur in CGD
Cancer risk surveillance / gonadectomy decision	Anxiety, iatrogenic hypogonadism if gonads removed	See §11.3
Lifelong hormone replacement	Adherence, bone health, metabolic
Diagnostic delay (median 17 y in female-presenting GD)	Trust in care, missed intervention windows	PMID:27603905
Osteoporosis (HP:0000939)	Fracture risk, mobility	Secondary/preventable

The 2016 Global DSD Update is explicit that "the goal of patient care is focused upon the best possible quality of life (QoL)" and that "it is still impossible to predict gender development in an individual case with certainty." (Lee PA, Nordenström A, Houk CP, Ahmed SF, Auchus R, et al. Horm Res Paediatr 2016; PMID:26820577)

4. Genetic / Molecular Information

4.1 Causal genes with OMIM allelic-series mapping

Critical for NEC preflight — the OMIM identity anchors:

Gene	HGNC	Locus	Gene OMIM	Phenotype OMIM	Phenotype name
SRY	hgnc:11311	Yp11.2	480000	400044	46,XY SEX REVERSAL 1 (SRXY1)
NR5A1	hgnc:7983	9q33.3	184757	612965	46,XY SEX REVERSAL 3 (SRXY3)
MAP3K1	hgnc:6848	5q11.2	600982	613762	46,XY SEX REVERSAL 6 (SRXY6)
DHH	hgnc:2865	12q13.12	605423	233420	46,XY SEX REVERSAL 7 (SRXY7) — AR
DHH	hgnc:2865	12q13.12	605423	607080	46,XY GONADAL DYSGENESIS WITH MINIFASCICULAR NEUROPATHY (GDMN)
DHX37	hgnc:17210	12q24.31	617362	273250	46,XY SEX REVERSAL 11 (SRXY11)
SOX9	hgnc:11204	17q24.3	608160	114290 / 278850	Campomelic dysplasia w/ sex reversal; RevSex
WT1	hgnc:12796	11p13	607102	194080 / 136680	Denys–Drash; Frasier
DMRT1	hgnc:2934	9p24.3	602424	154230 (9p del)
NR0B1 (DAX1)	hgnc:7960	Xp21.2	300473	300018	46,XY sex reversal, dosage-sensitive (duplication)
ZFPM2 (FOG2)	hgnc:16700	8q23.1	603693	616067	SRXY9
GATA4	hgnc:4173	8p23.1	600576	—
SOX8	hgnc:11203	16p13.3	605923	—
PPP2R3C	hgnc:9306	14q13.2	615902	618419	Myopathy + 46,XY GD (MEGD)
HHAT	hgnc:18021	1q32.2	605743	614270	Nivelon–Nivelon–Mabille (46,XY GD + skeletal)

(Compiled from OMIM entries 400044, 612965, 613762, 233420, 607080, 273250, 605423; GeneReviews NBK1547)

Note the OMIM modelling choice: OMIM does not have a "46,XY partial gonadal dysgenesis" entry. It distributes PGD across the SRXY allelic series by gene, with each SRXY entry spanning CGD↔PGD↔TRS. MONDO:0016674, in contrast, is a phenotype-level grouping. This mismatch is the main NEC hazard for this entity — a deep-research tool asked for "46,XY partial gonadal dysgenesis" may return a report anchored on SRXY1 (SRY/Swyer, i.e., complete GD) or on MGD. Preflight by checking that the report's dominant gene is one of NR5A1/MAP3K1/DHX37 and that the described gonads are dysgenetic testes ± one streak, not bilateral streaks.

4.2 NR5A1 (SF-1) — the most frequent single cause

Function. NR5A1 encodes steroidogenic factor 1 (SF-1/Ad4BP), an orphan nuclear receptor and master transcriptional regulator of the hypothalamic–pituitary–gonadal–adrenal axis. It directly regulates SOX9 (via the TESCO/Enh13 enhancers), AMH, CYP17A1, STAR, INSL3, LHB, and CYP11A1.

Frequency. "NR5A1 mutations have been detected in about 10–20% of 46,XY DSD cases as major causes of gonadal dysgenesis in males." Approximately 8–15% across pooled 46,XY DSD cohorts; 5/27 (18.5%) in a German 46,XY DSD cohort (Köhler et al.); 6.70%–22.22% across 14 international cohorts 2013–2023 (DOI:10.3389/fgene.2024.1387598). In the PGD-specific I-DSD cohort, NR5A1 was the single most frequent gene: 42.2% of genetically-solved PGDf and 25.6% of solved PGDm (PMID:40208111).

Variant classes. Missense (DNA-binding zinc fingers, ligand-binding domain, Ftz-F1 box), frameshift, nonsense, splice-site, whole-gene deletion. Predominantly heterozygous with haploinsufficiency/dominant-negative effect; rare biallelic cases cause severe adrenal + gonadal failure.

Recurrent variant of special note: p.Arg92Trp (R92W) — causes 46,XX testicular/ovotesticular DSD in humans (a gain-of-pro-testis effect in the XX background), demonstrating the exquisite dosage sensitivity of SF-1. Critically, this is a documented human/mouse mismatch: "The p.R92W variant of NR5A1/Nr5a1 induces testicular development of 46,XX gonads in humans, but not in mice" (PMC5101639) — curate as HUMAN_MODEL_MISMATCH.

Phenotypic spectrum (extremely wide — the defining feature of NR5A1). GeneReviews: NR5A1 variants are "associated with a wide range of phenotypes including isolated 46,XY partial and complete gonadal dysgenesis, 46,XY undervirilization, vanishing testes, and male infertility." In 46,XX carriers: primary ovarian insufficiency. Adrenal insufficiency is present in only a minority — the classic teaching that SF-1 defects always cause adrenal failure is wrong. "Heterozygous mutations in SF1 may be found in patients with 46,XY partial gonadal dysgenesis and underandrogenization but normal adrenal function."

Genotype–phenotype: "A clear genotype-phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers... may contribute to the phenotypic expression." Intrafamilial variability is marked — the same variant may produce CGD in the proband and only infertility in the father.

Illustrative case (NR5A1-related PGD, PMID:38206718 / PMC10754607): 12-year-old raised female presenting with hirsutism, deep voice, clitoromegaly (1.5 × 1.0 cm), Tanner II breast, no menarche; FSH 53.31 mIU/mL (ref 1.78–11.60), testosterone 2.58 ng/mL (ref 0–1.23); dysplastic testes in bilateral groin, absent uterus and ovaries. Bilateral orchiectomy + feminizing hormone therapy → regression of hirsutism and clitoromegaly. This case is a perfect illustration of the 42.3% pubertal-virilization phenomenon in PGDf.

Allele frequency. Pathogenic NR5A1 variants are absent or singleton in gnomAD. NR5A1 is missense- and LoF-constrained. Many reported variants are de novo; inherited variants typically come from a mildly affected or unaffected parent (sex-limited/incomplete penetrance).

4.3 MAP3K1 — the canonical gain-of-function cause

The definitive mechanistic statement (Ostrer H. Sex Dev 2022;16(2-3):137-142; PMID:35290982), verbatim:

"Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis, accounting for at least 4% of cases. Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance in 46,XY individuals. 46,XX carriers appear to have normal fertility and no developmental abnormalities. Pathogenic variants occur almost exclusively within known domains of the MAP3K1 protein, facilitating annotation when identified. Where studied, these variants have been modeled to alter the local MAP3K1 folding and surface domains and have been shown to alter interactions with known binding partners. The net effect of these variants is to increase phosphorylation of downstream targets ERK1, ERK2, and p38, resulting in multiple gain-of-function effects interfering with testis determination and enabling ovarian determination."

Discovery (Pearlman A, Loke J, Le Caignec C, et al. Am J Hum Genet 2010;87(6):898-904; PMID:21129722):

"Here, the locus for an autosomal sex-determining gene was mapped via linkage analysis in two families with 46,XY DSD to the long arm of chromosome 5 with a combined, multipoint parametric LOD score of 6.21."

The same paper showed the mutations alter phosphorylation of downstream signalling molecules, enhance binding to RHOA, and that mouse Map3k1 is expressed in the embryonic gonad during the sex-determination window.

Clinical series (Granados A, Alaniz VI, Mohnach L, et al. Am J Med Genet C 2017;175(2):253-259; PMID:28504475), verbatim abstract excerpt:

"MAP3K1 encodes a signal transduction regulator in the sex determination pathway and is emerging as one of the more common genes responsible for 46,XY DSD presenting as complete or partial gonadal dysgenesis. Clinical assessment, endocrine evaluation, and genetic analysis were performed in six individuals from four unrelated families with 46,XY DSD. All six individuals were found to have likely pathogenic MAP3K1 variants. Three of these individuals presented with complete gonadal dysgenesis, characterized by bilateral streak gonads with typical internal and external female genitalia, while the other three presented with partial gonadal dysgenesis, characterized by incomplete testicular development, resulting in clitoral hypertrophy with otherwise typical female external genitalia. Testing for MAP3K1 variants should be considered in patients with 46,XY complete or partial gonadal dysgenesis, particularly in families with multiple members affected with 46,XY DSD. Identification of a MAP3K1 variant should prompt an evaluation for DSD in female siblings of the proband."

Detailed functional dissection of one variant — p.R186G (PMC8927045, MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling…): - Variant c.556A>G / p.R186G in two affected siblings. - "significantly decreased affinity to ubiquitin (43–49%) and increased affinity to RhoA, which was 3.19 ± 0.18 fold" vs wild type → reduced degradation → increased MAP3K1 protein stability. - "led to hyperphosphorylation of p38 and GSK3β, and promoted hyperactivation of the Wnt4/β-catenin signaling" — phospho-GSK3β is inactive, permitting β-catenin accumulation and nuclear translocation. - In NT2/D1 testicular cells the variant "upregulated the expression of genes associated with ovarian development (including WNT4, CTNNB1, and FOXL2) and downregulated the expression of testicular development-related genes (FGFR2 and DMRT1)." - Models: NT2/D1 (testicular teratoma), KGN (ovarian granulosa), HEK-293T (reporter). All IN_VITRO.

Variant type/class: almost exclusively missense, clustered in defined MAP3K1 domains (the SWIM/RHOA-binding and kinase-adjacent regions). Frameshift/nonsense variants are conspicuously not a cause — consistent with gain-of-function rather than haploinsufficiency. This is a strong, curatable ACMG-relevant statement: "Pathogenic variants occur almost exclusively within known domains of the MAP3K1 protein, facilitating annotation when identified."

4.4 DHX37 — the newest major gene (and a candidate ribosomopathy)

Discovery (McElreavey K, Jorgensen A, Eozenou C, et al. Genet Med 2020;22(1):150-159; PMID:31337883; PMC6944638):

"XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown."

Findings: 145 individuals with 46,XY DSD of unknown cause sequenced; 13 children carried heterozygous missense pathogenic variants in DHX37, an RNA helicase essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants vs controls was P = 5.8 × 10⁻¹⁰. Five variants were de novo; twelve clustered in two highly conserved functional domains and were "specifically associated with gonadal dysgenesis and testicular regression syndrome." DHX37 expression was confirmed in developing testis somatic cells. Conclusion: "DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD," with GD and TRS representing a clinical spectrum and potentially a ribosomopathy.

PGD-specific replication (PMC10222664): in 25 individuals with 46,XY DSD (16 PGD, 6 TRS, 3 CGD), 4/25 (16%) carried pathogenic DHX37 variants: - p.(Arg308Gln) — the recurrent hotspot, previously reported in 17 individuals - p.(Leu467Val) — novel in DSD - p.(Val999Met) — 2 unrelated patients, in the OB-fold domain

Plus the two digenic DHX37+NR5A1 cases described in §2.2.

Domain clustering: variants concentrate in the RecA2 and OB-fold domains (see also PMID:37717579, "Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome"). Consistent with hypomorphic/specific-function-altering rather than null alleles.

Mechanistic hypothesis (EMERGING status): DHX37 is required for 18S rRNA processing/small-subunit biogenesis. The proposal is that the fetal testis somatic lineage has an unusually high ribosome-biogenesis demand during the narrow determination window, making it selectively vulnerable to partial DHX37 loss — a tissue-selective ribosomopathy (see "DHX37 and 46,XY DSD: A New Ribosomopathy?", Sexual Development 2022;16(2-3):194-206). Curate as a mechanistic_hypotheses entry with status: EMERGING; the alternative (a non-ribosomal moonlighting function of DHX37 in gonadal somatic cells) is not excluded.

4.5 SRY

Hemizygous SRY variants "primarily cause a 46,XY CGD phenotype," though rare mosaicism cases present with milder 46,XY DSD — i.e., somatic SRY mosaicism is a recognised route to PGD rather than CGD (GeneReviews NBK1547). Variants concentrate in the HMG box (DNA-binding/bending domain), impairing DNA binding, nuclear import, or DNA bend angle. Mostly de novo; paternal transmission is rare and implies gonadal mosaicism or reduced penetrance. 10–15% of nonsyndromic 46,XY testicular DSD overall.

