46,XY partial gonadal dysgenesis

Mendelian MONDO:0016674 Pathograph 36 Show in embeddings browser Disorder of sex development Gonadal development disorder

46,XY partial gonadal dysgenesis (46,XY PGD) is a genetically heterogeneous disorder of testis determination in which an individual with a nonmosaic 46,XY karyotype develops incompletely rather than absently differentiated testes. The defining contrast with 46,XY complete gonadal dysgenesis is that residual testicular tissue persists: dysgenetic testes with hypoplastic seminiferous tubules retain partial fetal Sertoli-cell (anti-Müllerian hormone) and Leydig-cell (androgen) output. Because fetal androgen exposure is partial rather than absent, external genitalia are typically ambiguous — spanning almost-female to almost-male — instead of typically female, and Müllerian regression is partial and variable rather than uniformly failed. Most individuals present with atypical genitalia in infancy. Retained gonads drive spontaneous puberty in most individuals raised male (80% of those with at least one gonad), and unwanted virilization in a substantial minority raised female (42% of those with gonads). Y-bearing dysgenetic gonadal tissue confers gonadoblastoma and invasive germ-cell tumor risk, which is real but lower than in the complete form.

Ask OpenScientist

Ask a research question about 46,XY partial gonadal dysgenesis. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

🔗

Mappings

MONDO

MONDO:0016674 46,XY partial gonadal dysgenesis

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

📘

Definitions

46,XY partial gonadal dysgenesis case definition

The modeled disease requires a nonmosaic 46,XY karyotype and incomplete testis determination, evidenced by histologically dysgenetic but present testicular tissue and/or partial fetal testicular hormone output. The external genital phenotype is typically ambiguous rather than typically female, and Müllerian structures may be partially retained.

CASE_DEFINITION This entry models the partial phenotype specifically. 46,XY complete gonadal dysgenesis (Swyer syndrome, bilateral streak gonads with typical female genitalia and full Müllerian persistence) is a distinct entity curated separately; 45,X/46,XY mixed gonadal dysgenesis is a sex-chromosome DSD; testicular regression syndrome, ovotesticular DSD, androgen insensitivity, and androgen synthesis defects are differential diagnoses. Gene-anchored subtypes whose published spectrum spans partial and complete disease are included here only for their partial presentations.

Show evidence (2 references)

PMID:40208111 SUPPORT Human Clinical

"46,XY gonadal dysgenesis is classified as complete (CGD) or partial (PGD) subtypes."

Establishes the complete/partial dichotomy that this entry's case definition operationalizes.

PMID:28504475 SUPPORT Human Clinical

"the other three presented with partial gonadal dysgenesis, characterized by incomplete testicular development"

Supplies the defining "incomplete testicular development" criterion that distinguishes partial from complete disease.

👪

Inheritance

Autosomal dominant inheritance HP:0000006

Most identified molecular causes of partial disease — NR5A1, MAP3K1, WT1, DHX37, SOX9-regulatory — are heterozygous and sex-limited dominant, with gene-specific penetrance. NR5A1 in particular shows markedly incomplete penetrance and intrafamilial phenotypic variability, which complicates cascade counseling.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:33296094 SUPPORT 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 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 cause the recessive partial form, classically with minifascicular polyneuropathy.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:11017805 SUPPORT 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.

Digenic inheritance HP:0010984

In a subset of partial gonadal dysgenesis, pathogenic variants at two loci co-occur and are jointly invoked to explain the phenotype. The best-documented pair is DHX37 plus NR5A1: in a Brazilian series, two of the patients carrying a deleterious DHX37 variant also carried a pathogenic NR5A1 variant, and the authors proposed digenic inheritance. Oligogenic modification has also been proposed for NR5A1 splice-variant families, where co-inherited rare OTX2 or PROP1 variants may modulate penetrance. Because the Inheritance class has no genes slot, the contributing loci are named here: DHX37 and NR5A1 for the digenic pair, and OTX2 and PROP1 as proposed modifiers. All four have records in the genetic section, with OTX2 and PROP1 typed as MODIFIER.

Digenic inheritance

Show evidence (2 references)

PMID:37240737 SUPPORT Human Clinical

"For both patients carrying DHX37 and NR5A1 pathogenic variants, a digenic inheritance is suggested."

Directly asserts digenic inheritance for the DHX37+NR5A1 double heterozygotes in a partial-gonadal-dysgenesis cohort.

PMID:33296094 SUPPORT 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)."

Supports an oligogenic modifier model as a proposed ("possibly") explanation for the incomplete penetrance, not an established second-locus requirement.

◆

Subtypes

gene

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

NR5A1 hgnc:7983 Autosomal dominant inheritance

Heterozygous NR5A1 (SF-1) loss-of-function variants are the most frequently identified molecular cause in partial disease specifically. Haploinsufficiency typically produces the milder end of the testis-development spectrum — dysgenetic testes with often spontaneous puberty — and shows marked intrafamilial variability and incomplete penetrance. Adrenal function was preserved in the partial-dysgenesis series cited here, and most NR5A1 46,XY DSD occurs without adrenal insufficiency, but NR5A1/SF-1 also governs adrenal development and primary adrenal failure was the presentation in the first reported human NR5A1 case. Preserved adrenal function should therefore be confirmed rather than assumed.

Show evidence (4 references)

PMID:40208111 SUPPORT 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 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.

PMID:38206718 SUPPORT Human Clinical

"More commonly, NR5A1 mutations happening in individuals with 46,XY DSD are associated with varying severity but without adrenal insufficiency"

Supports absent adrenal insufficiency as the usual - but explicitly not universal - situation in NR5A1-related 46,XY DSD.

+ 1 more reference

WT1-related 46,XY partial gonadal dysgenesis (Denys-Drash/Frasier continuum)

WT1 hgnc:12796 Autosomal dominant inheritance

Heterozygous WT1 variants cause a syndromic form in which the disorder of testicular development is accompanied by steroid-resistant nephrotic syndrome and Wilms tumor predisposition. The historical Denys-Drash and Frasier designations are now recognized as a phenotypic continuum. A genotype-severity correlation is classically described (missense and intron-9 splice variants giving severe dysgenesis; nonsense variants and whole-gene deletions giving haploinsufficiency with milder dysgenesis and later-onset nephropathy), but the case curated here is a whole-gene deletion that nonetheless caused severe partial dysgenesis with gonadoblastoma in infancy and bilateral Wilms tumour, and its authors present it as showing the deletion phenotype can be more severe than previously thought. The correlation should therefore not be used to reassure. A WT1 defect should be sought promptly in 46,XY gonadal dysgenesis even without a detected renal abnormality.

Show evidence (2 references)

PMID:25613702 SUPPORT Human Clinical

"We describe a newborn with 46,XY severe partial gonadal dysgenesis"

Directly documents WT1-associated partial gonadal dysgenesis.

PMID:32352694 SUPPORT Other

"Additional common findings can include disorders of testicular development (with or without abnormalities of the external genitalia and/or müllerian structures) and Wilms tumor."

Supports the syndromic gonadal-plus-renal/oncologic character of this subtype.

molecular

Molecularly unresolved 46,XY partial gonadal dysgenesis

A majority of individuals meeting the partial case definition receive no molecular diagnosis with currently available testing, so an explicitly unresolved subtype is retained rather than forcing every case into a gene-anchored bin.

Show evidence (2 references)

PMID:40208111 SUPPORT Human Clinical

"A genetic etiology was identified in 42% of the cohort"

A 42% diagnostic yield implies that most of this large registry cohort remained molecularly unresolved.

PMID:37240737 SUPPORT Human Clinical

"Several genes are known to be involved in sex development pathways, however approximately 50% of all cases remain elusive."

Directly supports a large molecularly unexplained fraction.

Discussions and Knowledge Gaps

In 46,XY partial gonadal dysgenesis with functionally significant residual testicular tissue, what is the age-stratified gonadal tumor risk for a retained gonad (as opposed to the prevalence found at gonadectomy), how much does labioscrotal position and hCG responsiveness modify it, and is any surveillance strategy sensitive enough to make gonad retention safe?

KNOWLEDGE GAP OPEN gap_xy_pgd_gonad_retention_risk_benefit

Attached to

pathophysiology#Gonadal germ-cell neoplasia risk pathophysiology#Residual pubertal gonadal steroid capacity

Published tumor figures are prevalence-at-gonadectomy in referral cohorts, not incidence in retained gonads, and are therefore the wrong denominator for the decision clinicians actually face. Because partial disease — unlike complete disease — offers a genuine functional reason to retain gonads, this denominator problem is decision-critical rather than academic. No validated surveillance protocol exists, and imaging and tumor markers are known to miss lesions.

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 (2 references)

PMID:40208111 SUPPORT Human Clinical

"though further study is needed to determine the risk of developing gonadal tumors."

The cohort's own authors identify this precise gap.

PMID:34070473 SUPPORT Human Clinical

"the limitation of tumor markers and US or MRI/CT to detect them and missing guidelines for surveillance."

Directly documents the absence of a reliable surveillance strategy.

What accounts for the roughly half of 46,XY partial gonadal dysgenesis cases that remain molecularly unexplained after panel and exome testing — non-coding regulatory variation, oligogenic burden, mosaicism confined to the gonad, or genes not yet implicated?

KNOWLEDGE GAP OPEN gap_xy_pgd_molecular_yield

Attached to

pathophysiology#Attenuated pro-testis network activation

Diagnostic yield has plateaued near 40-50% despite broad sequencing. The documented digenic DHX37/NR5A1 cases and the dosage-sensitive SOX9 enhancer architecture both suggest that single-gene coding analysis is structurally unable to capture the remainder.

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:37240737 SUPPORT Human Clinical

"approximately 50% of all cases remain elusive."

Directly quantifies the unexplained fraction.

PMID:40208111 SUPPORT Human Clinical

"A genetic etiology was identified in 42% of the cohort"

Confirms the plateaued diagnostic yield in a large contemporary cohort.

PMID:35249806 SUPPORT Other

"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."

An expert review independently confirms that established testis-determining genes account for only a minority of cases.

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#Attenuated pro-testis network activation

NR5A1 is the gene most characteristically implicated in 46,XY partial gonadal dysgenesis, so the fidelity of its animal models directly determines how much mechanistic weight mouse data can carry for this disease. A direct human-versus-mouse comparison of the identical p.R92W allele found the gonadal consequence to be species-divergent: disruption of male gonadal development in both, but ovary-to-testis conversion only in humans. This means the NR5A1-dependent sex-determination network is not fully conserved, and murine rescue or knockout results should not be treated as directly predictive of the human partial phenotype's severity or threshold behavior. Evidence exists in the model; what is uncertain is its translational validity.

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 (2 references)

PMID:27833742 SUPPORT 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.

PMID:27833742 SUPPORT Model Organism

"Our findings provide novel insights into the conservation and divergence in the molecular networks"

The authors frame the result explicitly in terms of network conservation versus divergence, which is the translational-validity question this record tracks.

⚙

Pathophysiology

Attenuated pro-testis network activation

Partial rather than complete loss of pro-testis transcriptional drive. Heterozygous NR5A1 haploinsufficiency, partial SOX9 enhancer loss, hypomorphic SRY alleles, and WT1 dosage reduction each leave residual pro-testis output. Because the SRY-SOX9-SF1 network is dosage-sensitive and its enhancers act synergistically, intermediate network output produces intermediate — not absent — testis determination. This dose-dependence is the mechanistic reason partial and complete dysgenesis are a spectrum caused by overlapping genes rather than distinct gene sets.

NR5A1 hgnc:7983 SOX9 hgnc:11204 SRY hgnc:11311 WT1 hgnc:12796

sex determination GO:0007530 ↓ DECREASED male gonad development GO:0008584 ↓ DECREASED

Downstream

Incomplete testicular differentiation Residual pro-testis network activity supports partial supporting-cell commitment and rudimentary cord formation rather than the complete failure seen in Swyer syndrome.

Show evidence (2 references)

PMID:27463801 SUPPORT Human Clinical

"Heterozygous SF1 loss-of-function mutations in these cases resulted in mild DSD manifestations, such as dysgenetic testes, spontaneous puberty, and preserved adrenal function."

Directly links partial (heterozygous) loss of SF-1 function to the mild, residual-function end of the phenotype spectrum.

PMID:30552336 SUPPORT In Vitro

"All three enhancers showed synergistic activity and together drive SOX9 in the testis."