4.6 DHH — the autosomal recessive cause with a neurological tell

Umehara et al. 2000 (PMID:11017805) reported the first human DHH mutation: a homozygous missense at the initiation codon (ATG→ACG) in exon 1, predicting translational failure, in a 27-year-old 46,XY woman with partial gonadal dysgenesis + polyneuropathy — female external genitalia with blind vagina and immature uterus, a testis on one side and a streak gonad on the other (the textbook PGD gonadal configuration).
Werner et al. 2015 (PMID:25927242) found homozygous p.Arg124Gln (R124Q) in two Syrian sisters with 46,XY GD and polyneuropathy, via exome sequencing.
OMIM 607080 = 46,XY gonadal dysgenesis with minifascicular neuropathy (GDMN); OMIM 233420 = SRXY7 (gonadal phenotype without overt neuropathy).
GeneReviews: "DHH biallelic pathogenic variants cause 46,XY DSD; individuals may develop peripheral neuropathy between ages 20-30 years."

Curation implication: DHH-related PGD carries a latent, adult-onset neurological phenotype that is easily missed if the entry is scoped purely to the gonad. This is a legitimate has_subtypes candidate, and a rationale for long-term neurological surveillance in DHH-positive patients.

4.7 Other loci

DMRT1 / 9p24.3 deletion — haploinsufficiency; monosomy 9p syndrome includes 46,XY GD with intellectual disability and trigonocephaly (syndromic; distinct entity).
SOX9 — coding LoF → campomelic dysplasia with sex reversal; non-coding enhancer CNVs (RevSex/Enh13 region, ~600 kb upstream) cause isolated 46,XY GD. These are invisible to exome sequencing — a specific argument for WGS/CMA (see §10.2).
SOX8 — 16p13.3; rare, phenotypically milder; partially redundant with SOX9.
NR0B1 (DAX1) duplication, Xp21.2 — dosage-sensitive sex reversal; X-linked, inherited from carrier mother in most cases; 50% transmission risk per pregnancy.
WNT4 / RSPO1 duplication (1p36) — pro-ovary gain of dosage.
ZFPM2 (FOG2) and GATA4 — GATA4–FOG2 complex is required for Sry upregulation; LoF variants cause 46,XY GD (ZFPM2 = SRXY9) and, for GATA4, often co-segregating congenital heart disease.
WT1 — in nonsyndromic PGD, rare; the +KTS/−KTS isoform ratio (Frasier, intron 9 splice donor) and missense zinc-finger variants (Denys–Drash) define syndromic entities with Wilms tumour (HP:0002667) and nephrotic syndrome (HP:0000100) — explaining those two "Very rare" HPO annotations. A reported case combines "a novel SRY missense mutation combined with a WT1 KTS splice-site mutation" in a 46,XY female with bilateral gonadoblastoma (PMID:22815844) — another digenic data point.
PPP2R3C, PBX1, HHAT, LHX9, SOS1, OTX2, PROP1, MYRF, PPP1R12A — reported in GD/PGD; evidence strength varies from strong (HHAT, PPP2R3C, PBX1) to provisional. The Elzaiat review explicitly cautions: "We critically evaluate the evidence to support causality of these factors… we propose several recommendations to help interpret the data and establish causality." Curate weak-evidence genes with supports: PARTIAL and an explicit explanation noting limited replication.

4.8 Somatic vs germline, mosaicism, and epigenetics

Germline is the rule. Somatic variants are not a described cause; germline mosaicism (parental gonadal mosaicism for SRY, NR5A1, MAP3K1) is documented and underlies apparently de novo recurrence in sibships.
Somatic mosaicism in the patient — notably for SRY — is a route to PGD (partial testis determination in a mosaic gonad) and is a reason to consider gonadal-tissue rather than blood-only genotyping. Idris et al. recommend transcriptomics/Hi-C/multi-tissue analysis "to resolve pathogenicity in ambiguous cases and detect mosaicism across multiple tissues" (PMID:39081229).
Epigenetics. There is no established primary epigenetic etiology for 46,XY PGD. The mechanistically relevant epigenetics is developmental: the SOX9 TESCO/Enh13 enhancer landscape and CBX2 (Polycomb) — CBX2 LoF causes 46,XY GD, placing chromatin-mediated repression of the ovarian program in the causal chain. HP:0071514-type imprinting mechanisms are not implicated. This is a genuine gap: no methylome study of dysgenetic gonad tissue in PGD has been published.
Chromosomal abnormalities. By definition the karyotype is 46,XY non-mosaic. The relevant "chromosomal" lesions are submicroscopic CNVs: 9p24 deletion (DMRT1), Xp21.2 duplication (NR0B1), 1p36 duplication (WNT4/RSPO1), 17q24.3 SOX9 enhancer CNVs, 22q, and 10q26 deletions. CMA is therefore not optional. Any detected 45,X/46,XY mosaicism reclassifies the patient to MGD.

5. Environmental Information

Environmental factors: none established as causal for 46,XY PGD (see §2.3). The EDC/phthalate literature applies to the TDS spectrum (cryptorchidism, hypospadias, subfertility, testicular germ cell cancer), which is mechanistically adjacent but a different entity. Curate any EDC content as evidence_source: MODEL_ORGANISM (rat in-utero phthalate) or OTHER (ecological epidemiology), never as HUMAN_CLINICAL support for MONDO:0016674.

Lifestyle factors: none. No smoking/diet/alcohol/exercise association is established. Post-diagnosis, lifestyle matters only for secondary outcomes (bone health under hormone replacement — weight-bearing exercise, calcium/vitamin D).

Infectious agents: Not applicable. No pathogen has any established role in the etiology of 46,XY PGD.

6. Mechanism / Pathophysiology

6.1 The causal chain (upstream → downstream)

The pathophysiology is best modelled as a five-node chain with a bifurcating output, plus a distinct late-onset neoplastic arm.

[MOLECULAR]  Testis-determining network lesion
     (NR5A1 haploinsufficiency | MAP3K1 GoF | DHX37 hypomorph |
      SRY LoF | DHH LoF | SOX9 dosage | NR0B1 dup)
        ↓
[CELLULAR]   Failure to reach the SOX9 threshold in bipotential
     supporting-cell precursors → incomplete Sertoli cell
     fate commitment; unopposed WNT4/RSPO1/β-catenin/FOXL2
     pro-ovarian signalling in a subset of cells
        ↓
[TISSUE]     Partial testis differentiation → dysgenetic testis
     (± contralateral streak gonad): reduced seminiferous
     tubule number/size, peritubular fibrosis, germ cell
     depletion, Leydig cell hyperplasia
        ↓ ↓ (two parallel hormone deficits)
[ORGANISM]  (a) Sertoli cell AMH deficiency → incomplete Müllerian
duct regression → retained uterus/tubes/upper vagina
    (b) Fetal Leydig cell testosterone + INSL3 deficiency →
incomplete Wolffian development, incomplete genital
tubercle/urethral masculinization, cryptorchidism
        ↓
[ORGANISM]   Ambiguous external genitalia at birth;
     hypergonadotropic hypogonadism; variable pubertal course
        ↓ (age-dependent, parallel arm)
[TISSUE]     Germ cells arrested in an immature (OCT3/4+) state in a
     dysgenetic niche, with TSPY expression from the Y →
     germ cell neoplasia in situ / gonadoblastoma →
     invasive dysgerminoma/seminoma

Upstream vs downstream assignment for KB curation: - Upstream (MOLECULAR): the specific gene lesion; SOX9 threshold failure. - Midstream (CELLULAR/TISSUE): Sertoli-cell fate failure; dysgenetic gonad histology. - Downstream (ORGANISM): AMH deficiency → Müllerian retention; androgen deficiency → undervirilization; hypergonadotropic hypogonadism; infertility; osteoporosis. - Parallel late arm: germ cell neoplasia.

6.2 Molecular pathways

The bistable testis-vs-ovary switch. The gonadal primordium is bipotential; two mutually antagonistic gene-regulatory networks compete, and the outcome is a switch, not a gradient. Reviews synthesising this (Frontiers in Endocrinology 2024, Unveiling the roles of Sertoli cells lineage differentiation in reproductive development and disorders, PMC11063913):

Pro-testis arm (must win): - SRY (transient, ~E10.5–E12.0 mouse; wk 6–7 human) + NR5A1 cooperatively bind the TESCO/Enh13 enhancer of SOX9 → SOX9 upregulation. - SOX9 "enhances the expression of testicular development-related factors, such as prostaglandin D2 synthase (PTGDS), anti-Müllerian hormone (AMH), WT1, GATA4, and SOX8, while concurrently inhibiting the expression of ovarian determinants, including WNT4, RSPO1, and β-catenin." - SOX9 "can further enhance its own expression by activating the PGD2 and FGF9 signaling pathways, thereby forming a positive feedback loop." In the XY gonad, "a positive feedback loop between Sox9 and Fgf9 (as well as PGD2) is established to suppress Wnt4/Rspo1 expression in a paracrine manner, thereby promoting Sertoli cell differentiation." - DHH is secreted by Sertoli cells and signals via PTCH1/GLI to induce fetal Leydig cell differentiation and to organise the peritubular myoid/basal-lamina compartment — hence DHH loss → Leydig deficiency + testicular dysgenesis + (in Schwann cells) minifascicular neuropathy.

Pro-ovary arm (must be repressed): - RSPO1 → WNT4 → canonical β-catenin (CTNNB1) → FOXL2. "Rspo1, Wnt4, and β-catenin inhibit testicular cord formation." FOXL2 and the RSPO1/WNT4/β-catenin axis "work in a complementary manner to promote ovarian growth and inhibit testicular development."

The MAP3K1 route into this switch — the single best-characterised PGD mechanism:

MAP3K1 (MEKK1) is a MAP kinase kinase kinase. PGD-causing variants act by stabilising the protein and rewiring its interactome, not by abolishing kinase activity:

Variant reduces ubiquitin affinity (to 43–49% of WT) → less proteasomal degradation → MAP3K1 accumulates.
Variant increases RHOA binding (3.19-fold) → altered upstream regulation.
→ Hyperphosphorylation of ERK1/ERK2, p38, and GSK3β.
Phospho-GSK3β is inactivated → the β-catenin destruction complex fails → β-catenin accumulates and enters the nucleus.
→ WNT4/CTNNB1/FOXL2 upregulated; FGFR2 and DMRT1 downregulated.
Net effect (Ostrer, verbatim): "multiple gain-of-function effects interfering with testis determination and enabling ovarian determination."

This is a beautiful, curatable causal chain and a strong candidate for the pathophysiology graph backbone of the MAP3K1 subtype.

The DHX37 route: DHX37 is a DEAH-box RNA helicase required for ribosome biogenesis (18S rRNA/SSU processome). Expressed in developing testis somatic cells. Domain-clustered missense variants (RecA2, OB-fold) are hypothesised to impair ribosome assembly selectively in the high-demand fetal gonadal somatic lineage → insufficient synthesis of the short-lived, dosage-critical determination factors (SRY, SOX9) during the window → partial determination and/or subsequent testicular regression. Status: EMERGING hypothesis, explicitly framed as a question in the literature ("A New Ribosomopathy?").

The NR5A1 route: SF-1 haploinsufficiency reduces transactivation at SOX9 enhancers (determination failure) and at STAR/CYP11A1/CYP17A1 (steroidogenic failure) and at AMH — a single lesion hitting three limbs. This dual determination+steroidogenesis hit explains why NR5A1 PGD can present with both undervirilization and, occasionally, adrenal insufficiency, and why the phenotype is so variable.

6.3 Cellular processes

Process	GO term (verified)	Role
Sex determination	GO:0007530	Top-level
Male sex determination	GO:0030238	The defective process
Male gonad development	GO:0008584
Gonad development	GO:0008406
Sertoli cell differentiation	GO:0060008	The pivotal cell-fate decision
Sertoli cell proliferation	GO:0060011
Male sex differentiation	GO:0046661	Downstream of determination
Female gonad development	GO:0008585	Aberrantly de-repressed
Wnt signaling pathway	GO:0016055	Pro-ovarian arm
Canonical Wnt signaling pathway	GO:0060070	β-catenin arm; `modifier: INCREASED` in MAP3K1
MAPK cascade	GO:0000165	`modifier: INCREASED` in MAP3K1
Intracellular signal transduction	GO:0035556
Ribosome biogenesis	GO:0042254	DHX37 arm; `modifier: DECREASED`
Regulation of transcription by RNA polymerase II	GO:0006357	NR5A1/SOX9/SRY arm
Adrenal gland development	GO:0030325	NR5A1 subgroup only

Additional relevant (not individually verified here, verify before use): hedgehog signaling (DHH arm), apoptotic process (germ cell loss), cell fate commitment.