Establishes that SOX9 testis expression is under dosage-sensitive, synergistic multi-enhancer control, which is the general basis for graded network output. Graded PARTIAL because this paper reports sex reversal rather than a partial phenotype, so it supports dosage-sensitivity in principle and not a partial SOX9 presentation specifically.

MAP3K1 gain-of-function pro-ovarian signaling bias

Pathogenic MAP3K1 variants increase phosphorylation of ERK1, ERK2, and p38 and hyperactivate Wnt4/beta-catenin/FOXL2 signaling, biasing the bipotential gonad toward the ovarian program. Where the bias is incomplete, testis determination is attenuated rather than abolished, yielding partial dysgenesis.

MAP3K1 hgnc:6848

sex determination GO:0007530 ⚠ ABNORMAL

Downstream

Incomplete testicular differentiation A partial pro-ovarian shift leaves incompletely differentiated testicular tissue.

Show evidence (2 references)

PMID:35290982 SUPPORT Other

"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."

Defines the direction and signaling consequence of MAP3K1 variants.

PMID:21129722 SUPPORT In Vitro

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

Provides the functional evidence in patient-derived cells.

DHH paracrine hedgehog signaling failure

Biallelic DHH loss removes Sertoli-derived hedgehog signaling to the interstitial compartment, impairing fetal Leydig-cell and peritubular myoid-cell development. Because the supporting-cell lineage itself still forms, the gonad is dysgenetic rather than streak. The same signal is required for perineurial development in peripheral nerve, which is why this subtype couples partial gonadal dysgenesis with minifascicular neuropathy.

Sertoli cell CL:0000216 Leydig cell CL:0000178

DHH hgnc:2865

Leydig cell differentiation GO:0033327 ↓ DECREASED

Downstream

Incomplete testicular differentiation Loss of the paracrine differentiation signal yields dysgenetic testicular tissue.

Show evidence (3 references)

PMID:25927242 SUPPORT Human Clinical

"The gonads of one patient showed partial gonadal dysgenesis with loss of Leydig cells in tubular areas"

Directly documents Leydig-cell loss in histologically confirmed DHH-related partial gonadal dysgenesis, which is the evidence for the decreased Leydig-cell-differentiation annotation on this node.

PMID:25927242 SUPPORT Human Clinical

"Gonadal dysgenesis in these cases may be due to impairment of Sertoli cell-Leydig cell interaction during gonadal development."

States the Sertoli-to-Leydig paracrine mechanism this node models.

PMID:11017805 SUPPORT Human Clinical

"Sural nerve pathology revealed peculiar findings characterized by extensive minifascicular formation within the endoneurium and with a decreased density of myelinated fibers."

Documents the peripheral-nerve arm of DHH loss that accompanies the partial gonadal phenotype.

DHX37-related ribosome-biogenesis defect

Heterozygous DHX37 variants affect a putative RNA helicase required for ribosome biogenesis. How this translates into a gonad-restricted phenotype is unresolved; the gonadal primordium may be selectively vulnerable to reduced ribosome output during its narrow determination window.

DHX37 hgnc:17210

Downstream

Incomplete testicular differentiation DHX37-associated partial disease converges on incomplete testis differentiation through intermediates that have not been established.

Show evidence (3 references)

PMID:37240737 SUPPORT Human Clinical

"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."

Supports the molecular identity of DHX37 and its causal role in partial disease.

PMID:31337883 SUPPORT Human Clinical

"Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis."

Gonadal-somatic-cell-restricted expression provides the tissue-specificity rationale for a ribosome-biogenesis gene producing a gonad-limited phenotype.

PMID:31337883 SUPPORT Human Clinical

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

The authors' own hedged framing ("raises the possibility") is the best available statement of the proposed ribosomopathy mechanism, which remains unproven.

Incomplete testicular differentiation

The convergent lesion of this disease. Diverse triggers produce a gonad that contains recognizable but abnormal testicular tissue — most characteristically hypoplastic seminiferous tubules — rather than the fibrous bilateral streaks of complete gonadal dysgenesis. Preservation of some Sertoli and Leydig cells is what makes every downstream feature of this disease partial: partial AMH, partial androgen, partial Müllerian regression, partial masculinization, and sometimes sufficient function for spontaneous puberty.

Sertoli cell CL:0000216 Leydig cell CL:0000178

male gonad development GO:0008584 ↓ DECREASED Sertoli cell differentiation GO:0060008 ↓ DECREASED

Downstream

Partial fetal AMH secretion Residual Sertoli cells secrete some anti-Müllerian hormone, so Müllerian regression is partial and variable rather than uniformly absent.

Partial fetal testicular androgen secretion Residual Leydig cells produce some testosterone, giving intermediate masculinization of the external genitalia.

Dysgenetic Y-bearing germ-cell niche Germ cells persist in a poorly differentiated gonadal environment containing Y-chromosome material, creating a tumor-prone niche.

Impaired spermatogenesis Hypoplastic seminiferous tubules cannot support normal germ-cell maturation.

Residual pubertal gonadal steroid capacity Surviving Leydig cells can respond to pubertal gonadotropin drive, giving a variable capacity for spontaneous pubertal androgen production.

Show evidence (1 reference)

PMID:38206718 SUPPORT Human Clinical

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

Directly documents the defining histology — present but hypoplastic tubules, not fibrous streak tissue.

Partial fetal AMH secretion

Fetal Sertoli-cell AMH output is reduced but not abolished, so Müllerian-duct regression is incomplete and variable. This is a key point of divergence from complete gonadal dysgenesis, where absent AMH gives uniform Müllerian persistence with a uterus.

Sertoli cell CL:0000216

Downstream

Variable Müllerian-duct retention Depending on how much AMH the dysgenetic testes produce, Müllerian derivatives may be fully regressed, rudimentary, or retained.

Show evidence (1 reference)

PMID:38206718 SUPPORT Human Clinical

"SF-1 binds to and activates testis-specific enhancer of SOX9 core (TESCO), and associates with SOX9 to regulate the anti-Müllerian hormone expression, which lead to the regression of Müllerian structures."

Establishes the SF-1/SOX9 to AMH to Müllerian-regression axis whose partial failure produces variable Müllerian retention.

Partial fetal testicular androgen secretion

Fetal Leydig-cell androgen output is intermediate. Because external genital masculinization is a dose-dependent, time-windowed response to fetal testosterone and dihydrotestosterone, intermediate androgen produces the hallmark ambiguous phenotype rather than either typical male or typical female anatomy.

Leydig cell CL:0000178

androgen biosynthetic process GO:0006702 ↓ DECREASED male sex differentiation GO:0046661 ↓ DECREASED

Downstream

Ambiguous external genital development Intermediate fetal androgen exposure yields a genital phenotype anywhere between almost-female and almost-male.

Show evidence (1 reference)

PMID:28504475 SUPPORT Human Clinical

"incomplete testicular development, resulting in clitoral hypertrophy with otherwise typical female external genitalia"

Documents an intermediate androgen effect on external genital development.

Ambiguous external genital development

The graded genital phenotype of partial disease, encompassing penoscrotal hypospadias, micropenis, bifid scrotum, cryptorchidism, and clitoral hypertrophy in varying combinations.

Downstream

Ambiguous genitalia The HPO-grounded external-genital phenotype.

Penoscrotal hypospadias Incomplete urethral fusion from insufficient fetal androgen.

Cryptorchidism Dysgenetic testes descend poorly because descent depends on gonadal hormone output.

Clitoral hypertrophy Partial androgen exposure enlarges the phallic structure in an otherwise female configuration.

Show evidence (1 reference)

PMID:33296094 SUPPORT Human Clinical

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

Directly documents the undervirilized genital constellation in partial disease.

Residual pubertal gonadal steroid capacity

Retained dysgenetic gonads may respond to pubertal gonadotropin drive. This is the single most clinically consequential difference from complete gonadal dysgenesis, because it means an individual with retained gonads may either complete puberty spontaneously (an advantage if raised male) or virilize against the sex of rearing (a harm if raised female). Whether residual function exists is partly predictable before puberty from gonadal position and the testosterone response to hCG stimulation. Where residual function is inadequate, hypergonadotropic hypogonadism supervenes.

Leydig cell CL:0000178

steroid hormone biosynthetic process GO:0120178 ⚠ ABNORMAL

Downstream

Spontaneous puberty in retained-gonad individuals Sufficient residual Leydig function permits unassisted pubertal progression.

Pubertal virilization discordant with female rearing In individuals raised female who retain gonads, the same residual steroidogenic capacity produces unwanted virilization at puberty.

Hypergonadotropic hypogonadism When residual function is inadequate, gonadal steroid and inhibin feedback fail and FSH and LH rise.

Delayed puberty Insufficient residual gonadal steroid output delays pubertal onset, and in a minority of individuals raised female this is the presenting complaint.

Show evidence (1 reference)

PMID:40208111 SUPPORT Human Clinical

"Labioscrotal gonads at presentation and testosterone response to human chorionic gonadotropin predicted onset of spontaneous puberty."

Directly supports predictable residual Leydig function.

Dysgenetic Y-bearing germ-cell niche

Germ cells arrested in a poorly differentiated gonadal environment containing Y-chromosome material can escape normal maturation and give rise to gonadoblastoma and then invasive germ-cell tumor. Partial dysgenesis carries a lower but still substantially elevated risk compared with complete dysgenesis, and the risk is further graded by gonadal position, being lowest in scrotal gonads.

germ cell CL:0000586

Downstream

Gonadal germ-cell neoplasia risk The dysgenetic niche permits precursor lesions and invasive germ-cell tumors.

Show evidence (1 reference)

PMID:34070473 SUPPORT Human Clinical

"the presence of Y chromosomal material serves as a risk factor for malignant transformation"

Supports the Y-bearing dysgenetic gonadal substrate as the tumor risk factor.

Gonadal germ-cell neoplasia risk

Partial gonadal dysgenesis carries a clinically important risk of gonadoblastoma and invasive germ-cell tumor. Reported percentages vary with ascertainment; the most internally consistent comparison comes from a single registry cohort scoring complete and partial disease side by side, which found the partial form intermediate between complete disease and the general population, and lower in individuals raised male (whose gonads are more often scrotal) than in those raised female.

Downstream

Gonadoblastoma Gonadoblastoma is the characteristic precursor neoplasm in dysgenetic gonads.

Dysgerminoma Precursor lesions can progress to invasive seminomatous germ-cell tumor.

Show evidence (2 references)

PMID:40208111 SUPPORT Human Clinical

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

Supplies the partial-versus-complete gradient and the female-versus-male rearing difference within one cohort.

PMID:32905884 SUPPORT Human Clinical

"The highest risk (36 %) was observed in 46,XY patients with gonadal dysgenesis (GD): complete GD (33 %) and partial GD (23 %)"

Provides an independent multicenter cohort estimate for the partial form.

Variable Müllerian-duct retention

Müllerian derivatives may be absent, rudimentary, or present depending on residual fetal AMH. Unlike complete gonadal dysgenesis, a uterus cannot be assumed, and its presence or absence must be established by imaging or surgical inspection before reproductive counseling.

Show evidence (1 reference)

PMID:32352694 SUPPORT Other

"with or without abnormalities of the external genitalia and/or müllerian structures"

Supports variability of Müllerian involvement across disorders of testicular development.

Impaired spermatogenesis

Hypoplastic seminiferous tubules and reduced testicular volume impair or abolish sperm production, so infertility is usual even in individuals raised male who virilize adequately.

germ cell CL:0000586

Downstream

Azoospermia Absent sperm in the ejaculate is the usual finding when semen analysis is performed.

Show evidence (1 reference)

PMID:33296094 SUPPORT Human Clinical

"low bitesticular volume and azoospermia in P2"

Directly documents azoospermia with reduced testicular volume.

Spontaneous puberty in retained-gonad individuals

A majority of individuals with partial disease raised male and retaining at least one gonad enter and progress through puberty without hormone treatment. This is a genuine functional advantage of the partial over the complete form and is a central argument in gonad-retention decisions.

Show evidence (2 references)

PMID:40208111 SUPPORT Human Clinical

"Many PGD patients with preserved gonads have the potential to develop puberty spontaneously"

Directly supports spontaneous pubertal potential with preserved gonads.

PMID:25580123 SUPPORT Human Clinical

"All had spontaneous puberty; only one needed androgen therapy."

Independent long-term confirmation in patients reared as males with at least one scrotal testis, corroborating the registry finding.

Pubertal virilization discordant with female rearing

Residual Leydig function in an individual raised female produces unwanted androgenic changes at puberty — hirsutism, voice deepening, and clitoral enlargement. This is a distinctively partial-disease problem: it does not arise from residual gonadal function in the complete form, where the gonads are nonfunctional. (Virilization can still occur in complete dysgenesis, but by a different route — androgen secretion by a gonadal germ-cell tumour.)

Downstream

Hirsutism Androgen-driven terminal hair growth in an androgen-dependent distribution.

Show evidence (1 reference)

PMID:38206718 SUPPORT Human Clinical

"A 12-year-old individual raised as a girl was admitted to the hospital due to hirsutism and a deep voice that began at 11 years old."

Directly documents pubertal virilization discordant with female rearing.

✶

Histopathology

Dysgenetic testis with hypoplastic seminiferous tubules

The defining histology of partial disease. Unlike the homogeneous fibrous streak tissue of complete gonadal dysgenesis, the gonad contains recognizable seminiferous tubules that are hypoplastic and disorganized. Establishing this distinction on the gonadectomy specimen is what confirms partial rather than complete disease.

Show evidence (1 reference)

PMID:38206718 SUPPORT Human Clinical

"hypoplastic seminiferous tubules seen under the microscope, consistent with the dysplastic testicular tissue."

Directly documents the hypoplastic-tubule histology.

Gonadoblastoma and germ cell neoplasia in situ in dysgenetic gonads

Resected gonads may harbor precursor lesions or invasive tumor. Because neoplasia can be focal, a limited biopsy with benign histology is not a reliable exclusion test.

Show evidence (2 references)

PMID:34070473 SUPPORT Human Clinical

"pre-invasive tumors such as germ cell neoplasia in situ (GCNIS) or gonadoblastoma, which is commonly observed in complete or partial dysgenesis"

Directly supports precursor lesions in partial dysgenesis.

PMID:34070473 SUPPORT Human Clinical

"Tissue samples had been previously taken laparoscopically with benign histology."

Illustrates that a limited laparoscopic biopsy reported as benign can precede a later tumour. Graded PARTIAL and flagged for provenance: this patient in the cited series had complete androgen insensitivity, not partial gonadal dysgenesis, so the sampling-limitation principle transfers but the tumour substrate and risk are not those of a dysgenetic gonad.

⬡

Pathograph

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

●

Phenotypes

Endocrine 3

Adrenal insufficiency HP:0000846

Show evidence (2 references)

PMID:38206718 SUPPORT Human Clinical

"NR5A1 mutations in humans was first described in a patient with 46,XY DSD, Müllerian structures, and primary adrenal failure"

Documents adrenal failure in NR5A1-related 46,XY DSD.

PMID:38206718 SUPPORT Human Clinical

"More commonly, NR5A1 mutations happening in individuals with 46,XY DSD are associated with varying severity but without adrenal insufficiency"

Establishes that adrenal involvement is the exception, which is why this phenotype carries no frequency band and is scoped to the NR5A1 subtype.

Hypergonadotropic hypogonadism HP:0000815

Show evidence (1 reference)

PMID:38206718 SUPPORT Human Clinical

"follicle stimulating hormone 53.31 mIU/mL (1.78 to 11.60)"

Markedly elevated FSH indicates primary gonadal failure. Graded PARTIAL because in this same patient testosterone was elevated rather than low - a compensated, partially functional gonad, which illustrates that the hypergonadotropic pattern in partial disease need not come with androgen deficiency.

Delayed puberty OCCASIONAL HP:0000823

Show evidence (1 reference)

PMID:40208111 SUPPORT Human Clinical

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

The reported 18% in the female-assigned subgroup falls in the OCCASIONAL (5-29%) band. Note this is the proportion who *presented* with delayed puberty, not the proportion who develop it; the true prevalence of delayed puberty is likely higher, so this band is conservative.

Genitourinary 8

Gonadal dysgenesis HP:0000133

Show evidence (1 reference)

PMID:38206718 SUPPORT Human Clinical

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

Directly documents dysgenetic testicular histology.

Cryptorchidism HP:0000028

Show evidence (1 reference)

PMID:33296094 SUPPORT 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 Human Clinical

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

Directly documents clitoral hypertrophy in partial disease.

Micropenis HP:0000054

Show evidence (1 reference)

PMID:38206718 SUPPORT Human Clinical

"46,XY DSD: characterized by ambiguous or female appearance of external genitalia, including hypospadias, micropenis, cryptorchidism, and testicular dysgenesis."

Lists micropenis within the 46,XY DSD undervirilization constellation that includes testicular dysgenesis. Graded PARTIAL because this is a category-level description rather than a partial-dysgenesis cohort finding.

Decreased testicular size HP:0008734

Show evidence (1 reference)

PMID:33296094 SUPPORT 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 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 Human Clinical

"low bitesticular volume and azoospermia in P2"

Azoospermia with low testicular volume supports infertility; the report does not itself use the word infertility, so support is graded partial.

Nephroblastoma HP:0002667

Show evidence (1 reference)

PMID:25613702 SUPPORT 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.

Integument 1

Hirsutism HP:0001007

Show evidence (1 reference)

PMID:38206718 SUPPORT Human Clinical

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

Directly documents hirsutism from pubertal virilization.

Nervous System 1

Peripheral neuropathy HP:0009830

Show evidence (1 reference)

PMID:11017805 SUPPORT Human Clinical

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

Directly documents polyneuropathy in the DHH subtype.

Other 7

Ambiguous genitalia VERY_FREQUENT HP:0000062

Show evidence (1 reference)

PMID:40208111 SUPPORT Human Clinical

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

Supports atypical genitalia as the usual presentation. Band derivation (declared departure from the default "most" -> FREQUENT mapping in docs/frequency-evidence-guidelines.md): the same abstract reports that only 18% of the female-assigned subgroup presented with delayed puberty and 8% with virilization, leaving at least ~74% of that subgroup presenting with atypical genitalia, and the male-assigned subgroup is atypical-genitalia ascertained by definition. Pooled across both subgroups this exceeds the 80% VERY_FREQUENT threshold. The band is therefore derived arithmetic, not a directly reported percentage.

Penoscrotal hypospadias HP:0000808

Show evidence (1 reference)

PMID:33296094 SUPPORT Human Clinical

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

Directly documents penoscrotal hypospadias in molecularly confirmed partial disease.

Presence of uterus in 46,XY individual HP:0034546

Show evidence (2 references)

PMID:38206718 SUPPORT Human Clinical

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

Documents a retained rudimentary uterus in a molecularly confirmed 46,XY partial gonadal dysgenesis case.

PMID:32352694 SUPPORT Other

"disorders of testicular development (with or without abnormalities of the external genitalia and/or müllerian structures)"

Supports Müllerian involvement as a variable rather than obligate feature of disorders of testicular development.

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

Show evidence (2 references)

PMID:35137906 SUPPORT Human Clinical

"AMH and inhibin B levels were significantly lower in cases than in controls"

The measured finding: AMH is significantly reduced in 46,XY DSD with genital ambiguity and palpable gonads. Graded PARTIAL because the cohort was partial androgen insensitivity, 5-alpha-reductase deficiency and idiopathic 46,XY DSD rather than partial gonadal dysgenesis specifically.

PMID:38206718 SUPPORT Human Clinical

"associates with SOX9 to regulate the anti-Müllerian hormone expression, which lead to the regression of Müllerian structures."

Supplies the mechanism behind the measured reduction - AMH is the Sertoli-derived output of the disrupted SF-1/SOX9 program.

Gonadoblastoma OCCASIONAL HP:0000150

Show evidence (2 references)

PMID:40208111 SUPPORT Human Clinical

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

The 8.8-19.7% range across the two partial subgroups falls in the OCCASIONAL (5-29%) band. Two caveats: the figure aggregates germ cell neoplasia in situ, gonadoblastoma and invasive tumour rather than gonadoblastoma alone, and it is prevalence found at gonadectomy in a referral registry rather than incidence in a retained gonad - the denominator problem this entry's gap_xy_pgd_gonad_retention_risk_benefit discussion treats as decision-critical.

PMID:25613702 SUPPORT Human Clinical

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

Directly documents very early gonadoblastoma in partial disease.

Dysgerminoma HP:0100621

Show evidence (1 reference)

PMID:39371651 SUPPORT Human Clinical

"All three patients developed seminomatous cancers."

Documents seminomatous tumors in 46,XY gonadal dysgenesis; in this small series the tumor cases were pure and mixed dysgenesis, so this is extrapolative for the partial form specifically.

Steroid-resistant nephrotic syndrome HP:0012588

Show evidence (1 reference)

PMID:32352694 SUPPORT 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.

🧬

Genetic Associations

NR5A1 (Causal heterozygous loss-of-function variant; the most frequently identified cause of the partial phenotype specifically)

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

Show evidence (2 references)

PMID:27463801 SUPPORT 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.

PMID:40208111 SUPPORT Human Clinical

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

Establishes NR5A1 as the characteristic partial-disease gene.

OTX2 (Proposed penetrance modifier co-inherited from the non-transmitting parent in an NR5A1 splice-variant family)

Gene: OTX2 hgnc:8522 relationship_type: MODIFIER variant_origin: GERMLINE

Show evidence (1 reference)

PMID:33296094 SUPPORT 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 hedged wording ("possibly modulated") is why this is a PARTIAL modifier record rather than a causative one.

PROP1 (Proposed penetrance modifier co-inherited from the non-transmitting parent in an NR5A1 splice-variant family)

Gene: PROP1 hgnc:9455 relationship_type: MODIFIER variant_origin: GERMLINE

Show evidence (1 reference)

PMID:33296094 SUPPORT 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)."

Supports a proposed oligogenic modifier contribution in the second proband of the same family.

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

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

Show evidence (2 references)

PMID:35290982 SUPPORT 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 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 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:25613702 SUPPORT 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 Human Clinical

"Nonsense mutations and deletions only lead to WT1 haploinsufficiency and, hence, to less severe gonadal dysgenesis and late-onset nephropathy."

This states the classically described genotype-severity correlation, but it is the paper's BACKGROUND framing of prior belief, not its finding - graded PARTIAL for that reason and paired with the refuting conclusion below.

PMID:25613702 REFUTE Human Clinical

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

The paper's own conclusion refutes the deletion-equals-milder-disease rule quoted above, so the correlation must not be used to reassure about a deletion genotype.

DHX37 (Causal heterozygous variant, recurrently p.(Arg308Gln); in a subset acts together with an NR5A1 variant in a digenic model)

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

Show evidence (1 reference)

PMID:37240737 SUPPORT 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.

DHH (Causal biallelic loss-of-function variant, classically with minifascicular polyneuropathy)

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

Show evidence (1 reference)

PMID:11017805 SUPPORT 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.

SRY (Y-linked variant, definitively causal for 46,XY gonadal dysgenesis as a class but of unclassified relationship to the partial entity specifically; listed here as part of the testis-determination network rather than as an evidenced partial-phenotype cause)

Gene: SRY hgnc:11311 relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (2 references)

PMID:40208111 SUPPORT Human Clinical

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

Places SRY on the complete side of the complete/partial contrast; retained to document the network membership, not to assert a partial subtype.

PMID:31745530 SUPPORT Human Clinical

"Pathogenic variants were found in sex-determining region Y (SRY; n = 3)"

In this series the three SRY carriers fell in the complete-gonadal-dysgenesis group, which is why SRY is not given a partial subtype here.

SOX9 (Deletion affecting upstream testis-specific enhancer sequence, causal for 46,XY sex reversal but of unclassified relationship to the partial entity; the published 46,XY enhancer-deletion phenotype is complete, so SOX9 is recorded here as a gene of the wider testis-determination network rather than as a partial-phenotype cause)

Gene: SOX9 hgnc:11204 relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (2 references)

PMID:30552336 SUPPORT Human Clinical

"loss of one copy in 46,XY DSD patients"

Establishes heterozygous enhancer loss as the 46,XY mechanism. Graded PARTIAL because the phenotype this paper reports for 46,XY enhancer deletion is sex reversal, not a graded partial phenotype.

PMID:30552336 REFUTE Human Clinical

"SOX9 enhancers that, when duplicated or deleted, result in 46,XX or 46,XY sex reversal, respectively."

Records that the published 46,XY enhancer-deletion outcome is sex reversal, which argues against assigning this lesion a partial-phenotype subtype in this entry.