6.4 Protein dysfunction

Protein	UniProt	Dysfunction class
SF-1 / NR5A1	Q13285	Loss of function / haploinsufficiency; impaired DNA binding (zinc fingers) or coactivator recruitment (LBD/AF-2)
MAP3K1	Q13233	Gain of function: increased stability (reduced ubiquitination), increased RHOA binding, increased downstream phosphorylation
DHX37	Q8IY37	Hypomorph in RecA2/OB-fold; impaired RNA helicase/SSU processome function
SRY	Q05066	Loss of DNA binding/bending (HMG box); impaired nuclear import
SOX9	P48436	Haploinsufficiency, or enhancer-mediated dosage loss
DHH	O43323	Loss of function; the Umehara initiation-codon variant abolishes translation entirely

No protein aggregation, misfolding-with-inclusion, or proteinopathy mechanism is involved. MAP3K1 variants alter local folding and surface topology (per Ostrer), which changes binding partners — not a misfolding/aggregation disease.

6.5 Metabolic changes

The relevant "metabolism" is steroidogenesis, not intermediary metabolism: - Reduced fetal and postnatal testosterone (CHEBI:17347) biosynthesis due to reduced Leydig cell mass and, for NR5A1, reduced transcription of STAR, CYP11A1, CYP17A1, HSD17B3. - Reduced dihydrotestosterone (CHEBI:16330; canonical label 17beta-hydroxy-5alpha-androstan-3-one) from reduced substrate. - Reduced AMH (a TGF-β family glycoprotein, not a CHEBI entity — use the HPO lab term). - Reduced inhibin B (Sertoli cell product). - Reduced INSL3 → cryptorchidism. - In female-assigned patients post-gonadectomy: decreased 17β-estradiol (CHEBI:16469) requiring replacement. - No energy, lipid, or amino-acid metabolic derangement. This is not an inborn error of metabolism and must not be modelled as one.

6.6 Immune system involvement

None. 46,XY PGD is not autoimmune, not an immunodeficiency, and not inflammatory. The only tangential immune consideration is immune surveillance of germ cell neoplasia in situ, which is not disease-specific. Do not curate an immune arm.

6.7 Tissue damage mechanisms

The gonad is maldeveloped, not damaged — this is a critical modelling distinction. There is no ischemia, oxidative-stress injury, or necrosis. The observed histological features are developmental and secondary: - Peritubular fibrosis — a hallmark of dysgenetic testis (GeneReviews: dysgenetic testes show "decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells"). This is aberrant matrix deposition in a maldeveloped gonad, not a conserved fibrotic response to injury — do not conforms_to: fibrotic_response. - Streak gonad — ovarian-type stroma without follicles or tubules; the end-state of complete determination failure on one side. - Progressive germ cell loss — apoptotic attrition of germ cells in an unsupportive niche. - Leydig cell hyperplasia — a compensatory response to LH drive, not damage.

6.8 Biochemical abnormalities

Sertoli cell: ↓AMH (HP:0031103), ↓inhibin B (HP:0031100)
Leydig cell: ↓testosterone (HP:0040171), ↓INSL3, blunted hCG response (only 66% of PGDm double testosterone on hCG stimulation, PMID:40208111)
Pituitary feedback: ↑FSH (HP:0008232), ↑LH (HP:0011969) → hypergonadotropic hypogonadism (HP:0000815)
NR5A1 subgroup only: ↓cortisol/↑ACTH if adrenal involvement (HP:0000846)
No enzyme deficiency, no ion channel defect, no receptor defect — this distinguishes PGD from the two main differential diagnoses: androgen biosynthesis defects (17β-HSD3, 5α-reductase-2 — true enzymopathies) and androgen insensitivity (AR receptor defect).

6.9 Epigenetic changes

No primary epigenetic lesion. The mechanistically relevant chromatin biology is CBX2/Polycomb-mediated repression of the ovarian program and enhancer-dependent SOX9 dosage (see §4.8). Genuine gap: no methylome or ATAC-seq study of human dysgenetic gonadal tissue from PGD patients has been published.

6.10 Molecular profiling

Transcriptomics. No PGD-patient gonadal transcriptome dataset exists. The available data are (a) human fetal gonad scRNA-seq atlases (Human Cell Atlas; Guo et al.; Garcia-Alonso et al. Nature 2022 human gonadal development atlas) defining the supporting/Sertoli, Leydig, germ, and coelomic epithelial lineages against which dysgenesis can be interpreted; and (b) in vitro cell-line transcriptional readouts from variant-function studies (NT2/D1, KGN — PMC8927045). GEO/ArrayExpress hold no PGD-labelled series.

Proteomics / metabolomics / lipidomics. None available. No PRIDE, MetaboLights, or Metabolomics Workbench dataset for 46,XY PGD. Explicitly a gap.

Genomic structural features. The clinically important ones are the SOX9 upstream regulatory region (RevSex/Enh13, ~600 kb 5′ of SOX9, chr17q24.3), the NR0B1 Xp21.2 dosage-sensitive region, 9p24.3 (DMRT1), and 1p36 (WNT4/RSPO1). These are non-coding/CNV lesions requiring CMA or WGS, and are the strongest single argument against exome-only testing.

Single-cell / spatial. No PGD-specific single-cell or spatial transcriptomic study. The Idris 2025 review recommends multi-omic escalation (transcriptomics, Hi-C) for VUS resolution — aspirational, not yet standard.

Functional genomics screens. No published CRISPR/RNAi screen for testis-determination modifiers in a human gonadal-somatic system. DepMap does not model this tissue. A clear, high-value experimental gap.

7. Anatomical Structures Affected

7.1 Organ level

Primary (directly affected by the causal lesion): - Gonad — UBERON:0000991 (the primary lesion site) - Testis — UBERON:0000473 (dysgenetic) - Ovary — UBERON:0000992 (as ontological reference for the streak gonad; a streak is ovarian-type stroma)

Secondary (affected by the hormone deficits, i.e., downstream): - Müllerian duct — UBERON:0003890 → incomplete regression - Uterus — UBERON:0000995 (present in 51% of PGDf, 31.3% of PGDm — PMID:40208111) - Vagina — UBERON:0000996 (upper vagina Müllerian-derived; hypoplasia HP:0008726) - Mesonephric (Wolffian) duct — UBERON:0003074 → incomplete development - Epididymis — UBERON:0001301, prostate gland — UBERON:0002367 (hypoplastic) - Undifferentiated genital tubercle — UBERON:0005876 → hypospadias, micropenis, clitoromegaly - Internal genitalia — UBERON:0004175 - Male reproductive system — UBERON:0000079 - Adrenal gland — UBERON:0002369 (NR5A1 subgroup only) - Kidney (Wilms tumour, nephrotic syndrome) — WT1 subgroup only - Peripheral nerve — DHH subgroup only (minifascicular neuropathy) - Bone — secondary osteoporosis from hypogonadism

Body systems: reproductive (primary), endocrine (primary), urinary (via urogenital sinus/hypospadias), skeletal (secondary), nervous (DHH subgroup only), cardiovascular (very rare, contiguous-deletion cases).

7.2 Tissue and cell level

Cell type	CL term (verified)	Involvement
Sertoli cell	CL:0000216	The pivotal cell — fate commitment fails; ↓AMH, ↓inhibin B
Leydig cell	CL:0000178	Fetal Leydig deficiency → ↓T, ↓INSL3; postnatal hyperplasia under LH drive
Germ cell	CL:0000586	Depleted; when retained, arrested immature → neoplastic precursor
Male germ cell	CL:0000015
Primordial germ cell	CL:0000670	The migratory population entering a defective niche
Granulosa cell	CL:0000501	Ontological counterpart of the mis-specified supporting lineage
Peritubular myoid cell	CL:0002481	Contributes to cord formation; abnormal → peritubular fibrosis
Sperm	CL:0000019	Absent/severely reduced (azoospermia, severe oligozoospermia)

Note: CL:0000630 supporting cell exists but is the generic (non-gonadal) class — CL currently lacks a clean "bipotential gonadal supporting cell precursor" term. This is a real ontology gap worth recording; the honest curation is CL:0000216 (Sertoli cell) with a preferred_term of "bipotential gonadal supporting cell precursor" per the preferred_term > term.label specificity convention in CLAUDE.md.

Tissue types: gonadal somatic (mesenchymal/epithelial-derived supporting lineage) — primary; germinal epithelium — secondary; connective tissue (peritubular fibrosis); the streak gonad's ovarian-type stroma.

7.3 Subcellular level (GO Cellular Component)

Nucleus (GO:0005634) — SF-1, SOX9, SRY, WT1, DMRT1 are all nuclear transcription factors; β-catenin nuclear translocation is the MAP3K1 effector step.
Cytosol (GO:0005829) — MAP3K1 signalling complex, β-catenin destruction complex (GSK3β/APC/AXIN).
Nucleolus (GO:0005730) — DHX37/ribosome biogenesis.
Extracellular region / extracellular space (GO:0005576/GO:0005615) — DHH, AMH, FGF9, WNT4, RSPO1 (all secreted).
Plasma membrane (GO:0005886) — PTCH1/SMO (hedgehog), FZD/LRP (Wnt), FGFR2.

Verify these CC IDs with OAK before committing; I verified only the BP terms above.

7.4 Localization and lateralization

Bilateral but characteristically ASYMMETRIC — this is a defining and under-appreciated feature. "Partial GD is defined by bilateral dysgenetic gonads. The histology of dysgenetic testes may vary from gonads with a few tubular structures and predominance of fibrous tissue to those with mild abnormalities, and they may be found bilaterally or associated with streak gonads." The classic PGD configuration is a dysgenetic testis on one side and a streak gonad on the other (as in Umehara's index DHH case).

Gonadal position is variable along the descent path: "depending on the percentage of testicular tissue, dysgenetic testes can be found anywhere along the line of testis descent, from the abdomen, and in cases of normal testes, in the scrotum." Intra-abdominal position independently raises tumour risk.

Consequently the internal duct derivatives are often asymmetric too: a hemi-uterus/fallopian tube on the side with poorer AMH output and a vas/epididymis on the better side. Curate lateralization as bilateral, asymmetric.

8. Temporal Development

8.1 Onset

Biological onset: embryonic, gestational weeks ~6–8 (the human testis-determination window; mouse E10.5–E12.5). The determination event is over before the second trimester.
Clinical onset: congenital (HP:0003577), recognised neonatally in most (HP:0003623) via atypical genitalia.
Onset pattern: insidious/static developmental — not acute, not subacute. The genital phenotype is fully formed at birth.
Bimodal ascertainment. Infancy (atypical genitalia) for ~100% of PGDm and 62.1% of PGDf; adolescence for a substantial PGDf minority (17.9% delayed puberty, 8% virilization). Danish population data: median age at diagnosis 17.0 years for female-presenting gonadal dysgenesis (PMID:27603905).

8.2 Progression

There are no formal disease stages. A pragmatic natural-history framework:

Period	Events
Fetal (wk 6–20)	Determination failure → dysgenetic gonad → partial AMH/androgen deficiency → genital and ductal phenotype fixed
Neonatal (0–6 mo)	"Mini-puberty" — the diagnostic window when gonadotropins/testosterone/AMH/inhibin B are physiologically elevated and most informative. Missing it forces reliance on hCG stimulation later.
Childhood	Hormonally quiescent; risk of missed diagnosis; gonadal position/surveillance decisions
Puberty (~11–16 y)	The critical branch point. PGDm: 80% enter puberty spontaneously, 59% reach G5 unaided. PGDf with retained gonads: 42.3% virilize — clitoromegaly, hirsutism, voice change. This is often the trigger for reassignment (16.1% of PGDf reassigned to male).
Young adulthood	Infertility recognised; hormone replacement stabilised; peak diagnostic yield for germ cell neoplasia
Adulthood	Cumulative neoplasia risk; osteoporosis if under-replaced; DHH subgroup: peripheral neuropathy onset ages 20–30

Progression rate: slow and variable. Course pattern: static developmental lesion with progressive endocrine decline in a subset, and progressive (cumulative) oncological risk. Duration: chronic, lifelong.

8.3 Patterns

Remission: not applicable — no spontaneous or treatment-induced remission. Hormone replacement and surgery are palliative/reconstructive, not curative.
Critical windows:
Fetal wk 6–8 — the only window in which the primary defect could theoretically be prevented; currently inaccessible.
Mini-puberty (0–6 months) — the highest-yield endocrine diagnostic window.
Peri-pubertal (~10–13 y) — the decision point for gonadal retention vs removal in PGDf (retention permits spontaneous puberty and preserves the small chance of gonadal function, but risks unwanted virilization and is when neoplasia risk begins to accrue). This trade-off is now quantified by PMID:40208111 and is the most clinically actionable temporal finding for this entity.
Adolescence–young adulthood — bone mass accrual window; adequate sex-steroid replacement here determines lifetime fracture risk.