ZFPM2 (Candidate causal missense variant impairing the FOG2-GATA4 interaction; reported zygosity is mixed (one patient heterozygous, the other carrying a heterozygous plus a homozygous variant))

Gene: ZFPM2 hgnc:16700 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:24549039 SUPPORT 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."

Provides functional support for the FOG2-GATA4 mechanism in two patients; the small n and lack of partial/complete separation keep this PARTIAL.

💊

Medical Actions

Individualized gonadal management (retention versus gonadectomy)

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

Gonadal management in partial disease is materially different from the complete form, where nonfunctional gonads are removed without a functional trade-off. Here the gonads may carry genuine endocrine value, so the decision balances tumor risk against retained function and must be individualized. Factors favoring retention include labioscrotal gonad position, a preserved hCG-stimulated testosterone response, and male sex of rearing, all of which associate with both lower tumor risk and a real prospect of spontaneous puberty. Factors favoring gonadectomy include intra-abdominal position, absent residual function, female sex of rearing (where retained gonads risk unwanted virilization in 42%), and a WT1 genotype. There is no validated surveillance protocol for retained gonads — imaging and tumor markers are unreliable — so retention entails accepting an unmonitorable residual risk, which should be disclosed. Decisions should be made by an experienced multidisciplinary team with developmentally appropriate patient participation.

Mechanism Target:

INHIBITS Dysgenetic Y-bearing germ-cell niche — Gonadectomy removes the tumor-susceptible Y-bearing dysgenetic tissue.

Show evidence (1 reference)

PMID:32352694 SUPPORT Other

"Prevent whenever possible gonadoblastoma by prophylactic gonadectomy in those with a disorder of testicular development."

Supports prophylactic gonadectomy as the tumor-prevention intervention.

Target Phenotypes: Gonadoblastoma HP:0000150

Show evidence (2 references)

PMID:40208111 SUPPORT Human Clinical

"Many PGD patients with preserved gonads have the potential to develop puberty spontaneously, though further study is needed to determine the risk of developing gonadal tumors."

Directly supports the retention-versus-removal trade-off and the unresolved tumor risk that makes it a judgment rather than a protocol.

PMID:38206718 SUPPORT Human Clinical

"The patient underwent bilateral orchiectomy at age 12 years and was given a feminizing hormonal treatment of 0.5 mg/day of estradiol valerate tablets."

A worked example of gonadectomy chosen in an individual raised female who was virilizing.

Sex-steroid replacement concordant with sex of rearing

Category: Therapeutic Action: Hormone Replacement Therapy NCIT:C15599

Agent: estradiol CHEBI:23965 testosterone CHEBI:17347

Replacement is needed when residual gonadal function is inadequate or after gonadectomy, and the steroid chosen follows the sex of rearing rather than the karyotype. Individuals raised female receive estrogen (with progestogen if an endometrium-bearing uterus is present); individuals raised male receive testosterone. Two features are distinctive to partial disease. First, replacement is often only partially required, since residual function may carry a patient part of the way through puberty. Second, in individuals raised female with retained gonads, estrogen may be given specifically to counter unwanted endogenous virilization — a therapeutic problem that does not arise in the complete form. Induction should be individualized and multidisciplinary; regimen detail is extrapolated from broader congenital gonadal-hormone-deficiency guidance rather than from partial-dysgenesis-specific trials.

Mechanism Target:

BYPASSES Residual pubertal gonadal steroid capacity — Exogenous sex steroid supplements or replaces inadequate residual gonadal output.

Show evidence (1 reference)

PMID:35353710 SUPPORT Other

"recommendations for puberty induction with oestrogen or testosterone."

Supports sex-steroid induction for gonadal hormone deficiency.

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

Show evidence (2 references)

PMID:35353710 SUPPORT Other

"Puberty induction should be individualised but considered at 11 years in girls"

Supports individualized, timely pubertal induction.

PMID:38206718 SUPPORT Human Clinical

"The patient recovered well after surgery and hormonal treatment and had a regression in hirsutism and clitoromegaly."

Documents estrogen replacement reversing virilization in an individual raised female.

Genital reconstructive surgery

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

Hypospadias repair and orchidopexy may be undertaken in individuals raised male; genitoplasty may be considered in those raised female. This is the most contested aspect of care: the field has moved away from early corrective surgery toward deferral, careful diagnosis, family education, and individualized decisions by a multidisciplinary team, with long-term outcome data remaining conflicting. Orchidopexy has an additional rationale here beyond cosmesis and fertility, since a palpable scrotal gonad is more amenable to examination and is associated with lower tumor risk.

Show evidence (2 references)

PMID:23276787 SUPPORT Other

"The focus of treatment has shifted from early gender assignment and corrective surgery to careful diagnosis, proper education of patients and their families, and individualized treatment by a multi-disciplinary team."

Directly supports the shift away from early corrective surgery.

PMID:23276787 SUPPORT Other

"Conflicting data on long-term outcomes of these individuals have been reported in the literature."

Supports genuine outcome uncertainty rather than a settled surgical standard.

Renal surveillance and Wilms tumor monitoring

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

Applies specifically to the WT1-related subtype. Monitor for proteinuria every six months to age ten and yearly thereafter, and screen for Wilms tumor every three months to age seven. Critically, the glomerulopathy must NOT be treated with immunosuppressants, which are ineffective and potentially toxic; renin-angiotensin-aldosterone system inhibition is the preferred approach.

Show evidence (2 references)

PMID:32352694 SUPPORT 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"

Directly supplies the surveillance schedule for the WT1 subtype.

PMID:32352694 SUPPORT Other

"Avoid treating glomerulopathy with immunosuppressants, as they are not effective and potentially toxic."

A GeneReviews agents-to-avoid warning that materially changes management in this subtype.

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

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

Follow-up should continue well past pubertal completion. Gonadotropins drift upward over years even in individuals who virilized spontaneously, so periodic FSH, LH, and testosterone assessment is needed to detect emerging androgen deficiency and start replacement. Growth prognosis is generally good and does not itself require intervention. A long-term series also found cognitive impairment in a minority and recommended screening for learning disabilities; that observation comes from a single small cohort and should be treated as a prompt to remain alert rather than an established disease feature.

Show evidence (2 references)

PMID:25580123 SUPPORT Human Clinical

"At the last evaluation, FSH was high or high-normal in 8/10; LH was high or high-normal in 5/10; testosterone was decreased in one."

Documents late gonadotropin elevation and emerging androgen deficiency, justifying ongoing endocrine surveillance.

PMID:25580123 SUPPORT Human Clinical

"Though additional studies are required, screening for learning disabilities is advisable."

The authors' own hedged recommendation from a 10-patient series; graded PARTIAL because the cognitive finding is not an established feature of the disease.

Gene-specific genetic counseling

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

Counseling must be gene-specific. NR5A1 families require explicit discussion of markedly incomplete penetrance (<50%) and intrafamilial variability, so an unaffected carrier parent or sibling is expected rather than surprising. MAP3K1 identification should prompt DSD evaluation of female siblings. WT1 findings convert counseling into active surveillance. Digenic DHX37/NR5A1 findings complicate simple recurrence arithmetic. DHH families should be counseled about later neuropathy.

Show evidence (2 references)

PMID:28504475 SUPPORT Human Clinical

"Identification of a MAP3K1 variant should prompt an evaluation for DSD in female siblings of the proband."

Supplies a gene-specific cascade-testing recommendation.

PMID:33296094 SUPPORT Human Clinical

"Segregation analysis across three generations showed incomplete penetrance (<50%) and phenotypic variability among the carriers"

Supports the penetrance counseling point for NR5A1 families.

Psychosocial support, disclosure, and sex-of-rearing counseling

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

Partial gonadal dysgenesis raises sex-of-rearing questions more acutely than the complete form, because the genital phenotype is genuinely intermediate and endogenous puberty may not match the assigned sex. Sex reassignment later in life occurs in a meaningful minority. Care should include staged, developmentally appropriate disclosure, psychological and peer support, support for autonomy and gender identity, and fertility and sexual-health counseling.

Show evidence (2 references)

PMID:40208111 SUPPORT Human Clinical

"Sex was reassigned in 16.1% and 5.3% of individuals with PGDf and PGDm, respectively."

Quantifies later sex reassignment, supporting the need for autonomy-centered counseling.

PMID:35353710 SUPPORT Other

"Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders"

Supports psychosocial and fertility-focused support.

🔬

Biochemical Markers

Follicle-stimulating hormone (INCREASED)

Context: FSH is elevated when residual gonadal function is insufficient, reflecting loss of inhibin B and steroid feedback. FSH may be normal in individuals with well-preserved residual function, so a normal value does not exclude the diagnosis.

Pathograph Readouts

Readout Of Residual pubertal gonadal steroid capacity Negative Diagnostic

Elevated FSH reports inadequate residual gonadal function; a normal FSH is compatible with preserved function.

Show evidence (1 reference)

PMID:38206718 SUPPORT Human Clinical

"follicle stimulating hormone 53.31 mIU/mL (1.78 to 11.60)"

Elevated FSH reports failing gonadal feedback.

Show evidence (1 reference)

PMID:38206718 SUPPORT Human Clinical

"follicle stimulating hormone 53.31 mIU/mL (1.78 to 11.60) and testosterone 2.58 ng/mL (0–1.23) were elevated."

Directly documents markedly elevated FSH in partial disease.

Testosterone response to hCG stimulation (ABNORMAL)

Context: Unlike complete gonadal dysgenesis, where the gonad cannot respond, the hCG stimulation test in partial disease measures genuinely variable residual Leydig-cell capacity. Its value is prognostic as well as diagnostic: the testosterone response predicts whether spontaneous puberty will occur.

Pathograph Readouts

Readout Of Residual pubertal gonadal steroid capacity Positive Prognostic

A preserved testosterone rise after hCG predicts spontaneous pubertal onset; a blunted response predicts the need for induction.

Show evidence (1 reference)

PMID:40208111 SUPPORT Human Clinical

"testosterone response to human chorionic gonadotropin predicted onset of spontaneous puberty."

Directly establishes the prognostic value of the hCG test.

Show evidence (1 reference)

PMID:40208111 SUPPORT Human Clinical

"Labioscrotal gonads at presentation and testosterone response to human chorionic gonadotropin predicted onset of spontaneous puberty."

Directly supports use of the hCG-stimulated testosterone response.

Anti-Müllerian hormone (DECREASED)

Context: AMH is a Sertoli-cell product, so it is expected to index surviving Sertoli-cell mass and therefore the degree of testicular differentiation. Caveat on the evidence: no partial-versus-complete AMH comparison with quotable numbers was found for this entry, so the widely repeated clinical expectation that AMH is low-but-detectable in partial disease (versus undetectable in the complete form) is stated here as an inference from the mechanism, not as an evidenced discriminator. Interpret an individual AMH against age- and sex-appropriate assay ranges rather than as a categorical partial/complete test.

Pathograph Readouts

Readout Of Partial fetal AMH secretion Positive Diagnostic

AMH indexes surviving Sertoli-cell mass and therefore the degree of testicular differentiation.

Show evidence (1 reference)

PMID:38206718 SUPPORT Human Clinical

"associates with SOX9 to regulate the anti-Müllerian hormone expression, which lead to the regression of Müllerian structures."

Supports AMH as the Sertoli-derived signal whose level reflects the testicular program; this source states the mechanism rather than reporting a measured AMH value.

Show evidence (2 references)

PMID:38206718 SUPPORT Human Clinical

"SF-1 binds to and activates testis-specific enhancer of SOX9 core (TESCO), and associates with SOX9 to regulate the anti-Müllerian hormone expression"

Establishes the SF-1/SOX9 control of AMH; graded PARTIAL because the source does not report a quantitative AMH level in the partial phenotype.

PMID:35137906 SUPPORT Human Clinical

"AMH and inhibin B levels were significantly lower in cases than in controls"

Case-control confirmation that AMH is reduced in 46,XY DSD with genital ambiguity and palpable gonads. Graded PARTIAL because the cohort was partial androgen insensitivity, 5-alpha-reductase deficiency and idiopathic 46,XY DSD rather than partial gonadal dysgenesis specifically.

Inhibin B (DECREASED)

Context: Inhibin B is the other Sertoli-cell product used alongside AMH to gauge gonadal reserve. It is reduced in 46,XY DSD with genital ambiguity, and has been proposed as the more discriminating of the two between DSD categories. As with AMH, no partial-gonadal-dysgenesis-specific reference values were located, so this record is qualitative.