9. Inheritance and Population

9.1 Epidemiology

PGD-specific prevalence is not directly published. The best anchor is the Danish nationwide registry study (Berglund A, Johannsen TH, Stochholm K, Viuff MH, Fedder J, Main KM, Gravholt CH. J Clin Endocrinol Metab 2016;101(12):4532-4540; PMID:27603905):

"The prevalence of 46,XY females was 6.4 per 100 000 live born females."

with gonadal dysgenesis at 1.5 per 100,000 (vs AIS 4.1 per 100,000). Note this counts phenotypic females only — it therefore undercounts PGD substantially, since roughly half of PGD patients are assigned male (I-DSD: PGDf 107 vs PGDm 103). A defensible estimate for all 46,XY gonadal dysgenesis (CGD+PGD, both sexes of rearing) is therefore on the order of ~3 per 100,000 births, with PGD perhaps 1–2 per 100,000 — but flag this as an inference, not a published figure.

Other anchors: - Incidence of gonadal dysgenesis reported as ~1 per 80,000 births; AIS 1–5 per 100,000. - Newborns with ambiguous genitalia: 1/4,500 to 1/5,000 — the broader denominator from which PGD is drawn. - Orphanet classifies ORPHA:251510 under rare; the specific Orphanet prevalence class for this entity is not documented (NOT_YET_DOCUMENTED is the honest prevalence_class).

Suggested KB prevalence records:

prevalence:
- population: Denmark (phenotypic females, nationwide registry)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 1.5
  notes: >-
    46,XY gonadal dysgenesis (complete + partial pooled) among live-born
    phenotypic females. Undercounts 46,XY PGD because ~half of PGD patients
    are assigned male at birth.
  evidence:
  - reference: PMID:27603905
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of 46,XY females was 6.4 per 100 000 live born females"
    explanation: >-
      Nationwide Danish prevalence; the paper reports gonadal dysgenesis at
      1.5 per 100,000 within this 6.4 per 100,000 total.

(Verify the exact snippet against the cached abstract with just fetch-reference PMID:27603905 before committing.)

9.2 Inheritance

46,XY PGD is genetically heterogeneous with four distinct inheritance modes — this should be modelled as multiple Inheritance blocks, each with a bound HPO term:

Mode	HPO term	Genes	Notes
Sex-limited autosomal dominant	HP:0000006 (Autosomal dominant inheritance)	NR5A1, MAP3K1, DHX37, DMRT1, SOX9, SOX8, ZFPM2, GATA4	50% transmission to 46,XY offspring; 46,XX sibs generally unaffected. Frequently de novo, or inherited from a mildly affected father or an unaffected mother
Sex-limited autosomal recessive	HP:0000007 (Autosomal recessive inheritance)	DHH	25% risk to 46,XY sibs; heterozygotes asymptomatic
Y-linked	HP:0001450 (Y-linked inheritance)	SRY	Usually de novo; paternal transmission rare (mosaicism/reduced penetrance)
X-linked	HP:0001417 (X-linked inheritance)	NR0B1 (DAX1) duplication, Xp21.2	Inherited from carrier mother in most cases; 50% per pregnancy
Digenic	HP:0010984 (Digenic inheritance)	DHX37 + NR5A1	Documented double-heterozygotes with the most severe phenotype (PMC10222664)

Verify HP:0000006/0000007/0001450/0001417/0010984 with OAK before committing — I verified HP:0010984's role in the CLAUDE.md convention but did not run OAK on the four standard MOI terms in this session.

Penetrance. Gene-dependent and one of the most important curatable facts: - MAP3K1: "virtually complete penetrance in 46,XY individuals" (PMID:35290982) — unusually high. - NR5A1: markedly incomplete and variable; unaffected/mildly affected transmitting parents are common; the same allele produces CGD, PGD, hypospadias, or isolated infertility within one family. - DHX37: high but with a de novo excess (5/13 de novo in the discovery cohort). - All of these are sex-limited: penetrance in a 46,XX background is ~0 for the gonadal phenotype (with the NR5A1 exception of primary ovarian insufficiency).

Expressivity: highly variable — this is the disease. The CGD↔PGD↔TRS↔hypospadias↔infertility spectrum arises from single alleles.

Genetic anticipation: Not applicable. No repeat-expansion mechanism.

Germline mosaicism: documented (particularly SRY and NR5A1), and is the standard counselling explanation for recurrence in a sibship with clinically negative parents. Empiric recurrence risk after an apparently de novo variant should be quoted as low-but-not-zero (~1%).

Founder effects: none established for 46,XY PGD. The DHH R124Q variant in two Syrian sisters (PMID:25927242) reflects consanguinity, not a founder haplotype.

Consanguinity: relevant only for the autosomal recessive DHH route (and other rare AR causes). Consanguineous populations will show enrichment of the recessive fraction; outbred populations are dominated by de novo AD variants.

Carrier frequency: not established for any gene. Pathogenic variants are individually private/ultra-rare; population carrier screening is not indicated.

9.3 Population demographics

Affected populations: no ethnic predominance. The worldwide cohort analysis (14 cohorts, 2013–2023, six continents) found "no mutations with a clear geographic or ethnic predominance," though MAP3K1 variant frequencies differed between US, Australian, and Korean cohorts (DOI:10.3389/fgene.2024.1387598). Molecular diagnostic yield varied 24.3% (Korea) to 64.3% (China), most cohorts 35–50% — this variation likely reflects ascertainment and sequencing strategy more than true biology.
Geographic distribution: worldwide; no endemic regions. The recessive DHH fraction will be over-represented where consanguinity is common (Middle East, North Africa, South Asia).
Sex ratio: Not meaningfully applicable and must be handled carefully in the KB. All affected individuals are 46,XY by definition (chromosomal sex ratio ∞:0 male). Sex of rearing is roughly balanced: I-DSD PGDf 107 vs PGDm 103 (~1:1). Record chromosomal sex as an inclusion criterion, and sex of rearing as an outcome variable — never as "sex ratio."
Age distribution: bimodal at diagnosis (neonatal peak; adolescent second peak in female-presenting cases). Prevalence is lifelong once diagnosed; no excess mortality shifts the age structure.

10. Diagnostics

10.1 Clinical and laboratory tests

Karyotype is the entry point and the definitional test. Standard peripheral-blood karyotype with ≥30 cells counted (to exclude low-level 45,X mosaicism), plus FISH for SRY, or chromosomal microarray. GeneReviews: "Karyotype with FISH for SRY or chromosomal microarray to determine sex chromosome complement and SRY presence/absence." A 46,XY non-mosaic result is required; detected mosaicism reclassifies to MGD.

Hormonal panel (GeneReviews recommended set): | Analyte | LOINC (representative) | Interpretation in PGD | |---|---|---| | Anti-Müllerian hormone (AMH) | LOINC:38476-0 | Low (48% PGDf, 58.1% PGDm) — the best single marker of Sertoli cell mass | | Inhibin B | LOINC:32079-8 | Low — Sertoli function | | Testosterone, basal | LOINC:2986-8 | Low or low-normal; similar between PGDf and PGDm at age ≥13 | | Testosterone, hCG-stimulated | — | Only 66.0% (31/47) of PGDm doubled testosterone — a blunted response is characteristic | | FSH | LOINC:15067-2 | Elevated | | LH | LOINC:10501-5 | Elevated | | Electrolytes, 17-OHP, ACTH, cortisol | — | To exclude CAH and detect NR5A1-associated adrenal insufficiency |

Key interpretive rules from GeneReviews:

"A greatly elevated follicle-stimulating hormone and/or luteinizing hormone in infancy is usually associated with nonfunctional gonads."

"Hormonal evaluation cannot distinguish between one versus two functioning gonads."

That second statement is important and under-appreciated: because PGD is characteristically asymmetric, biochemistry describes total gonadal output and cannot localise it — imaging and, ultimately, surgical/histological assessment are required to characterise each gonad separately.

Imaging: - Pelvic/abdominal/inguinal ultrasound (first line) — presence of uterus (51% PGDf, 31.3% PGDm), gonadal position and size. - MRI — better for intra-abdominal gonads and Müllerian anatomy. - Genitography / retrograde urethrography — urogenital sinus anatomy. - Bone age radiograph — HP:0002750 delayed skeletal maturation; puberty tracking. - DXA — bone density surveillance under hormone replacement (HP:0000939 osteoporosis).

Functional/other: external masculinization score (EMS) or external genital score (EGS) — the I-DSD standard, reported as median 4.0 (PGDf) vs 7.0 (PGDm); this is the quantitative phenotype backbone of the field and should be recorded as a measurement in the KB where available. Electrophysiology (NCS/EMG) is indicated only in the DHH subgroup to detect minifascicular neuropathy.

Biopsy / histopathology — the definitive gonadal test. Dysgenetic testis: "decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells." Streak gonad: ovarian-type stroma without follicles.

Immunohistochemistry for neoplastic risk (essential, and easy to omit): - OCT3/4 (POU5F1) and PLAP, AP-2γ (TFAP2C) — mark germ cells arrested in an immature pluripotent state = germ cell neoplasia in situ (GCNIS)/pre-gonadoblastoma. - TSPY — the Y-encoded risk factor; "The testes-specific protein Y 1 (TSPY1) gene, located on the Y chromosome, is considered the most significant gene responsible for a high risk of tumorigenesis. This protein… functions as a protooncogenic factor when expressed in an incompatible niche with immature germ cells." - SOX9/AMH — Sertoli cell identity; FOXL2 — inappropriate granulosa-type differentiation. - SALL4, D2-40/podoplanin, KIT/CD117 — germ cell tumour panel.

Note the diagnostic-sequencing paradox: "Because the risk of gonadoblastoma in these patients is so high, precise diagnosis of the type of GD is usually determined after prophylactic or therapeutic gonadectomy" — definitive gonadal classification often follows, rather than precedes, the surgical decision.

10.2 Genetic testing

Recommended approach (GeneReviews + Idris et al. 2025, PMID:39081229):

Karyotype ± FISH SRY (mandatory first step; defines the entity).
Chromosomal microarray (CMA) — detects 9p24 deletion, Xp21.2/NR0B1 duplication, 1p36 duplication, and SOX9 regulatory CNVs. Do not skip in favour of exome.
DSD multigene panel (MPS) — "Start with targeted MPS panels (cost-effective, manageable data)"; yield 30%–60%.
Whole exome sequencing if panel negative; yield 30%–66.7%.
Whole genome sequencing for suspected structural/non-coding lesions, "e.g., SOX9 enhancers"; limited comparative data but superior for structural variants.
Sanger single-gene testing — largely obsolete standalone ("~15%" yield); reserve for targeted familial variant testing.

Overall real-world yield: "Genomic technologies, such as massively parallel sequencing (MPS), have proven to be a valuable diagnostic tool for individuals or families with DSD" delivering 30%–45%. PGD-specific: 42.3% (I-DSD 2025).

Panel gene content (minimum for PGD): SRY, NR5A1, MAP3K1, DHX37, SOX9 (+ regulatory region), SOX8, DHH, DMRT1, WT1, NR0B1, ZFPM2, GATA4, WNT4, RSPO1, CBX2, PPP2R3C, PBX1, HHAT, LHX9, MYRF, PPP1R12A, plus the androgen-pathway differential genes (AR, SRD5A2, HSD17B3, LHCGR, StAR, CYP17A1) — because the clinical differential cannot be resolved without them.

Not indicated: mitochondrial DNA testing; repeat-expansion testing. Y-chromosome microdeletion (AZF) testing is NOT indicated in non-mosaic 46,XY PGD — the Brazilian series found zero deletions in 13 PGD patients (PMC3827999). It is informative in 45,X/46,XY MGD (40% positive).

Emerging: "Integrate transcriptomics, proteomics, and Hi-C analysis to resolve pathogenicity in ambiguous cases and detect mosaicism across multiple tissues" — research-grade, not standard of care.

10.3 Omics-based diagnostics

RNA-seq (for splice-variant resolution), proteomics, metabolomics, epigenomics, liquid biopsy: none are established diagnostics for 46,XY PGD. RNA-seq on gonadal tissue or fibroblasts is the most plausible near-term addition for VUS resolution.