Pathograph Readouts

Readout Of Incomplete testicular differentiation Positive Diagnostic

Low inhibin B indexes reduced functional Sertoli-cell mass and therefore the degree of testicular differentiation failure.

Show evidence (1 reference)

PMID:35137906 SUPPORT Human Clinical

"AMH and inhibin B levels were significantly lower in cases than in controls"

Supports reduced Sertoli-cell output in 46,XY DSD with ambiguous genitalia; extrapolative to partial gonadal dysgenesis specifically.

Show evidence (1 reference)

PMID:35137906 SUPPORT Human Clinical

"we can speculate that inhibin B levels may be used to differentiate among DSD cases."

The authors' own hedged proposal ("speculate") that inhibin B discriminates between DSD categories - recorded as a hypothesis, not established practice.

🔬

Diagnosis

Integrated clinical, endocrine, and karyotypic assessment

Assess external genital anatomy, gonadal palpability and position, family history, and syndromic features (renal, neurological), alongside age-appropriate FSH, LH, testosterone, and AMH. Confirm a nonmosaic 46,XY karyotype, since 45,X/46,XY mixed gonadal dysgenesis is the principal chromosomal mimic.

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 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

Human chorionic gonadotropin stimulation quantifies residual Leydig-cell testosterone capacity. In partial gonadal dysgenesis this is not merely a diagnostic discriminator against androgen-synthesis defects but a prognostic test, since the response predicts spontaneous puberty and therefore informs gonad-retention and sex-of-rearing discussions.

diagnostic procedure NCIT:C18020

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

Show evidence (1 reference)

PMID:40208111 SUPPORT Human Clinical

"testosterone response to human chorionic gonadotropin predicted onset of spontaneous puberty."

Directly supports the prognostic use of the hCG test.

Abdominopelvic imaging for gonadal position and Müllerian anatomy

Ultrasound, supplemented by MRI where indeterminate, locates the gonads and establishes whether Müllerian derivatives are present — which, unlike in complete disease, cannot be assumed.

Ultrasound NCIT:C17230

Show evidence (1 reference)

PMID:36424806 SUPPORT Other

"All patients with 46, XY DSD should undergo abdominopelvic ultrasonography by a trained radiologist."

Directly supports ultrasound in the diagnostic workup.

Broad molecular testing including WT1

Stepwise copy-number analysis followed by a DSD gene panel or exome/genome sequencing. WT1 deserves specific emphasis: it should be tested promptly in 46,XY gonadal dysgenesis even when no renal abnormality has been found, because a positive result triggers nephropathy and Wilms tumor surveillance. A negative result does not exclude the clinical diagnosis, since roughly half of cases remain molecularly unexplained.

genetic testing NCIT:C15709

Show evidence (3 references)

PMID:25613702 SUPPORT 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 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 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.

Gonadal histopathology to confirm partial rather than complete dysgenesis

Histological demonstration of hypoplastic seminiferous tubules — as opposed to homogeneous fibrous streak tissue — establishes the partial phenotype and should be accompanied by assessment for gonadoblastoma and germ cell neoplasia in situ.

diagnostic procedure NCIT:C18020

Show evidence (1 reference)

PMID:38206718 SUPPORT Human Clinical

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

Directly supports histology as the confirmatory test for partial disease.

🩻

Imaging Findings

Variable or absent Müllerian structures

Because AMH output is partial, Müllerian derivatives may be absent, rudimentary, or present. Imaging must therefore establish rather than assume the internal anatomy — the opposite of the expectation in complete gonadal dysgenesis.

Mri

Show evidence (2 references)

PMID:38206718 SUPPORT 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 Human Clinical

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

The discordant ultrasound finding from the same case, documenting a rudimentary Müllerian remnant.

Inguinal or intra-abdominal dysgenetic gonads

Gonads are frequently undescended and identifiable in the inguinal canal or abdomen. Gonadal position matters beyond localization: labioscrotal position predicts residual function and lower tumor risk.

Ultrasound

Show evidence (1 reference)

PMID:38206718 SUPPORT 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

Attenuated rather than absent activation of the pro-testis program permits partial Sertoli-cell and Leydig-cell differentiation. Partial fetal AMH gives incomplete Müllerian regression; partial fetal androgen gives incomplete masculinization. This graded, dose-dependent fetal hormone exposure is the mechanistic origin of the ambiguous genital phenotype and the single most important contrast with complete gonadal dysgenesis.

Show evidence (1 reference)

PMID:28504475 SUPPORT 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

Unlike complete disease, which usually remains unrecognized until puberty, most partial disease is detected at or shortly after birth because the external genitalia are visibly atypical.

Show evidence (1 reference)

PMID:40208111 SUPPORT Human Clinical

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

Directly supports the infantile recognition phase.

Variable pubertal phase

Age: adolescence

Retained dysgenetic gonads produce a bifurcated pubertal course determined by residual Leydig function. Individuals raised male frequently enter puberty spontaneously; individuals raised female with retained gonads may instead virilize unexpectedly, and a minority present for the first time in adolescence with delayed puberty. Labioscrotal gonad position and the testosterone response to hCG stimulation are the reported predictors of spontaneous puberty.

Show evidence (1 reference)

PMID:40208111 SUPPORT Human Clinical

"Among the PGDm (>13 years) with at least 1 gonad, 80% had spontaneous pubertal onset and 59% achieved Tanner G5 without hormone treatment. Labioscrotal gonads at presentation and testosterone response to human chorionic gonadotropin predicted onset of spontaneous puberty. In PGDf with gonads,..."

Directly supplies the bifurcated pubertal course and its predictors.

Long-term gonadal-tumor and fertility phase

Age: childhood through adulthood

Retained Y-bearing dysgenetic gonadal tissue remains at risk of gonadoblastoma and invasive germ-cell tumor throughout life, at a rate lower than complete disease but clearly elevated. Spermatogenesis is typically absent or severely impaired even when androgen production is adequate.

Show evidence (2 references)

PMID:40208111 SUPPORT Human Clinical

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

Directly supplies the partial-versus-complete tumor gradient in a single cohort with consistent ascertainment.

PMID:25580123 SUPPORT Human Clinical

"There is good prognosis for growth and spontaneous pubertal development but not for fertility."

A 13-20 year follow-up of partial-dysgenesis patients reared as males directly separates the favorable pubertal/growth outcome from the unfavorable fertility outcome.

Adult gonadal-reserve decline phase

Age: adulthood

Even in individuals who complete puberty spontaneously, gonadotropins may drift upward over long follow-up, which would indicate progressive erosion of the already-reduced gonadal reserve. The supporting observation comes from a single 10-patient centre series in which the prepubertal and final assessments used different denominators, so the trend is suggestive rather than established. Long-term endocrine follow-up is nonetheless warranted after apparently successful spontaneous puberty rather than discharge at pubertal completion.

Show evidence (1 reference)

PMID:25580123 SUPPORT 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 graded PARTIAL: n=10 single-centre, and the 3/6 and 8/10 fractions have different denominators, so this is not a within-patient longitudinal comparison.

📊

Prevalence

Worldwide

Unknown Unknown

46,XY partial gonadal dysgenesis is rare and no population-based prevalence estimate exists for the partial form specifically. The largest assembled series is a multinational registry cohort (210 partial cases), which is a referral-ascertained denominator and must not be converted into a population rate. The only nationwide estimate that bounds the problem is Danish: 1.5 per 100,000 live-born females for 46,XY gonadal dysgenesis presenting as a phenotypic female. That figure is deliberately NOT adopted as this entry's rate, because it ascertains only female-phenotype cases and therefore systematically excludes the large partial subgroup raised male; it is a lower bound on a different population, not a prevalence for this disease.

Show evidence (2 references)

PMID:40208111 SUPPORT Human Clinical

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

Documents registry-based ascertainment, supporting rarity while explicitly not supplying a population rate.

PMID:27603905 SUPPORT 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."

A nationwide Danish rate for female-phenotype 46,XY gonadal dysgenesis. It bounds rarity but is not adopted as this entry's rate because female-only ascertainment excludes partial cases raised male.

🔀

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 The principal contrast. In the complete form, testis determination fails entirely: gonads are bilateral fibrous streaks, fetal AMH and androgen are absent, external genitalia are typically female, Müllerian structures uniformly persist with a uterus, and there is no residual gonadal function to drive spontaneous puberty or unwanted virilization. Gonadal histology and evidence of any residual fetal or pubertal testicular hormone output distinguish the two. Tumor risk is higher in the complete form.

Show evidence (2 references)

PMID:40208111 SUPPORT 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 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 Mixed gonadal dysgenesis presents with similarly ambiguous genitalia and is the single most important mimic, but it is a sex-chromosome DSD. The distinction is made by formal karyotype with adequate cell counts, NOT by gonadal asymmetry: an asymmetric pair (a dysgenetic testis on one side and a streak on the other) is classically described in mixed gonadal dysgenesis but occurs in 46,XY partial gonadal dysgenesis too, so it does not separate the two.

Show evidence (1 reference)

PMID:34070473 SUPPORT 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 PAIS produces overlapping genital ambiguity but the gonads are normally differentiated testes: AMH is normal or high, Müllerian structures are absent, and testosterone is normal or elevated with a normal or exaggerated hCG response. In practice the two are readily conflated, and cohorts often carry a combined "partially virilized 46,XY DSD" label until molecular testing resolves them.

Show evidence (1 reference)

PMID:31745530 SUPPORT 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 5-alpha-reductase 2 deficiency, 17-beta-hydroxysteroid dehydrogenase 3 deficiency, and steroidogenic block disorders cause undervirilization despite differentiated testes. Normal AMH with a characteristic steroid-precursor profile after hCG distinguishes them from failure of testis determination.

Show evidence (1 reference)

PMID:34070473 SUPPORT 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 also produces ambiguous genitalia in a dysgenetic-appearing gonadal setting, but is defined by the presence of both ovarian follicular and testicular tubular tissue in the same individual. Only careful histological examination of the whole gonad separates it from partial gonadal dysgenesis.

Show evidence (1 reference)

PMID:38206718 SUPPORT 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 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.

{ }

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 (46,XY PGD) is a genetically heterogeneous
  disorder of testis determination in which an individual with a nonmosaic 46,XY
  karyotype develops incompletely rather than absently differentiated testes.
  The defining contrast with 46,XY complete gonadal dysgenesis is that residual
  testicular tissue persists: dysgenetic testes with hypoplastic seminiferous
  tubules retain partial fetal Sertoli-cell (anti-Müllerian hormone) and
  Leydig-cell (androgen) output. Because fetal androgen exposure is partial
  rather than absent, external genitalia are typically ambiguous — spanning
  almost-female to almost-male — instead of typically female, and Müllerian
  regression is partial and variable rather than uniformly failed. Most
  individuals present with atypical genitalia in infancy. Retained gonads drive
  spontaneous puberty in most individuals raised male (80% of those with at least
  one gonad), and unwanted virilization in a substantial minority raised female
  (42% of those with gonads). Y-bearing dysgenetic gonadal tissue confers
  gonadoblastoma and invasive germ-cell tumor risk, which is real but lower than
  in the complete form.
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: >-
    The modeled disease requires a nonmosaic 46,XY karyotype and incomplete
    testis determination, evidenced by histologically dysgenetic but present
    testicular tissue and/or partial fetal testicular hormone output. The
    external genital phenotype is typically ambiguous rather than typically
    female, and Müllerian structures may be partially retained.
  scope: >-
    This entry models the partial phenotype specifically. 46,XY complete gonadal
    dysgenesis (Swyer syndrome, bilateral streak gonads with typical female
    genitalia and full Müllerian persistence) is a distinct entity curated
    separately; 45,X/46,XY mixed gonadal dysgenesis is a sex-chromosome DSD;
    testicular regression syndrome, ovotesticular DSD, androgen insensitivity,
    and androgen synthesis defects are differential diagnoses. Gene-anchored
    subtypes whose published spectrum spans partial and complete disease are
    included here only for their partial presentations.
  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: >-
      46,XY gonadal dysgenesis is classified as complete (CGD) or partial (PGD)
      subtypes.
    explanation: >-
      Establishes the complete/partial dichotomy that this entry's case
      definition operationalizes.
  - 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
    explanation: >-
      Supplies the defining "incomplete testicular development" criterion that
      distinguishes partial from complete disease.
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.
  description: >-
    Heterozygous NR5A1 (SF-1) loss-of-function variants are the most frequently
    identified molecular cause in partial disease specifically. Haploinsufficiency
    typically produces the milder end of the testis-development spectrum —
    dysgenetic testes with often spontaneous puberty — and shows marked
    intrafamilial variability and incomplete penetrance. Adrenal function was
    preserved in the partial-dysgenesis series cited here, and most NR5A1 46,XY
    DSD occurs without adrenal insufficiency, but NR5A1/SF-1 also governs adrenal
    development and primary adrenal failure was the presentation in the first
    reported human NR5A1 case. Preserved adrenal function should therefore be
    confirmed rather than assumed.
  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.
  - 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.
  - 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: >-
      More commonly, NR5A1 mutations happening in individuals with 46,XY DSD are
      associated with varying severity but without adrenal insufficiency
    explanation: >-
      Supports absent adrenal insufficiency as the usual - but explicitly not
      universal - situation in NR5A1-related 46,XY DSD.
  - 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: >-
      NR5A1 mutations in humans was first described in a patient with 46,XY DSD,
      Müllerian structures, and primary adrenal failure
    explanation: >-
      Documents that adrenal failure can accompany NR5A1-related 46,XY DSD, which
      is why preserved adrenal function must be confirmed rather than assumed.
- 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.
  description: >-
    Sex-limited heterozygous gain-of-function MAP3K1 variants account for at least
    4% of nonsyndromic 46,XY gonadal dysgenesis and produce partial as well as
    complete presentations; partial cases characteristically show clitoral
    hypertrophy with otherwise typical female external genitalia. Only partial
    presentations belong in this entry.
  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.
  - 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.
- 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.
  description: >-
    Heterozygous WT1 variants cause a syndromic form in which the disorder of
    testicular development is accompanied by steroid-resistant nephrotic syndrome
    and Wilms tumor predisposition. The historical Denys-Drash and Frasier
    designations are now recognized as a phenotypic continuum. A genotype-severity
    correlation is classically described (missense and intron-9 splice variants
    giving severe dysgenesis; nonsense variants and whole-gene deletions giving
    haploinsufficiency with milder dysgenesis and later-onset nephropathy), but the
    case curated here is a whole-gene deletion that nonetheless caused severe
    partial dysgenesis with gonadoblastoma in infancy and bilateral Wilms tumour,
    and its authors present it as showing the deletion phenotype can be more severe
    than previously thought. The correlation should therefore not be used to
    reassure. A WT1 defect should be sought promptly in 46,XY gonadal dysgenesis
    even without a detected renal abnormality.
  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.
  - reference: PMID:32352694
    reference_title: WT1 Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additional common findings can include disorders of testicular development
      (with or without abnormalities of the external genitalia and/or müllerian
      structures) and Wilms tumor.
    explanation: Supports the syndromic gonadal-plus-renal/oncologic character of this subtype.
- 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.
  description: >-
    Biallelic DHH variants impair Sertoli-derived paracrine hedgehog signaling.
    Notably, the partial form is the presentation classically associated with
    minifascicular polyneuropathy, because DHH is also required for peripheral
    nerve perineurial development — an extra-gonadal feature that distinguishes
    this subtype and should prompt neurological evaluation.
  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.
  - 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.
  - 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.
- 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: >-
        Supports monoallelic DHX37 variants segregating with partial disease;
        two of the four variant carriers in this series additionally carried an
        NR5A1 variant, so the mode is not uniformly monogenic.
  description: >-
    Heterozygous variants in DHX37, encoding a putative RNA helicase required for
    ribosome biogenesis, cause partial gonadal dysgenesis and testicular
    regression syndrome. The recurrent p.(Arg308Gln) variant is the best-attested
    allele. In a subset of patients a DHX37 variant co-occurs with an NR5A1
    variant, supporting a digenic contribution (see the digenic inheritance
    block).
  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.
  - 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.
- name: ZFPM2-related PGD
  display_name: ZFPM2/FOG2-related 46,XY partial gonadal dysgenesis
  classification: gene
  genes:
  - preferred_term: ZFPM2
    term:
      id: hgnc:16700
      label: ZFPM2
  description: >-
    Missense variants in ZFPM2 (FOG2) impair the FOG2-GATA4 interaction required
    for early testis determination. Evidence is limited to a small number of
    patients and this subtype should be regarded as emerging rather than
    established.
  evidence:
  - reference: PMID:24549039
    reference_title: Mutations in the FOG2/ZFPM2 gene are associated with anomalies of human testis determination.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified independent missense mutations in FOG2 in two patients with
      46,XY gonadal dysgenesis.
    explanation: >-
      Supports ZFPM2 as a testis-determination gene in two patients; the report
      does not separate partial from complete presentations, so the subtype is
      curated with restraint.
- name: Molecularly unresolved PGD
  display_name: Molecularly unresolved 46,XY partial gonadal dysgenesis
  classification: molecular
  description: >-
    A majority of individuals meeting the partial case definition receive no
    molecular diagnosis with currently available testing, so an explicitly
    unresolved subtype is retained rather than forcing every case into a
    gene-anchored bin.
  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
    explanation: >-
      A 42% diagnostic yield implies that most of this large registry cohort
      remained molecularly unresolved.
  - 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: >-
      Several genes are known to be involved in sex development pathways, however
      approximately 50% of all cases remain elusive.
    explanation: Directly supports a large molecularly unexplained fraction.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    46,XY partial gonadal dysgenesis is rare and no population-based prevalence
    estimate exists for the partial form specifically. The largest assembled
    series is a multinational registry cohort (210 partial cases), which is a
    referral-ascertained denominator and must not be converted into a population
    rate. The only nationwide estimate that bounds the problem is Danish: 1.5 per
    100,000 live-born females for 46,XY gonadal dysgenesis presenting as a
    phenotypic female. That figure is deliberately NOT adopted as this entry's
    rate, because it ascertains only female-phenotype cases and therefore
    systematically excludes the large partial subgroup raised male; it is a lower
    bound on a different population, not a prevalence for this 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 registry-based ascertainment, supporting rarity while explicitly
      not supplying a population rate.
  - 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: >-
      A nationwide Danish rate for female-phenotype 46,XY gonadal dysgenesis. It
      bounds rarity but is not adopted as this entry's rate because
      female-only ascertainment excludes partial cases raised male.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Most identified molecular causes of partial disease — NR5A1, MAP3K1, WT1,
    DHX37, SOX9-regulatory — are heterozygous and sex-limited dominant, with
    gene-specific penetrance. NR5A1 in particular shows markedly incomplete
    penetrance and intrafamilial phenotypic variability, which complicates
    cascade counseling.
  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.
  - 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.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic DHH variants cause the recessive partial form, classically with
    minifascicular polyneuropathy.
  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.
- name: Digenic inheritance
  inheritance_term:
    preferred_term: Digenic inheritance
    term:
      id: HP:0010984
      label: Digenic inheritance
  description: >-
    In a subset of partial gonadal dysgenesis, pathogenic variants at two loci
    co-occur and are jointly invoked to explain the phenotype. The best-documented
    pair is DHX37 plus NR5A1: in a Brazilian series, two of the patients carrying
    a deleterious DHX37 variant also carried a pathogenic NR5A1 variant, and the
    authors proposed digenic inheritance. Oligogenic modification has also been
    proposed for NR5A1 splice-variant families, where co-inherited rare OTX2 or
    PROP1 variants may modulate penetrance. Because the Inheritance class has no
    genes slot, the contributing loci are named here: DHX37 and NR5A1 for the
    digenic pair, and OTX2 and PROP1 as proposed modifiers. All four have records
    in the genetic section, with OTX2 and PROP1 typed as MODIFIER.
  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: >-
      For both patients carrying DHX37 and NR5A1 pathogenic variants, a digenic
      inheritance is suggested.
    explanation: >-
      Directly asserts digenic inheritance for the DHX37+NR5A1 double
      heterozygotes in a partial-gonadal-dysgenesis cohort.
  - 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: >-
      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: >-
      Supports an oligogenic modifier model as a proposed ("possibly") explanation
      for the incomplete penetrance, not an established second-locus requirement.
progression:
- phase: Fetal partial testis-determination phase
  age_range: embryonic and fetal development
  notes: >-
    Attenuated rather than absent activation of the pro-testis program permits
    partial Sertoli-cell and Leydig-cell differentiation. Partial fetal AMH gives
    incomplete Müllerian regression; partial fetal androgen gives incomplete
    masculinization. This graded, dose-dependent fetal hormone exposure is the
    mechanistic origin of the ambiguous genital phenotype and the single most
    important contrast with complete gonadal dysgenesis.
  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.
- phase: Neonatal and infantile atypical-genitalia recognition phase
  age_range: birth to infancy
  notes: >-
    Unlike complete disease, which usually remains unrecognized until puberty,
    most partial disease is detected at or shortly after birth because the
    external genitalia are visibly atypical.
  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: Directly supports the infantile recognition phase.
- phase: Variable pubertal phase
  age_range: adolescence
  notes: >-
    Retained dysgenetic gonads produce a bifurcated pubertal course determined by
    residual Leydig function. Individuals raised male frequently enter puberty
    spontaneously; individuals raised female with retained gonads may instead
    virilize unexpectedly, and a minority present for the first time in
    adolescence with delayed puberty. Labioscrotal gonad position and the
    testosterone response to hCG stimulation are the reported predictors of
    spontaneous 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: >-
      Among the PGDm (>13 years) with at least 1 gonad, 80% had spontaneous
      pubertal onset and 59% achieved Tanner G5 without hormone treatment.
      Labioscrotal gonads at presentation and testosterone response to human
      chorionic gonadotropin predicted onset of spontaneous puberty. In PGDf with
      gonads, 42% developed spontaneous virilization at puberty.
    explanation: Directly supplies the bifurcated pubertal course and its predictors.
- phase: Long-term gonadal-tumor and fertility phase
  age_range: childhood through adulthood
  notes: >-
    Retained Y-bearing dysgenetic gonadal tissue remains at risk of
    gonadoblastoma and invasive germ-cell tumor throughout life, at a rate lower
    than complete disease but clearly elevated. Spermatogenesis is typically
    absent or severely impaired even when androgen production is adequate.
  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: >-
      Directly supplies the partial-versus-complete tumor gradient in a single
      cohort with consistent ascertainment.
  - 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: >-
      There is good prognosis for growth and spontaneous pubertal development but
      not for fertility.
    explanation: >-
      A 13-20 year follow-up of partial-dysgenesis patients reared as males
      directly separates the favorable pubertal/growth outcome from the
      unfavorable fertility outcome.
- phase: Adult gonadal-reserve decline phase
  age_range: adulthood
  notes: >-
    Even in individuals who complete puberty spontaneously, gonadotropins may
    drift upward over long follow-up, which would indicate progressive erosion of