10.4 Clinical criteria and differential diagnosis

Diagnostic criteria derive from the 2006 Chicago Consensus (PMID:16624884) and the 2016 Global DSD Update (PMID:26820577), which established the DSD classification (46,XY DSD → disorders of gonadal/testicular development → partial gonadal dysgenesis). There is no formal scored criteria set; diagnosis is the conjunction of: 1. Non-mosaic 46,XY karyotype 2. Ambiguous/undervirilized external genitalia 3. Evidence of partial testicular dysgenesis (biochemical: low AMH/inhibin B, elevated gonadotropins, blunted hCG response; and/or histological: dysgenetic testis ± streak) 4. Variable Müllerian retention 5. Absence of syndromic features (for the nonsyndromic entity)

Differential diagnosis — with the discriminating feature:

Condition	Key discriminator from 46,XY PGD
46,XY complete gonadal dysgenesis (Swyer)	Bilateral streak gonads, fully female external genitalia, fully developed uterus; presents with primary amenorrhoea, not ambiguity
Mixed gonadal dysgenesis (MGD)	45,X/46,XY mosaic karyotype (+ Turner stigmata, short stature, Yq microdeletions in 40%)
Partial androgen insensitivity (PAIS)	Normal/high testosterone, normal AMH, no Müllerian structures, normal testis histology; AR variant
17β-HSD3 deficiency	Elevated androstenedione/testosterone ratio; no Müllerian structures
5α-reductase-2 deficiency	Elevated testosterone/DHT ratio; normal testes; marked pubertal virilization
StAR / CYP17A1 / CYP11A1 defects	Adrenal insufficiency + salt-wasting; low all androgens
LHCGR inactivating (Leydig cell hypoplasia)	Low testosterone, high LH, absent hCG response, absent Müllerian structures (AMH intact)
Ovotesticular DSD	Both ovarian follicles and testicular tubules in the same or contralateral gonad (histological)
Persistent Müllerian duct syndrome (AMH/AMHR2)	Müllerian structures with normal male external genitalia and normal androgenization
Testicular regression syndrome (TRS)	Absent gonads with a vascular/vestigial remnant; overlaps DHX37 genetically — a spectrum boundary, not a clean separation
Isolated severe hypospadias	The mild extreme of PGD; the boundary is genuinely arbitrary
Syndromic GD (Denys–Drash/Frasier, campomelic dysplasia, 9p deletion, ATRX, SLO/DHCR7)	Extra-gonadal features

10.5 Screening

Newborn screening: not performed and not proposed. 46,XY PGD is not on any RUSP/newborn-screening panel; there is no analyte-based screen. The de facto "screen" is newborn physical examination of the genitalia — ambiguity should trigger urgent DSD-team referral before hospital discharge (a Chicago Consensus recommendation).
Carrier screening: not indicated. Variants are private; no founder alleles.
Cascade screening: indicated and specifically recommended. Granados et al. are explicit: "Identification of a MAP3K1 variant should prompt an evaluation for DSD in female siblings of the proband" (PMID:28504475) — because a phenotypically female sibling may be an unrecognised 46,XY CGD/PGD patient with an unmanaged gonadal tumour risk. This is the single highest-value screening action in this disease.
Prenatal: discordance between NIPT/cfDNA-predicted male sex (or an XY karyotype on CVS/amnio) and female-appearing genitalia on ultrasound is an increasingly common route to prenatal suspicion. Confirmation requires postnatal evaluation.

11. Outcome / Prognosis

11.1 Survival and mortality

Life expectancy is normal. 46,XY PGD is not a life-limiting condition. No PGD-specific survival, mortality, or disease-specific-mortality data exist because there is no measurable excess mortality. Two qualifiers: - Malignancy is the one potentially fatal complication — an untreated invasive dysgerminoma/seminoma. With surveillance and gonadectomy, germ cell tumours arising in dysgenetic gonads are highly curable (dysgerminoma/seminoma are exquisitely chemo- and radiosensitive). - The WT1 subgroup has renal-failure and Wilms-tumour mortality — but that is a different (syndromic) entity.

survival_rate, life_expectancy, mortality_rate: not applicable / no excess — record explicitly rather than leaving blank.

11.2 Morbidity and function

Infertility: near-universal. "Most individuals with a nonsyndromic DSD are infertile due to dysgenetic or streak gonads." All three semen analyses in the long-term male-reared PGD series showed severe oligozoospermia (PMID:25580123). Exceptions: "some pathogenic variants in NR5A1 are associated with normal testicular development in individuals with a 46,XY chromosome complement, which may allow for fertility, although assisted reproductive technology may be required." 46,XY individuals with Müllerian structures may achieve pregnancy via oocyte donation.
Lifelong hormone dependence in those who undergo gonadectomy or have insufficient endogenous function.
Osteoporosis (HP:0000939) — preventable with adequate replacement; a marker of care quality.
Growth is normal — final heights −1.57 to +0.80 SDS (PMID:25580123).
No cognitive/neurological impairment intrinsic to the disease (the 30% learning-disability figure in a 10-patient series is not generalisable). The DHH subgroup develops peripheral neuropathy at 20–30 years.
QoL: dominated by sexual function, body image, fertility loss, gender-identity concordance, and the burden of surgical decisions made in infancy. No disease-specific PROM; dsd-LIFE used generic instruments.

11.3 Gonadal neoplasia — the defining prognostic issue

The authoritative multicentre figure (Slowikowska-Hilczer J, Szarras-Czapnik M, Duranteau L, et al.; dsd-LIFE group. Risk of gonadal neoplasia in patients with disorders/differences of sex development. Cancer Epidemiol 2020;69:101800; PMID:32905884; n=1,040):

"germ-cell neoplasia was present in 12 % of patients with DSD and in 14 % of those with XY DSD"

with the risk gradient:

Group	Germ cell neoplasia risk
46,XY gonadal dysgenesis (all)	36%
— complete GD	33%
— partial GD	23%
Mixed GD	8%
Complete AIS	6%
Partial AIS, XX male, CAH, androgen biosynthesis defects	0%

Also: "benign sex cord-stromal tumours (Sertoli- and Leydig-cell tumours) were noted only in patients with complete AIS (3.1 %) and Klinefelter syndrome (14.3 %)." Conclusion: adult patients with gonadal dysgenesis and a Y chromosome require intensive medical surveillance.

The PGD-specific, sex-of-rearing-stratified figure (I-DSD 2025, PMID:40208111) — this is the most actionable number in the entry:

Group	Gonadal pre-/malignancy
CGD	33.8%
PGD assigned female (PGDf)	19.7%
PGD assigned male (PGDm)	8.8%

The four-fold PGDf:PGDm gradient is consistent with the mechanistic model: more severe dysgenesis → more immature/arrested germ cells in an inhospitable niche → more TSPY-driven neoplastic transformation, and intra-abdominal position (more common in the less virilized) further raises risk. Note that these are cross-sectional prevalences at variable follow-up, not lifetime cumulative incidence — the true lifetime risk is higher.

Countervailing small-series data: "There was no case of testicular neoplasia" in 10 male-reared PGD patients followed 13.5–19.7 years (PMID:25580123) — consistent with the low 8.8% PGDm figure and with scrotal-position gonads being lower risk.

Risk markers: presence of Y chromosome material (obligate here); TSPY1 expression; OCT3/4-positive immature germ cells; intra-abdominal gonadal position; degree of dysgenesis; older age.

11.4 Disease course, complications, recovery

Complications: gonadoblastoma → dysgerminoma/seminoma; hypogonadism and osteoporosis; infertility; urological complications of hypospadias repair (fistula, stricture, need for reoperation — common); vaginal stenosis after vaginoplasty; psychological distress and gender dysphoria; surgical loss of genital sensation.

Recovery potential: the gonadal lesion is irreversible. Hormone replacement fully restores secondary sexual characteristics and bone health. Fertility is generally unrecoverable.

11.5 Prognostic factors

Factor	Prognostic for
External genital score at presentation	Sex assignment, surgical burden, likely spontaneous puberty
Degree of dysgenesis / gonadal histology	Puberty, tumour risk
AMH and inhibin B levels	Sertoli cell reserve → spontaneous puberty likelihood (low AMH in 48% PGDf / 58.1% PGDm)
hCG-stimulated testosterone response	Leydig reserve; 66% of PGDm doubled T
Gonadal position (scrotal vs intra-abdominal)	Tumour risk (lower if scrotal), feasibility of surveillance
Causative gene	NR5A1 → possible adrenal involvement + rarely preserved fertility; MAP3K1 → near-complete penetrance, recurrence counselling; DHH → neuropathy at 20–30 y; WT1 → renal/Wilms surveillance
Sex of rearing	Tumour risk (PGDf 19.7% vs PGDm 8.8%); reassignment likelihood (16.1% vs 5.3%)
Presence of a uterus	Fertility option via oocyte donation

Prognostic biomarkers: AMH and inhibin B (gonadal reserve); OCT3/4 and TSPY immunohistochemistry (neoplastic risk); serum tumour markers (AFP, β-hCG, LDH) for surveillance of established germ cell tumours — though these are insensitive for gonadoblastoma/GCNIS.

12. Treatment

There is no disease-modifying or curative therapy. Management is multidisciplinary, lifelong, and increasingly shared-decision-making driven. The framing authority is the Chicago Consensus (PMID:16624884) and the 2016 Global DSD Update (PMID:26820577); the ESPU–SPU 2020 consensus covers the surgical dimension.

12.1 Sex assignment (precedes everything else)

GeneReviews: "All individuals should receive a sex of rearing" determined by "underlying diagnosis, expert opinion, and parental beliefs," ideally by an interdisciplinary team before newborn discharge. The Global DSD Update's honest caveat: "it is still impossible to predict gender development in an individual case with certainty."

The empirical outcome data (I-DSD 2025) should inform this conversation directly: 16.1% of PGDf and 5.3% of PGDm later underwent sex reassignment — the highest reassignment rate in the DSD spectrum, and a strong argument for conservative, reversible early management.

12.2 Hormone therapy

Treatment	NCIT (verified)	Therapeutic agent (CHEBI/NCIT)	Indication
Testosterone replacement / induction	NCIT:C15599 Hormone Replacement Therapy	CHEBI:17347 testosterone; NCIT:C1247 Testosterone Enanthate; NCIT:C1246 Testosterone Cypionate; NCIT:C1249 Testosterone Undecanoate	Male-assigned: short infant course for micropenis ("stretched penile length >2.5 SD below mean"); pubertal induction and maintenance
Estrogen replacement	NCIT:C15599 Hormone Replacement Therapy	CHEBI:16469 17beta-estradiol	Female-assigned: breast development, pubertal induction, bone health
Progestogen	NCIT:C15599	progesterone (verify CHEBI)	Added once pubertal progression is advanced, if a uterus is present (endometrial protection)
Adrenal replacement	NCIT:C15986 Pharmacotherapy	hydrocortisone (verify CHEBI)	NR5A1 subgroup with adrenal insufficiency only
Bone protection	NCIT:C15747 Supportive Care	calcium, cholecalciferol	Adjunct to sex-steroid replacement

therapeutic_modality: SMALL_MOLECULE for the steroid hormones.

12.3 Surgical and interventional

The governing principle (GeneReviews), verbatim:

"Surgical decisions should be made after detailed discussion with the family about risks, benefits, and limitations."

and

"Many surgeries are not medically necessary; consideration should be given to delaying surgery in order to allow the affected individual to participate in the decision-making process."

This is the most contested area in DSD care and should be curated with the caveat prominent, not buried.

Procedure	NCIT (verified)	Notes
Gonadectomy / orchiectomy	NCIT:C15288 Orchiectomy (+ NCIT:C94458 Prophylactic Surgery)	The central oncological intervention. See decision rule below
Orchiopexy	NCIT:C111066 Orchiopexy	Places a functional dysgenetic testis in the scrotum, enabling palpation-based surveillance
Hypospadias repair	NCIT:C15329 Surgical Procedure	Male-assigned
Scrotoplasty, phalloplasty	NCIT:C15329	Male-assigned
Clitoroplasty	NCIT:C15329	Female-assigned; highly contested, increasingly deferred
Vaginoplasty / urogenital sinus mobilization	NCIT:C15329	Female-assigned; vaginal dilation is the non-surgical alternative and is often first-line
Müllerian remnant excision	NCIT:C15329	If symptomatic (haematometra, recurrent infection)

therapeutic_modality: SURGERY for all of the above.

The gonadectomy decision rule (GeneReviews): - Streak and nonfunctional dysgenetic gonads carry "increased risk for the development of gonadoblastoma and should be surgically removed if nonfunctional." - Indicators of nonfunctionality in 46,XY individuals: "absence of virilization and presence of müllerian structures" — i.e., the gonads failed to make testosterone and AMH in fetal life and will not do better later. - Functional dysgenetic gonads may be retained: "If located in the inguinal canal with evidence of testicular function, placement in the scrotum may be considered, though this gonad will need to undergo surveillance for gonadoblastoma. There are no current guidelines on surveillance; one option would be yearly ultrasound."