    the already-reduced gonadal reserve. The supporting observation comes from a
    single 10-patient centre series in which the prepubertal and final assessments
    used different denominators, so the trend is suggestive rather than
    established. Long-term endocrine follow-up is nonetheless warranted after
    apparently successful spontaneous puberty rather than discharge at pubertal
    completion.
  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 graded PARTIAL: n=10
      single-centre, and the 3/6 and 8/10 fractions have different denominators, so
      this is not a within-patient longitudinal comparison.
pathophysiology:
- name: Attenuated pro-testis network activation
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Partial rather than complete loss of pro-testis transcriptional drive.
    Heterozygous NR5A1 haploinsufficiency, partial SOX9 enhancer loss, hypomorphic
    SRY alleles, and WT1 dosage reduction each leave residual pro-testis output.
    Because the SRY-SOX9-SF1 network is dosage-sensitive and its enhancers act
    synergistically, intermediate network output produces intermediate — not
    absent — testis determination. This dose-dependence is the mechanistic reason
    partial and complete dysgenesis are a spectrum caused by overlapping genes
    rather than distinct gene sets.
  genes:
  - preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  - preferred_term: SOX9
    term:
      id: hgnc:11204
      label: SOX9
  - preferred_term: SRY
    term:
      id: hgnc:11311
      label: SRY
  - preferred_term: WT1
    term:
      id: hgnc:12796
      label: WT1
  biological_processes:
  - preferred_term: sex determination
    term:
      id: GO:0007530
      label: sex determination
    modifier: DECREASED
  - preferred_term: male gonad development
    term:
      id: GO:0008584
      label: male gonad development
    modifier: DECREASED
  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: >-
      Heterozygous SF1 loss-of-function mutations in these cases resulted in mild
      DSD manifestations, such as dysgenetic testes, spontaneous puberty, and
      preserved adrenal function.
    explanation: >-
      Directly links partial (heterozygous) loss of SF-1 function to the mild,
      residual-function end of the phenotype spectrum.
  - reference: PMID:30552336
    reference_title: Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All three enhancers showed synergistic activity and together drive SOX9 in
      the testis.
    explanation: >-
      Establishes that SOX9 testis expression is under dosage-sensitive,
      synergistic multi-enhancer control, which is the general basis for graded
      network output. Graded PARTIAL because this paper reports sex reversal
      rather than a partial phenotype, so it supports dosage-sensitivity in
      principle and not a partial SOX9 presentation specifically.
  downstream:
  - target: Incomplete testicular differentiation
    causal_link_type: DIRECT
    description: >-
      Residual pro-testis network activity supports partial supporting-cell
      commitment and rudimentary cord formation rather than the complete failure
      seen in Swyer syndrome.
    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: >-
        mild DSD manifestations, such as dysgenetic testes
      explanation: Documents dysgenetic — that is, present but abnormal — testes as the endpoint.
- name: MAP3K1 gain-of-function pro-ovarian signaling bias
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Pathogenic MAP3K1 variants increase phosphorylation of ERK1, ERK2, and p38 and
    hyperactivate Wnt4/beta-catenin/FOXL2 signaling, biasing the bipotential gonad
    toward the ovarian program. Where the bias is incomplete, testis determination
    is attenuated rather than abolished, yielding partial dysgenesis.
  genes:
  - preferred_term: MAP3K1
    term:
      id: hgnc:6848
      label: MAP3K1
  biological_processes:
  - preferred_term: sex determination
    term:
      id: GO:0007530
      label: sex determination
    modifier: ABNORMAL
  evidence:
  - reference: PMID:35290982
    reference_title: "Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      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.
    explanation: Defines the direction and signaling consequence of MAP3K1 variants.
  - 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
    snippet: >-
      these mutations altered the phosphorylation of the downstream targets, p38
      and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex.
    explanation: Provides the functional evidence in patient-derived cells.
  downstream:
  - target: Incomplete testicular differentiation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - increased ERK1/2 and p38 phosphorylation
    - Wnt4/beta-catenin/FOXL2 hyperactivation
    - partial displacement of the testis program by the ovarian program
    description: A partial pro-ovarian shift leaves incompletely differentiated testicular tissue.
    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: OTHER
      snippet: >-
        Recent reports have shown that MAP3K1 genes mediate the development of
        the 46,XY DSD, which present as complete or partial gonadal dysgenesis.
      explanation: >-
        Ties the MAP3K1 lesion to partial as well as complete dysgenesis. Tagged
        OTHER rather than IN_VITRO because this sentence is the paper's background
        summary of prior reports, not its own experimental result.
    - 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
      snippet: >-
        Previous functional studies have demonstrated that some MAP3K1 variants
        result in the gain of protein function.
      explanation: >-
        Supports the gain-of-function direction that drives the Wnt4/beta-catenin/
        FOXL2 intermediate named on this edge.
- name: DHH paracrine hedgehog signaling failure
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Biallelic DHH loss removes Sertoli-derived hedgehog signaling to the
    interstitial compartment, impairing fetal Leydig-cell and peritubular
    myoid-cell development. Because the supporting-cell lineage itself still forms,
    the gonad is dysgenetic rather than streak. The same signal is required for
    perineurial development in peripheral nerve, which is why this subtype
    couples partial gonadal dysgenesis with minifascicular neuropathy.
  genes:
  - preferred_term: DHH
    term:
      id: hgnc:2865
      label: DHH
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
  biological_processes:
  - preferred_term: Leydig cell differentiation
    term:
      id: GO:0033327
      label: Leydig cell differentiation
    modifier: DECREASED
  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
    snippet: >-
      The gonads of one patient showed partial gonadal dysgenesis with loss of
      Leydig cells in tubular areas
    explanation: >-
      Directly documents Leydig-cell loss in histologically confirmed DHH-related
      partial gonadal dysgenesis, which is the evidence for the decreased
      Leydig-cell-differentiation annotation on this node.
  - 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: >-
      Gonadal dysgenesis in these cases may be due to impairment of Sertoli
      cell-Leydig cell interaction during gonadal development.
    explanation: >-
      States the Sertoli-to-Leydig paracrine mechanism this node models.
  - 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: >-
      Sural nerve pathology revealed peculiar findings characterized by extensive
      minifascicular formation within the endoneurium and with a decreased density
      of myelinated fibers.
    explanation: >-
      Documents the peripheral-nerve arm of DHH loss that accompanies the partial
      gonadal phenotype.
  downstream:
  - target: Incomplete testicular differentiation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - loss of Sertoli-to-interstitial hedgehog signaling
    - impaired fetal Leydig and peritubular myoid cell development
    description: Loss of the paracrine differentiation signal yields dysgenetic testicular tissue.
    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
      explanation: Links the DHH lesion to the partial gonadal endpoint.
- name: DHX37-related ribosome-biogenesis defect
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Heterozygous DHX37 variants affect a putative RNA helicase required for
    ribosome biogenesis. How this translates into a gonad-restricted phenotype is
    unresolved; the gonadal primordium may be selectively vulnerable to reduced
    ribosome output during its narrow determination window.
  genes:
  - preferred_term: DHX37
    term:
      id: hgnc:17210
      label: DHX37
  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: >-
      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: Supports the molecular identity of DHX37 and its causal role in partial disease.
  - 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: >-
      Consistent with a role in early testis development, DHX37 is expressed
      specifically in somatic cells of the developing human and mouse testis.
    explanation: >-
      Gonadal-somatic-cell-restricted expression provides the tissue-specificity
      rationale for a ribosome-biogenesis gene producing a gonad-limited
      phenotype.
  - 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: >-
      This raises the possibility that some forms of DSD may be a ribosomopathy.
    explanation: >-
      The authors' own hedged framing ("raises the possibility") is the best
      available statement of the proposed ribosomopathy mechanism, which remains
      unproven.
  downstream:
  - target: Incomplete testicular differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      DHX37-associated partial disease converges on incomplete testis
      differentiation through intermediates that have not been established.
    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: >-
        Our findings support the importance of DHX37 variants as a cause of
        disorders of sex development, implying a role in testis development.
      explanation: >-
        Supports a causal role while the hedged wording reflects the unresolved
        mechanism.
- name: Incomplete testicular differentiation
  role: central_effector
  biological_scale: TISSUE
  description: >-
    The convergent lesion of this disease. Diverse triggers produce a gonad that
    contains recognizable but abnormal testicular tissue — most characteristically
    hypoplastic seminiferous tubules — rather than the fibrous bilateral streaks
    of complete gonadal dysgenesis. Preservation of some Sertoli and Leydig cells
    is what makes every downstream feature of this disease partial: partial AMH,
    partial androgen, partial Müllerian regression, partial masculinization, and
    sometimes sufficient function for spontaneous puberty.
  biological_processes:
  - preferred_term: male gonad development
    term:
      id: GO:0008584
      label: male gonad development
    modifier: DECREASED
  - preferred_term: Sertoli cell differentiation
    term:
      id: GO:0060008
      label: Sertoli cell differentiation
    modifier: DECREASED
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
  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 the defining histology — present but hypoplastic tubules,
      not fibrous streak tissue.
  downstream:
  - target: Partial fetal AMH secretion
    causal_link_type: DIRECT
    description: >-
      Residual Sertoli cells secrete some anti-Müllerian hormone, so Müllerian
      regression is partial and variable rather than uniformly absent.
    evidence:
    - reference: PMID:32352694
      reference_title: WT1 Disorder.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        disorders of testicular development (with or without abnormalities of the
        external genitalia and/or müllerian structures)
      explanation: >-
        The explicit "with or without" Müllerian abnormality supports variable
        rather than uniform Müllerian persistence in dysgenetic testis disorders.
  - target: Partial fetal testicular androgen secretion
    causal_link_type: DIRECT
    description: >-
      Residual Leydig cells produce some testosterone, giving intermediate
      masculinization of the external genitalia.
    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: >-
        incomplete testicular development, resulting in clitoral hypertrophy with
        otherwise typical female external genitalia
      explanation: Clitoral hypertrophy is direct evidence of partial fetal androgen action.
  - target: Dysgenetic Y-bearing germ-cell niche
    causal_link_type: DIRECT
    description: >-
      Germ cells persist in a poorly differentiated gonadal environment containing
      Y-chromosome material, creating a tumor-prone niche.
    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: HUMAN_CLINICAL
      snippet: >-
        pre-invasive tumors such as germ cell neoplasia in situ (GCNIS) or
        gonadoblastoma, which is commonly observed in complete or partial
        dysgenesis
      explanation: Directly names partial dysgenesis as a tumor-prone gonadal substrate.
  - target: Impaired spermatogenesis
    causal_link_type: DIRECT
    description: >-
      Hypoplastic seminiferous tubules cannot support normal germ-cell maturation.
    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: Directly documents azoospermia in molecularly confirmed partial disease.
  - target: Residual pubertal gonadal steroid capacity
    causal_link_type: DIRECT
    description: >-
      Surviving Leydig cells can respond to pubertal gonadotropin drive, giving a
      variable capacity for spontaneous pubertal androgen production.
    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: >-
        Among the PGDm (>13 years) with at least 1 gonad, 80% had spontaneous
        pubertal onset
      explanation: Directly supports retained pubertal steroidogenic capacity in retained gonads.
- name: Partial fetal AMH secretion
  role: central_effector
  biological_scale: ORGANISM
  description: >-
    Fetal Sertoli-cell AMH output is reduced but not abolished, so Müllerian-duct
    regression is incomplete and variable. This is a key point of divergence from
    complete gonadal dysgenesis, where absent AMH gives uniform Müllerian
    persistence with a uterus.
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  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: >-
      SF-1 binds to and activates testis-specific enhancer of SOX9 core (TESCO),
      and associates with SOX9 to regulate the anti-Müllerian hormone expression,
      which lead to the regression of Müllerian structures.
    explanation: >-
      Establishes the SF-1/SOX9 to AMH to Müllerian-regression axis whose partial
      failure produces variable Müllerian retention.
  downstream:
  - target: Variable Müllerian-duct retention
    causal_link_type: DIRECT
    description: >-
      Depending on how much AMH the dysgenetic testes produce, Müllerian
      derivatives may be fully regressed, rudimentary, or retained.
    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 hypoechoic mass (considered
        primordial uterus) in posterior bladder
      explanation: >-
        A rudimentary (primordial) uterus in a molecularly confirmed partial case
        directly illustrates incomplete Müllerian regression - the intermediate
        state this node predicts.
    - 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 the same case MRI did not visualise the structure that ultrasound
        called a primordial uterus. The modality discordance is itself the point:
        Müllerian remnants in partial disease can be small enough to be
        equivocal, so retention must be assessed rather than assumed either way.
- name: Partial fetal testicular androgen secretion
  role: central_effector
  biological_scale: ORGANISM
  description: >-
    Fetal Leydig-cell androgen output is intermediate. Because external genital
    masculinization is a dose-dependent, time-windowed response to fetal
    testosterone and dihydrotestosterone, intermediate androgen produces the
    hallmark ambiguous phenotype rather than either typical male or typical female
    anatomy.
  cell_types:
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
  biological_processes:
  - preferred_term: androgen biosynthetic process
    term:
      id: GO:0006702
      label: androgen biosynthetic process
    modifier: DECREASED
  - preferred_term: male sex differentiation