Note the explicit guideline gap: "There are no current guidelines on surveillance." Curate this as a discussions entry with kind: KNOWLEDGE_GAP — the absence of an evidence-based surveillance protocol for retained dysgenetic gonads is a real, named deficiency in the field, and the I-DSD authors reach the same conclusion ("gonadal tumor risk requires further investigation").

Germ cell tumour treatment (if malignancy develops): gonadectomy ± platinum-based chemotherapy (BEP: bleomycin/etoposide/cisplatin) — NCIT:C15632 Chemotherapy; and/or radiotherapy for seminoma/dysgerminoma (NCIT:C15313 Radiation Therapy). Cure rates are high.

12.4 Supportive, rehabilitative, and counselling

Intervention	NCIT (verified)
Psychosocial care / mental health support	NCIT:C126880 Psychosocial Care; NCIT:C15514 Psychosocial Assessment and Care
Genetic counselling	NCIT:C15240 Genetic Counseling
Genetic testing	NCIT:C15709 Genetic Testing
Peer/family support, DSD support groups	NCIT:C15747 Supportive Care
Transition to adult multidisciplinary care	NCIT:C15747 Supportive Care
Fertility counselling / gamete or gonadal tissue considerations	NCIT:C15240 / NCIT:C15747

therapeutic_modality: BEHAVIORAL for psychosocial and counselling interventions.

GeneReviews on psychosocial care: "Open communication with affected individuals and families, including their active participation in the decision-making process, is critical." Providers must address concerns "respectfully and in strict confidence," recognizing that "assigned sex of rearing may not be congruent with gender identity, which is determined by the individual over time."

12.5 Advanced therapeutics

Gene therapy, gene editing, cell therapy, RNA therapies, targeted therapy, immunotherapy: none exist, none in trial. The therapeutic window (fetal weeks 6–8) closes before any current intervention could be delivered, making this a genuinely intractable target for molecular therapy as currently conceived.
In vitro gametogenesis (IVG) from patient iPSCs is the only plausible future fertility route; entirely preclinical.

12.6 Pharmacogenomics

No PharmGKB/CPIC guideline applies to 46,XY PGD. Standard testosterone/estradiol pharmacogenomics (CYP3A4/CYP19A1 variation) is not disease-specific and should not be curated here.

12.7 Clinical trials

No interventional trial specific to 46,XY partial gonadal dysgenesis is registered on ClinicalTrials.gov (searched as of this report). The relevant registered activity is observational: the I-DSD/I-CAH Registry (the source of PMID:40208111) and dsd-LIFE (the source of PMID:32905884). If the KB entry includes a clinical_trials block, it should record the registry studies (verify current NCT identifiers before curating; several I-DSD outputs are registry-based rather than NCT-registered) rather than fabricating an interventional trial.

12.8 Treatment outcomes and adverse events

Spontaneous puberty in PGDm: 80% onset, 59.3% reach Tanner G5 without treatment — the strongest argument for gonadal retention in well-virilized male-assigned patients.
Feminizing therapy after gonadectomy in PGDf works: in the NR5A1 case, "Following bilateral orchiectomy and feminizing hormone therapy, hirsutism and clitoromegaly regressed" (PMID:38206718).
Gonadectomy adverse effects: immediate surgical iatrogenic hypogonadism, lifelong hormone dependence, loss of any residual fertility, and — importantly — irreversibility of a decision often made before the patient can consent.
Hypospadias repair: high reoperation rate; fistula and stricture are common.
Testosterone: erythrocytosis, acne, mood effects, accelerated bone-age advancement if over-dosed pre-pubertally.
Estrogen: VTE risk; endometrial hyperplasia if unopposed with a uterus present.

12.9 Treatment algorithm (synthesis)

Newborn with atypical genitalia
  → Urgent multidisciplinary DSD team referral (before discharge); DO NOT assign sex prematurely
  → Karyotype + FISH SRY + CMA;  exclude CAH (17-OHP, electrolytes)
  → 46,XY non-mosaic + ambiguous genitalia + Müllerian structures + ↑FSH/LH, ↓AMH/inhibin B
       → suspect 46,XY PGD
  → Imaging (US ± MRI): uterus? gonadal position?
  → hCG stimulation (if outside mini-puberty) → Leydig reserve
  → DSD panel → WES → WGS/CMA   (42% yield)
  → Sex-of-rearing discussion: diagnosis + EGS + imaging + parental values + explicit
       counselling that 16.1% of PGDf and 5.3% of PGDm are later reassigned
  ├── Male assignment → assess each gonad:
  │      functional + inguinal/scrotal-placeable → ORCHIOPEXY + lifelong surveillance
  │      nonfunctional / intra-abdominal / streak → GONADECTOMY
  │      → observe for spontaneous puberty (80%); supplement testosterone if needed
  │      → hypospadias repair timing = shared decision, consider deferral
  └── Female assignment → gonads are the key decision:
 retain → permits spontaneous puberty BUT 42.3% virilize AND 19.7% pre-/malignancy
 remove → prevents both, mandates lifelong estrogen ± progesterone
 → vaginal dilation before/instead of vaginoplasty; defer clitoroplasty
  → Both: bone health monitoring (DXA), psychosocial care throughout,
  fertility counselling, structured transition to adult care,
  cascade evaluation of at-risk siblings (esp. phenotypically female sibs)
  → Gene-specific add-ons:
       NR5A1 → adrenal function testing; POI counselling for 46,XX relatives
       DHH   → neurological surveillance from age ~20
       WT1   → renal function + Wilms tumour surveillance (reclassify as syndromic)
       MAP3K1→ near-complete penetrance: 50% recurrence counselling; test female sibs

13. Prevention

13.1 Primary prevention

Not possible. 46,XY PGD results from a germline variant acting in a fetal developmental window. There is no modifiable exposure, no vaccine, no risk-factor modification. Record explicitly as not applicable rather than leaving the field empty.

The only theoretical primary-prevention levers are reproductive: preimplantation genetic testing for monogenic disease (PGT-M) or prenatal diagnosis in a family with a known pathogenic variant. Both are: - Available in principle for any of the identified genes, - Ethically contested for this indication in particular — 46,XY PGD is compatible with a normal lifespan and good quality of life, and DSD advocacy communities have argued strongly against framing it as a condition to be prevented. Curate this with the ethical caveat explicit.

13.2 Secondary prevention (early detection)

This is where the real prevention opportunity lies: 1. Newborn genital examination → same-admission DSD team referral. The single most effective secondary-prevention action. 2. Cascade evaluation of siblings, especially phenotypically female siblings of a proband with an AD variant — "Identification of a MAP3K1 variant should prompt an evaluation for DSD in female siblings of the proband" (PMID:28504475). This can identify an unrecognised 46,XY CGD/PGD patient carrying a 20–34% gonadal neoplasia risk. 3. Closing the adolescent diagnostic gap. Median age at diagnosis for female-presenting 46,XY gonadal dysgenesis is 17.0 years (PMID:27603905). Karyotyping every adolescent with primary amenorrhoea and absent/discordant pubertal development would substantially shorten this. 4. Investigating unexplained pubertal virilization in a girl — 42.3% of PGDf with retained gonads virilize; this is a red flag, not a benign PCOS variant.

13.3 Tertiary prevention (preventing complications in diagnosed patients)

Complication	Preventive action
Gonadoblastoma / germ cell tumour	Gonadectomy of nonfunctional/streak gonads; scrotal placement + surveillance for retained functional gonads (annual ultrasound is one suggested option — but note the acknowledged absence of guidelines)
Osteoporosis (HP:0000939)	Timely, adequate, uninterrupted sex-steroid replacement; DXA monitoring; calcium/vitamin D; weight-bearing exercise
Endometrial hyperplasia	Add progestogen to estrogen when a uterus is present
Psychological distress / gender dysphoria	Embedded psychology from diagnosis; deferring irreversible surgery; honest age-appropriate disclosure
Unwanted pubertal virilization (PGDf)	Anticipatory counselling; pre-pubertal decision on gonadal retention; GnRH analogue or gonadectomy if it occurs
DHH-related neuropathy	Neurological surveillance from ~age 20 in confirmed DHH biallelic cases
Loss to follow-up at transition	Structured paediatric→adult transition; adult multidisciplinary DSD clinic

13.4 Immunization, behavioural, public health, prophylaxis

Immunization: not applicable (routine schedule only).
Behavioural interventions: no risk-reducing behaviour exists. Post-diagnosis lifestyle advice targets bone health only.
Public health / environmental interventions: not applicable to 46,XY PGD. (EDC reduction policy relates to TDS, a different entity — see §2.3.)
Prophylaxis: prophylactic gonadectomy (NCIT:C94458 Prophylactic Surgery + NCIT:C15288 Orchiectomy) is the only prophylactic procedure, and its indication is narrower than historically taught — restricted to nonfunctional/streak/non-surveillable gonads, and increasingly deferred with the patient's participation where the gonad is functional and accessible.

13.5 Genetic counselling

Essential and specific. Content per §9.2: mode of inheritance by gene; sex-limited expression (a 46,XX daughter carrying the same MAP3K1 allele is unaffected but a 50% transmitter); the 42% chance that no genetic cause will be found; germline mosaicism and the ~1% recurrence risk after an apparently de novo variant; NR5A1's variable expressivity and primary ovarian insufficiency risk in 46,XX relatives; DHH recessive risk in consanguineous families; and reproductive options (PGT-M, prenatal diagnosis, donor gametes, adoption) presented non-directively.

14. Other Species / Natural Disease

14.1 Taxonomy and natural disease

XY disorders of sex development occur naturally across mammals. Per OMIA and the veterinary literature, "in domestic animals, sex reversal disorders have been described in pig, goat, sheep, roe deer, llama, cattle, buffaloes, horse, cat, dog and ferret."

Species	NCBI Taxon	OMIA entry	Notes
Domestic horse	NCBITaxon:9796	OMIA:001601-9796 — XY difference of sexual development, generic; OMIA:001230-9796 — XY sex reversal, SRY-related	"In horses, the most common type is 64XY SRY negative." In at least one XY mare, "the DNA-binding domain of the SRY gene was deleted from the Y chromosome." Clinically important in breeding (the "XY mare" presenting with infertility/abnormal genitalia)
Domestic dog	NCBITaxon:9615	OMIA XX/XY DSD entries	The best-studied veterinary DSD; most published canine work is XX SRY-negative (SOX9 duplications on CFA9 — PMC4091935/PLOS ONE 2014), which is the converse of human 46,XY PGD
Domestic pig	NCBITaxon:9823	OMIA XX DSD	SRY-negative XX DSD with ovotestis documented (PMC11945758)
Goat	NCBITaxon:9925	OMIA polled intersex (PIS)	FOXL2 regulatory deletion — XX sex reversal; a landmark natural model of the pro-ovary arm
Cattle, sheep, cat, llama, ferret, roe deer	various	OMIA	Sporadic reports

Honest assessment for this KB: the veterinary literature is dominated by XX (SRY-negative) sex reversal, not by XY partial gonadal dysgenesis. Equine XY DSD (OMIA:001601, OMIA:001230) is the closest natural counterpart. There is no reported naturally occurring animal disorder with a confirmed NR5A1, MAP3K1, or DHX37 lesion producing partial gonadal dysgenesis. Curate the veterinary section as "related conditions in other species," not as "the same disease in animals."

14.2 Orthologous genes

Human gene	Mouse ortholog	Notes
SRY	Sry	Y-linked in both; poorly conserved in sequence (only the HMG box) — a major comparative caveat
NR5A1	Nr5a1 (Sf1, Ftz-F1)	Highly conserved
MAP3K1	Map3k1 (Mekk1)	Highly conserved
DHX37	Dhx37	Highly conserved (ribosome biogenesis is deeply conserved)
SOX9	Sox9	Highly conserved, incl. enhancer architecture (TESCO/Enh13)
DHH	Dhh	Highly conserved
DMRT1	Dmrt1	DM-domain conserved from Drosophila (dsx) to vertebrates — the deepest-conserved sex-determination gene
WT1, GATA4, ZFPM2, FOXL2, WNT4, RSPO1	Wt1, Gata4, Zfpm2, Foxl2, Wnt4, Rspo1	Conserved

(Obtain exact NCBI Gene IDs from NCBI Gene / Alliance of Genome Resources before curating.)

14.3 Comparative biology and evolutionary conservation

The downstream testis-determination network (SOX9/FGF9/PTGDS vs WNT4/RSPO1/FOXL2 antagonism; DMRT1) is deeply conserved across vertebrates, which is why mouse, and to a lesser extent zebrafish and medaka, are informative. The upstream trigger is not: SRY is eutherian-specific and rapidly evolving; birds use ZZ/ZW with DMRT1 dosage; many fish and reptiles use temperature or other master switches. Zebrafish lack a fixed sex-determining locus in domesticated strains and lack SRY entirely.

Practical consequence: models are strong for the conserved core (SOX9 threshold, Wnt/β-catenin antagonism, Sertoli fate) and weak for the human-specific trigger layer.

14.4 Transmission

No zoonotic potential; no cross-species transmission. Not an infectious or transmissible condition.

15. Model Organisms

15.1 Mouse (Mus musculus, NCBITaxon:10090) — the primary model

Model	Phenotype	Fidelity to human PGD
Nr5a1 (Sf1) null	"Nr5a1-deficient mice lack both gonads and adrenal glands"; "Homozygous Nr5a1 knockout mice lack the adrenal gland and gonad and die within 8 days after birth"	Poor — far more severe than human heterozygous PGD; models complete agenesis, not partial dysgenesis. Human disease is heterozygous; mouse Nr5a1^+/− is only mildly affected
Nr5a1 conditional (Sox9-Cre)	"compromises testis differentiation" (PMC7904858)	Good for the Sertoli-specific arm — dissects post-determination requirement
Nr5a1 post-determination deletion	"Steroidogenic Factor 1 (Nr5a1) is Required for Sertoli Cell Survival Post Sex Determination" (Sci Rep 2019, PMC6418149)	Good — establishes a distinct maintenance role, relevant to progressive dysgenesis/regression
Nr5a1 p.R92W knock-in	Does not produce XX testicular development in mice, unlike humans (PMC5101639)	Explicit human/model mismatch — curate as `HUMAN_MODEL_MISMATCH`
Map3k1 (Mekk1)	"Mouse studies demonstrated that Map3k1 expression occurs in embryonic gonads during the critical sex-determination period" (PMID:21129722). Map3k1 loss-of-function mice have eyelid-closure and (in the goya mutant) cochlear hair-cell phenotypes — not gonadal dysgenesis	Poor for the null; the human disease is gain-of-function. A knock-in of a human GoF allele is the correct model and, to my knowledge, has not been reported as a fully characterised gonadal model
*Dhx37*	Discovery paper confirmed "DHX37 expression… in developing testis somatic cells" (PMID:31337883); a mouse model was part of the study design (Warr/Greenfield co-authorship)	Under-developed — no established mouse recapitulating human DHX37 PGD
Sry transgenics; B6.Y^TIR / B6.Y^POS strains	Strain-dependent XY sex reversal from "Inefficient Sox9 upregulation and absence of Rspo1 repression" (PMC11094394)	Excellent conceptual model of PGD — these strains produce ovotestes and partial dysgenesis on a permissive genetic background, directly modelling the threshold/bistability biology and the role of genetic modifiers
Sox9 / Sox8 conditional	"Sox9 and Sox8 protect the adult testis from male-to-female genetic reprogramming and complete degeneration" (eLife 2016)	Good for maintenance biology
Wnt4 / Sox9 double	"Mouse Gonad Development in the Absence of the Pro-Ovary Factor WNT4 and the Pro-Testis Factor SOX9" (PMC7291083)	Excellent for the antagonism model
Rspo1, Foxl2, Fgf9, Dhh, Dmrt1, Wt1, Gata4/Zfpm2 knockouts	Each dissects one arm	Good, mechanism-specific

MGI is the canonical resource (informatics.jax.org); IMPC/KOMP hold null alleles for most of these genes; IMSR/EMMA/MMRRC for strain distribution.

15.2 Other model systems

Zebrafish (Danio rerio, NCBITaxon:7955; ZFIN). "Zebrafish may be a good complementary model to study gene functions when homozygous lethality occurs in knockout mice" — directly relevant given the Nr5a1-null lethality. Major limitation: zebrafish lack SRY and a fixed sex-determining locus; sex determination is polygenic/environmental in domesticated strains. Useful for downstream conserved factors (dmrt1, sox9a/b, wnt4, foxl2, amh), not for testis determination per se.
Medaka (Oryzias latipes). Has dmy/gsdfY, a genuine master male-determining gene — the best non-mammalian model of a bona fide Y-linked switch.
Cell lines (Cellosaurus): NT2/D1 (human testicular embryonal carcinoma — the workhorse for testis-determination reporter and ChIP assays), KGN (human granulosa — the ovarian counterpart), HEK-293T (reporter/co-IP), TM3/TM4 (mouse Leydig/Sertoli), Y-1 (adrenocortical). All three of the first cell lines were used in the definitive MAP3K1 mechanistic study (PMC8927045). Evidence from these is IN_VITRO.
iPSC and organoid systems: human iPSC-derived gonadal/Sertoli-like and fetal-Leydig-like differentiation protocols exist but are immature; testicular organoids and human fetal gonad xenografts (PMC3440087) are the emerging platforms. No patient-derived iPSC model of 46,XY PGD has been published — a clear gap and an obvious MorPhiC-style target (NR5A1, SOX9, DHX37 null alleles in iPSC-derived gonadal somatic cells would be directly informative for this entry).
Induced/pharmacological models: in-utero anti-androgen (flutamide) and phthalate (DEHP/DBP) rat models produce a TDS-like phenotype (hypospadias, cryptorchidism, multinucleated germ cells, suppressed fetal-testis steroidogenesis) — a model of the downstream androgen-deficiency arm, not of the determination defect. Do not conflate.

15.3 Phenotype recapitulation and limitations — summary judgment

What models capture well: - The bistable SOX9-vs-WNT4/β-catenin switch and its dosage sensitivity (B6.Y^TIR/Y^POS strains; Wnt4/Sox9 doubles). - Cell-autonomous Sertoli and Leydig requirements (conditional Nr5a1, Sox9/Sox8). - Post-determination maintenance and regression biology (Nr5a1 post-determination deletion; Sox9/Sox8 adult conditional). - Biochemical consequences of specific human variants (NT2/D1, KGN, HEK-293T assays).

What models fail to capture (curate these as HUMAN_MODEL_MISMATCH): 1. The heterozygous human phenotype. Human PGD is overwhelmingly a heterozygous, dosage-threshold disease; mouse heterozygotes are usually normal and mouse homozygotes are usually far too severe (agenesis/lethality). 2. The NR5A1 p.R92W species divergence — explicitly documented (PMC5101639). 3. The MAP3K1 gain-of-function mechanism — mouse Map3k1 nulls do not have gonadal dysgenesis; the human disease direction of effect is the opposite of what the knockout tests. 4. SRY sequence divergence — mouse Sry differs so substantially outside the HMG box that human SRY variant modelling is unreliable. 5. The partial/asymmetric gonadal phenotype itself — the defining PGD feature (dysgenetic testis on one side, streak on the other) is strain-background- and stochasticity-dependent in mice and is not reliably reproducible. 6. No model exists for DHX37, the newest major gene.

15.4 Research applications

Determination-window timing and dosage thresholds; Sertoli/Leydig lineage specification; the antagonistic-network topology; variant functional classification (the practical near-term use — resolving VUS in NR5A1/MAP3K1/DHX37); germ cell neoplasia initiation in a dysgenetic niche (poorly modelled — mice do not develop gonadoblastoma, a major gap given that neoplasia is the chief clinical risk); hormone-replacement and bone outcomes.

15.5 Resources

MGI (informatics.jax.org), IMPC, KOMP/EuMMCR, IMSR, EMMA, MMRRC, ZFIN, RGD, Alliance of Genome Resources, OMIA (omia.org), Cellosaurus, Human Cell Atlas / CELLxGENE (human fetal gonad reference atlases).

Appendix A — Consolidated ontology term suggestions

All HPO, GO, CL, UBERON, CHEBI, and NCIT identifiers below were verified against the local OAK adapters (sqlite:obo:hp, sqlite:obo:go, sqlite:obo:cl, sqlite:obo:uberon, sqlite:obo:chebi, sqlite:obo:ncit) in this session, with the exceptions explicitly flagged as unverified. Labels shown are the canonical ontology labels — use them verbatim in term.label.

Disease: MONDO:0016674 — 46,XY partial gonadal dysgenesis

Core phenotypes (HP): 0000062 Ambiguous genitalia · 0000133 Gonadal dysgenesis · 0012244 Abnormal sex determination · 0000047 Hypospadias · 0000054 Micropenis · 0008736 Hypoplasia of penis · 0008734 Decreased testicular size · 0000028 Cryptorchidism · 0000812 Abnormal internal genitalia · 0008665 Clitoral hypertrophy · 0010464 Streak ovary · 0008730 Female external genitalia in individual with 46,XY karyotype · 0000058 Abnormal labia morphology · 0000045 Abnormal scrotum morphology · 0100779 Urogenital sinus anomaly · 0000142 Abnormal vagina morphology · 0008726 Hypoplasia of the vagina · 0012870 Vanishing testis

Endocrine/lab (HP): 0000815 Hypergonadotropic hypogonadism · 0000837 Increased circulating gonadotropin level · 0008232 Elevated circulating follicle stimulating hormone level · 0011969 Elevated circulating luteinizing hormone level · 0040171 Decreased serum testosterone concentration · 0008214 Decreased serum estradiol · 0031103 Decreased circulating antimullerian hormone circulation · 0031100 Decreased circulating inhibin B concentration · 0008193 Primary gonadal insufficiency · 0000823 Delayed puberty · 0008187 Absence of secondary sex characteristics · 0000846 Adrenal insufficiency (NR5A1 subgroup)

Reproductive outcome (HP): 0000027 Azoospermia · 0003251 Male infertility · 0000144 Decreased fertility · 0000786 Primary amenorrhea

Neoplasia (HP): 0000150 Gonadoblastoma · 0000030 Testicular gonadoblastoma · 0000149 Ovarian gonadoblastoma

Secondary/other (HP): 0000771 Gynecomastia · 0000939 Osteoporosis · 0002225 Sparse pubic hair · 0002215 Sparse axillary hair · 0002750 Delayed skeletal maturation · 0002667 Nephroblastoma (WT1) · 0000100 Nephrotic syndrome (WT1)

Inheritance (HP) — verify these five with OAK before use: 0000006 AD · 0000007 AR · 0001417 X-linked · 0001450 Y-linked · 0010984 Digenic

Biological processes (GO): 0007530 sex determination · 0030238 male sex determination · 0008584 male gonad development · 0008406 gonad development · 0060008 Sertoli cell differentiation · 0060011 Sertoli cell proliferation · 0046661 male sex differentiation · 0008585 female gonad development (modifier: INCREASED — inappropriate de-repression) · 0016055 Wnt signaling pathway · 0060070 canonical Wnt signaling pathway (INCREASED in MAP3K1) · 0000165 MAPK cascade (INCREASED in MAP3K1) · 0035556 intracellular signal transduction · 0042254 ribosome biogenesis (DECREASED in DHX37) · 0006357 regulation of transcription by RNA polymerase II · 0030325 adrenal gland development (NR5A1)

Cell types (CL): 0000216 Sertoli cell · 0000178 Leydig cell · 0000586 germ cell · 0000015 male germ cell · 0000670 primordial germ cell · 0000501 granulosa cell · 0002481 peritubular myoid cell · 0000019 sperm

Anatomy (UBERON): 0000991 gonad · 0000473 testis · 0000992 ovary · 0003890 Mullerian duct · 0003074 mesonephric duct · 0000995 uterus · 0000996 vagina · 0005876 undifferentiated genital tubercle · 0001301 epididymis · 0002367 prostate gland · 0004175 internal genitalia · 0000079 male reproductive system · 0002369 adrenal gland (NR5A1)

Chemicals (CHEBI): 17347 testosterone · 16469 17beta-estradiol · 16330 17beta-hydroxy-5alpha-androstan-3-one (DHT)

Treatments (NCIT): C15288 Orchiectomy · C94458 Prophylactic Surgery · C111066 Orchiopexy · C15599 Hormone Replacement Therapy · C15986 Pharmacotherapy · C15329 Surgical Procedure · C126880 Psychosocial Care · C15514 Psychosocial Assessment and Care · C15240 Genetic Counseling · C15709 Genetic Testing · C15747 Supportive Care · C1247 Testosterone Enanthate · C1246 Testosterone Cypionate · C1249 Testosterone Undecanoate · C15632 Chemotherapy (germ cell tumour) · C15313 Radiation Therapy (dysgerminoma/seminoma)

Genes (HGNC, lowercase prefix per repo convention): hgnc:11311 SRY · hgnc:7983 NR5A1 · hgnc:6848 MAP3K1 · hgnc:17210 DHX37 · hgnc:2865 DHH · hgnc:11204 SOX9 · hgnc:11203 SOX8 · hgnc:2934 DMRT1 · hgnc:12796 WT1 · hgnc:7960 NR0B1 · hgnc:16700 ZFPM2 · hgnc:4173 GATA4 · hgnc:9306 PPP2R3C · hgnc:18021 HHAT — verify each HGNC numeric ID with just validate-terms before committing.

Appendix B — Curation guidance specific to this KB

Module conformance. No existing kb/modules/ module fits this disease well. Candidate anchors: none of the cancer hallmark, fibrosis, senescence, lysosomal, or metabolic-intoxication modules apply. The gonadal-neoplasia arm has partial affinity to genome_instability_mutation but the mechanism (TSPY-driven transformation of an arrested germ cell in a dysgenetic niche) is distinct. Do NOT force conforms_to: fibrotic_response for peritubular fibrosis — it is developmental matrix abnormality, not injury-driven fibrosis. If a module is warranted, the right one to create would be a conserved "bipotential-fate-switch failure" module capturing the SOX9-threshold/Wnt-antagonism logic, which would also serve 46,XX testicular/ovotesticular DSD and 46,XY CGD.
Grouping candidacy. 46,XY PGD is a natural member of a "46,XY Disorders of Testicular Development" grouping alongside 46,XY CGD, TRS, MGD, and ovotesticular DSD (grouping_basis: SHARED_MECHANISM, NECESSARY criteria: HAS_INHERITANCE/karyotype + HAS_PHENOTYPE HP:0000133). It is also a member of Digenic_and_Oligogenic_Disorders on the strength of the DHX37+NR5A1 double-heterozygotes.
Subtypes. Model gene-defined subtypes (NR5A1-related, MAP3K1-related, DHX37-related, SRY-related, DHH-related) with short slug-friendly names. The DHH subtype carries the distinctive adult neuropathy; the NR5A1 subtype carries adrenal insufficiency and 46,XX POI in relatives; the WT1 route should be excluded as syndromic.
biological_scale tags: gene lesion → MOLECULAR; SOX9-threshold/Sertoli fate failure → CELLULAR; dysgenetic gonad → TISSUE; Müllerian retention, undervirilization, hypergonadotropic hypogonadism → ORGANISM.
Frequency discipline. Use the I-DSD 2025 numbers (PMID:40208111) as the only source of frequency: values. Omit frequency: for the Orphanet editorial bands.
Evidence-source tagging. Registry/cohort/case series → HUMAN_CLINICAL. NT2/D1, KGN, HEK-293T variant-function assays → IN_VITRO. Mouse/rat/zebrafish → MODEL_ORGANISM. Structural/docking predictions of MAP3K1 folding → COMPUTATIONAL. Guideline consensus statements without primary data → OTHER.
Three discussions entries are warranted:
KNOWLEDGE_GAP: "There are no current guidelines on surveillance" for retained functional dysgenetic gonads (GeneReviews, corroborated by PMID:40208111).
KNOWLEDGE_GAP: 42–58% of cases remain genetically unexplained after exome sequencing.
HUMAN_MODEL_MISMATCH: NR5A1 p.R92W produces XX testicular development in humans but not mice (PMC5101639); and separately, mouse Map3k1 nulls do not model the human gain-of-function disease.
Before committing any evidence item, run the full stack: just fetch-reference PMID:<id> for every PMID cited here (I have not populated references_cache/), then just validate, just validate-references, just validate-terms. Several snippets in this report are paraphrases produced by page-summarisation and must be replaced with exact abstract substrings verified against the cached file. The verbatim-quoted passages (marked with > blockquotes and explicit "verbatim" labels) are the safest starting points but still require substring verification.

Sources

Primary literature (PMID-cited) - Elzaiat M, McElreavey K, Bashamboo A. Genetics of 46,XY gonadal dysgenesis. Best Pract Res Clin Endocrinol Metab 2022;36(1):101633. PMID:35249806 - Tadokoro-Cuccaro R, et al. Phenotypic Variation and Pubertal Outcomes in Males and Females With 46,XY Partial Gonadal Dysgenesis. J Clin Endocrinol Metab 2025. PMID:40208111 - McElreavey K, et al. Pathogenic variants in the DEAH-box RNA helicase DHX37… Genet Med 2020;22(1):150-159. PMID:31337883 - Ostrer H. Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review. Sex Dev 2022. PMID:35290982 - Pearlman A, et al. Mutations in MAP3K1 cause 46,XY disorders of sex development… Am J Hum Genet 2010;87(6):898-904. PMID:21129722 - Granados A, et al. MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature. Am J Med Genet C 2017. PMID:28504475 - Slowikowska-Hilczer J, et al. Risk of gonadal neoplasia in patients with disorders/differences of sex development. Cancer Epidemiol 2020;69:101800. PMID:32905884 - Berglund A, et al. Incidence, Prevalence, Diagnostic Delay, and Clinical Presentation of Female 46,XY Disorders of Sex Development. J Clin Endocrinol Metab 2016;101(12):4532-4540. PMID:27603905 - Hughes IA, Houk C, Ahmed SF, Lee PA. Consensus statement on management of intersex disorders. Arch Dis Child 2006;91(7):554-63. PMID:16624884 - Lee PA, et al. Global Disorders of Sex Development Update since 2006. Horm Res Paediatr 2016. PMID:26820577 - Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males. Int J Endocrinol 2014. PMID:25580123 - NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review. PMID:38206718 - DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis - MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling… - Screening of Y chromosome microdeletions in 46,XY partial gonadal dysgenesis… - Idris et al. Genomic technologies and the diagnosis of 46,XY differences of sex development. Andrology 2025. PMID:39081229 - Worldwide cohort study of 46,XY DSD genetic diagnoses. Front Genet 2024. DOI:10.3389/fgene.2024.1387598 - Two Novel Heterozygous Variants in RecA2 Domain of DHX37… PMID:37717579 - 46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH)… PMID:25927242 - Skakkebaek NE, et al. Testicular dysgenesis syndrome: possible role of endocrine disrupters. PMID:16522521 - Is testicular dysgenesis syndrome a genetic, endocrine, or environmental disease…? PMID:29183799 - The p.R92W variant of NR5A1/Nr5a1 induces testicular development of 46,XX gonads in humans, but not in mice - Steroidogenic Factor 1 (Nr5a1) is Required for Sertoli Cell Survival Post Sex Determination - The conditional deletion of Nr5a1 in Sox9-Cre mice compromises testis differentiation - Unveiling the roles of Sertoli cells lineage differentiation in reproductive development and disorders - Inefficient Sox9 upregulation and absence of Rspo1 repression lead to sex reversal in the B6.XYTIR mouse gonad - A 46,XY female DSD patient with bilateral gonadoblastoma, a novel SRY missense mutation combined with a WT1 KTS splice-site mutation. PMID:22815844

Databases and reference resources - GeneReviews: Nonsyndromic Disorders of Testicular Development Overview (NBK1547) - MONDO:0016674 — Monarch Initiative - Orphanet: 46,XY partial gonadal dysgenesis (ORPHA:251510) - GARD: 46,XY partial gonadal dysgenesis - HPO annotations — ontology.jax.org - OMIM 400044 (SRXY1) · 612965 (SRXY3/NR5A1) · 613762 (SRXY6/MAP3K1) · 233420 (SRXY7/DHH) · 273250 (SRXY11/DHX37) · 607080 (GDMN) - OMIA:001601-9796 — XY difference of sexual development, horse · OMIA:001230-9796 — XY sex reversal, SRY-related, horse - ESPU–SPU Consensus statement 2020: Management of Differences of Sex Development - Sox9 Duplications Are a Relevant Cause of Sry-Negative XX Sex Reversal Dogs - Human Fetal Testis Xenografts Are Resistant to Phthalate-Induced Endocrine Disruption

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	134
Resolved	122
Unresolved (possible confabulation)	1
Obsolete	1
Unverifiable	10
Terms whose name was checked	85
Terms named correctly	71
Terms named as a different term	10
Terms whose name is worth a second look	4

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0016674 (10 mentions) - the report calls it "MONDO", "Monarch Initiative"; MONDO calls it 46,XY partial gonadal dysgenesis
HP:0008232 (2 mentions) - the report calls it "Elevated circulating follicle stimulating hormone level", "Pituitary feedback: ↑FSH"; HP calls it Elevated circulating follicle stimulating hormone level
HP:0000846 (2 mentions) - the report calls it "Adrenal insufficiency", "NR5A1 subgroup only: ↓cortisol/↑ACTH if adrenal involvement"; HP calls it Adrenal insufficiency
HP:0031103 (2 mentions) - the report calls it "Sertoli cell: ↓AMH"; HP calls it Decreased circulating antimullerian hormone circulation
CHEBI:17347 (2 mentions) - the report calls it "Reduced fetal and postnatal testosterone"; CHEBI calls it testosterone
UBERON:0000473 (1 mention) - the report calls it "dysgenetic"; UBERON calls it testis
UBERON:0002367 (1 mention) - the report calls it "hypoplastic"; UBERON calls it prostate gland
UBERON:0002369 (1 mention) - the report calls it "NR5A1 subgroup only"; UBERON calls it adrenal gland
NCIT:C15599 (3 mentions) - the report calls it "Progestogen"; NCIT calls it Hormone Replacement Therapy
NCIT:C15329 (5 mentions) - the report calls it "Scrotoplasty, phalloplasty", "Clitoroplasty", "Vaginoplasty / urogenital sinus mobilization", "Müllerian remnant excision"; NCIT calls it Surgical Procedure

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

HP:0071514 (1 mention) - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0040171 (2 mentions) - the report calls it "Decreased serum testosterone concentration", "Leydig cell: ↓testosterone"; HP calls it Decreased serum testosterone concentration, and lists "Decreased testosterone" among its other names
CHEBI:16469 (2 mentions) - the report calls it "decreased 17β-estradiol"; CHEBI calls it 17beta-estradiol, and lists "cis-estradiol" among its other names
NCBITaxon:9615 (1 mention) - the report calls it "Domestic dog"; NCBITaxon calls it Canis lupus familiaris, and lists "Canis domesticus" among its other names
NCBITaxon:9823 (1 mention) - the report calls it "Domestic pig"; NCBITaxon calls it Sus scrofa, and lists "pig" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

MONDO:0016674 - called "MONDO", "Monarch Initiative"
HP:0008232 - called "Elevated circulating follicle stimulating hormone level", "Pituitary feedback: ↑FSH"
HP:0040171 - called "Decreased serum testosterone concentration", "Leydig cell: ↓testosterone"
HP:0000846 - called "Adrenal insufficiency", "NR5A1 subgroup only: ↓cortisol/↑ACTH if adrenal involvement"
NCIT:C15329 - called "Scrotoplasty, phalloplasty", "Clitoroplasty", "Vaginoplasty / urogenital sinus mobilization", "Müllerian remnant excision"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: Orphanet, ORPHA, GARD, LOINC, OMIA.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	37
Resolved	37
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	37
On topic	28
Off topic	0

All extracted references resolved successfully.

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OpenScientist Report

Mappings

Definitions

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Imaging Findings

Progression

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

1.1 Definition

1.2 Key identifiers

1.3 Synonyms and alternative names

1.4 Data provenance character

2. Etiology

2.1 Primary causal factors

2.2 Genetic risk/causal factors

2.3 Environmental risk factors

2.4 Protective factors

2.5 Gene–environment interaction

3. Phenotypes

3.1 HPO annotation set (ORPHA:251510, retrieved from JAX HPO API; all IDs and labels verified against sqlite:obo:hp via OAK)

3.2 PGD-specific quantitative phenotype data — I-DSD Registry 2025 (the best available)

3.3 Phenotype characteristics

3.4 Quality-of-life impact (per phenotype where possible)

4. Genetic / Molecular Information

4.1 Causal genes with OMIM allelic-series mapping

4.2 NR5A1 (SF-1) — the most frequent single cause

4.3 MAP3K1 — the canonical gain-of-function cause

4.4 DHX37 — the newest major gene (and a candidate ribosomopathy)

4.5 SRY

4.6 DHH — the autosomal recessive cause with a neurological tell

4.7 Other loci

4.8 Somatic vs germline, mosaicism, and epigenetics

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 The causal chain (upstream → downstream)

6.2 Molecular pathways

6.3 Cellular processes

6.4 Protein dysfunction

6.5 Metabolic changes

6.6 Immune system involvement

6.7 Tissue damage mechanisms

6.8 Biochemical abnormalities

6.9 Epigenetic changes

6.10 Molecular profiling

7. Anatomical Structures Affected

7.1 Organ level

7.2 Tissue and cell level

7.3 Subcellular level (GO Cellular Component)

7.4 Localization and lateralization

8. Temporal Development

8.1 Onset

8.2 Progression

8.3 Patterns

9. Inheritance and Population

9.1 Epidemiology

9.2 Inheritance

9.3 Population demographics

10. Diagnostics

10.1 Clinical and laboratory tests

10.2 Genetic testing

10.3 Omics-based diagnostics

10.4 Clinical criteria and differential diagnosis

3.1 HPO annotation set (ORPHA:251510, retrieved from JAX HPO API; all IDs and labels verified against `sqlite:obo:hp` via OAK)