    term:
      id: GO:0046661
      label: male sex differentiation
    modifier: DECREASED
  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: >-
      incomplete testicular development, resulting in clitoral hypertrophy with
      otherwise typical female external genitalia
    explanation: Documents an intermediate androgen effect on external genital development.
  downstream:
  - target: Ambiguous external genital development
    causal_link_type: DIRECT
    description: >-
      Intermediate fetal androgen exposure yields a genital phenotype anywhere
      between almost-female and almost-male.
    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: Directly supports atypical genitalia as the usual presenting anatomy.
- name: Ambiguous external genital development
  role: consequence
  biological_scale: ORGANISM
  description: >-
    The graded genital phenotype of partial disease, encompassing penoscrotal
    hypospadias, micropenis, bifid scrotum, cryptorchidism, and clitoral
    hypertrophy in varying combinations.
  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
    explanation: Directly documents the undervirilized genital constellation in partial disease.
  downstream:
  - target: Ambiguous genitalia
    causal_link_type: DIRECT
    description: The HPO-grounded external-genital phenotype.
    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: Supports atypical/ambiguous genitalia as the characteristic phenotype.
  - target: Penoscrotal hypospadias
    causal_link_type: DIRECT
    description: Incomplete urethral fusion from insufficient fetal androgen.
    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.
  - target: Cryptorchidism
    causal_link_type: DIRECT
    description: >-
      Dysgenetic testes descend poorly because descent depends on gonadal
      hormone output.
    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.
  - target: Clitoral hypertrophy
    causal_link_type: DIRECT
    description: Partial androgen exposure enlarges the phallic structure in an otherwise female configuration.
    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.
- name: Residual pubertal gonadal steroid capacity
  role: central_effector
  biological_scale: ORGANISM
  description: >-
    Retained dysgenetic gonads may respond to pubertal gonadotropin drive. This is
    the single most clinically consequential difference from complete gonadal
    dysgenesis, because it means an individual with retained gonads may either
    complete puberty spontaneously (an advantage if raised male) or virilize
    against the sex of rearing (a harm if raised female). Whether residual
    function exists is partly predictable before puberty from gonadal position and
    the testosterone response to hCG stimulation. Where residual function is
    inadequate, hypergonadotropic hypogonadism supervenes.
  cell_types:
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
  biological_processes:
  - preferred_term: steroid hormone biosynthetic process
    term:
      id: GO:0120178
      label: steroid hormone biosynthetic process
    modifier: ABNORMAL
  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: >-
      Labioscrotal gonads at presentation and testosterone response to human
      chorionic gonadotropin predicted onset of spontaneous puberty.
    explanation: Directly supports predictable residual Leydig function.
  downstream:
  - target: Spontaneous puberty in retained-gonad individuals
    causal_link_type: DIRECT
    description: Sufficient residual Leydig function permits unassisted pubertal progression.
    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: >-
        80% had spontaneous pubertal onset and 59% achieved Tanner G5 without
        hormone treatment.
      explanation: Directly quantifies spontaneous pubertal progression.
  - target: Pubertal virilization discordant with female rearing
    causal_link_type: DIRECT
    description: >-
      In individuals raised female who retain gonads, the same residual
      steroidogenic capacity produces unwanted virilization at 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: >-
        In PGDf with gonads, 42% developed spontaneous virilization at puberty.
      explanation: Directly quantifies discordant pubertal virilization.
  - target: Hypergonadotropic hypogonadism
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - insufficient gonadal steroid and inhibin output
    - loss of negative feedback on pituitary gonadotropin secretion
    description: >-
      When residual function is inadequate, gonadal steroid and inhibin feedback
      fail and FSH and LH rise.
    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: >-
        follicle stimulating hormone 53.31 mIU/mL (1.78 to 11.60) and testosterone
        2.58 ng/mL (0–1.23) were elevated.
      explanation: >-
        Documents markedly elevated FSH — the hypergonadotropic pattern — in a
        molecularly confirmed partial case.
  - target: Delayed puberty
    causal_link_type: DIRECT
    description: >-
      Insufficient residual gonadal steroid output delays pubertal onset, and in a
      minority of individuals raised female this is the presenting complaint.
    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: Directly quantifies delayed puberty as a presentation of partial disease.
- name: Dysgenetic Y-bearing germ-cell niche
  role: central_effector
  biological_scale: TISSUE
  description: >-
    Germ cells arrested in a poorly differentiated gonadal environment containing
    Y-chromosome material can escape normal maturation and give rise to
    gonadoblastoma and then invasive germ-cell tumor. Partial dysgenesis carries a
    lower but still substantially elevated risk compared with complete dysgenesis,
    and the risk is further graded by gonadal position, being lowest in scrotal
    gonads.
  cell_types:
  - preferred_term: germ cell
    term:
      id: CL:0000586
      label: germ cell
  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: HUMAN_CLINICAL
    snippet: >-
      the presence of Y chromosomal material serves as a risk factor for malignant
      transformation
    explanation: Supports the Y-bearing dysgenetic gonadal substrate as the tumor risk factor.
  downstream:
  - target: Gonadal germ-cell neoplasia risk
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - persistence of developmentally arrested germ cells
    - germ cell neoplasia in situ or gonadoblastoma precursor formation
    description: The dysgenetic niche permits precursor lesions and invasive germ-cell tumors.
    evidence:
    - reference: PMID:32905884
      reference_title: Risk of gonadal neoplasia in patients with disorders/differences of sex development.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The highest risk (36 %) was observed in 46,XY patients with gonadal
        dysgenesis (GD): complete GD (33 %) and partial GD (23 %)
      explanation: >-
        Supplies a cohort estimate for partial disease alongside the complete-form
        comparator.
- name: Gonadal germ-cell neoplasia risk
  role: consequence
  biological_scale: ORGANISM
  description: >-
    Partial gonadal dysgenesis carries a clinically important risk of
    gonadoblastoma and invasive germ-cell tumor. Reported percentages vary with
    ascertainment; the most internally consistent comparison comes from a single
    registry cohort scoring complete and partial disease side by side, which found
    the partial form intermediate between complete disease and the general
    population, and lower in individuals raised male (whose gonads are more often
    scrotal) than in those raised female.
  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: >-
      Supplies the partial-versus-complete gradient and the female-versus-male
      rearing difference within one cohort.
  - reference: PMID:32905884
    reference_title: Risk of gonadal neoplasia in patients with disorders/differences of sex development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The highest risk (36 %) was observed in 46,XY patients with gonadal
      dysgenesis (GD): complete GD (33 %) and partial GD (23 %)
    explanation: Provides an independent multicenter cohort estimate for the partial form.
  downstream:
  - target: Gonadoblastoma
    causal_link_type: DIRECT
    description: Gonadoblastoma is the characteristic precursor neoplasm in dysgenetic gonads.
    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: >-
        Gonadectomy was performed at the age of 1 month and the microscopy was
        thought to be suggestive for a gonadoblastoma.
      explanation: Directly documents gonadoblastoma in partial gonadal dysgenesis.
  - target: Dysgerminoma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - gonadoblastoma or germ cell neoplasia in situ
    - progression to invasive germ-cell tumor
    description: Precursor lesions can progress to invasive seminomatous germ-cell tumor.
    evidence:
    - reference: PMID:39371651
      reference_title: "Germ Cell Tumors in 46, XY Gonadal Dysgenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All three patients developed seminomatous cancers.
      explanation: >-
        Supports seminomatous germ-cell tumor as the invasive endpoint in 46,XY
        gonadal dysgenesis; this small series' tumor cases were pure and mixed
        rather than partial dysgenesis, so it is extrapolative for the partial form.
- name: Variable Müllerian-duct retention
  role: consequence
  biological_scale: ORGANISM
  description: >-
    Müllerian derivatives may be absent, rudimentary, or present depending on
    residual fetal AMH. Unlike complete gonadal dysgenesis, a uterus cannot be
    assumed, and its presence or absence must be established by imaging or
    surgical inspection before reproductive counseling.
  evidence:
  - reference: PMID:32352694
    reference_title: WT1 Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      with or without abnormalities of the external genitalia and/or müllerian
      structures
    explanation: >-
      Supports variability of Müllerian involvement across disorders of testicular
      development.
- name: Impaired spermatogenesis
  role: consequence
  biological_scale: TISSUE
  description: >-
    Hypoplastic seminiferous tubules and reduced testicular volume impair or
    abolish sperm production, so infertility is usual even in individuals raised
    male who virilize adequately.
  cell_types:
  - preferred_term: germ cell
    term:
      id: CL:0000586
      label: germ cell
  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: Directly documents azoospermia with reduced testicular volume.
  downstream:
  - target: Azoospermia
    causal_link_type: DIRECT
    description: Absent sperm in the ejaculate is the usual finding when semen analysis is performed.
    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.
- name: Spontaneous puberty in retained-gonad individuals
  role: consequence
  biological_scale: ORGANISM
  description: >-
    A majority of individuals with partial disease raised male and retaining at
    least one gonad enter and progress through puberty without hormone treatment.
    This is a genuine functional advantage of the partial over the complete form
    and is a central argument in gonad-retention decisions.
  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: >-
      Many PGD patients with preserved gonads have the potential to develop
      puberty spontaneously
    explanation: Directly supports spontaneous pubertal potential with preserved gonads.
  - 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: >-
      All had spontaneous puberty; only one needed androgen therapy.
    explanation: >-
      Independent long-term confirmation in patients reared as males with at
      least one scrotal testis, corroborating the registry finding.
- name: Pubertal virilization discordant with female rearing
  role: consequence
  biological_scale: ORGANISM
  description: >-
    Residual Leydig function in an individual raised female produces unwanted
    androgenic changes at puberty — hirsutism, voice deepening, and clitoral
    enlargement. This is a distinctively partial-disease problem: it does not
    arise from residual gonadal function in the complete form, where the gonads
    are nonfunctional. (Virilization can still occur in complete dysgenesis, but
    by a different route — androgen secretion by a gonadal germ-cell tumour.)
  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: >-
      A 12-year-old individual raised as a girl was admitted to the hospital due
      to hirsutism and a deep voice that began at 11 years old.
    explanation: Directly documents pubertal virilization discordant with female rearing.
  downstream:
  - target: Hirsutism
    causal_link_type: DIRECT
    description: Androgen-driven terminal hair growth in an androgen-dependent distribution.
    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.
phenotypes:
- name: Ambiguous genitalia
  category: Reproductive
  description: >-
    The cardinal phenotype of partial disease. Intermediate fetal androgen
    exposure produces external genitalia spanning almost-female to almost-male,
    and this is what most often brings the diagnosis to attention in infancy.
  phenotype_term:
    preferred_term: Ambiguous genitalia
    term:
      id: HP:0000062
      label: Ambiguous genitalia
  frequency: VERY_FREQUENT
  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: >-
      Supports atypical genitalia as the usual presentation. Band derivation
      (declared departure from the default "most" -> FREQUENT mapping in
      docs/frequency-evidence-guidelines.md): the same abstract reports that only
      18% of the female-assigned subgroup presented with delayed puberty and 8%
      with virilization, leaving at least ~74% of that subgroup presenting with
      atypical genitalia, and the male-assigned subgroup is atypical-genitalia
      ascertained by definition. Pooled across both subgroups this exceeds the
      80% VERY_FREQUENT threshold. The band is therefore derived arithmetic, not a
      directly reported percentage.
- name: Gonadal dysgenesis
  category: Reproductive
  description: >-
    Incomplete testicular differentiation with histologically dysgenetic but
    present testicular tissue, most characteristically hypoplastic seminiferous
    tubules rather than fibrous streaks.
  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.
- 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.
- name: Cryptorchidism
  category: Reproductive
  description: >-
    Dysgenetic testes frequently fail to descend, since testicular descent depends
    on gonadal hormone output.
  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.
- 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.
- name: Presence of uterus in 46,XY individual
  category: Reproductive
  description: >-
    Because fetal AMH output is partial, Müllerian derivatives may persist. Unlike
    the complete form, where a uterus is the rule, retention here is variable and
    may be full, rudimentary, or absent — so it must be established by imaging or
    surgical inspection rather than assumed. No frequency band is given: the
    partial-cohort percentages are reported only in full-text tables, not in any
    snippet-verifiable abstract.
  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: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: >-
      Documents a retained rudimentary uterus in a molecularly confirmed 46,XY
      partial gonadal dysgenesis case.
  - reference: PMID:32352694
    reference_title: WT1 Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      disorders of testicular development (with or without abnormalities of the
      external genitalia and/or müllerian structures)
    explanation: >-
      Supports Müllerian involvement as a variable rather than obligate feature of
      disorders of testicular development.
- name: Micropenis
  category: Reproductive
  description: >-
    Insufficient fetal androgen exposure limits phallic growth. Part of the
    undervirilization constellation alongside penoscrotal hypospadias, and present
    in individuals at the more masculinized end of the spectrum.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  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: >-
      46,XY DSD: characterized by ambiguous or female appearance of external
      genitalia, including hypospadias, micropenis, cryptorchidism, and testicular
      dysgenesis.
    explanation: >-
      Lists micropenis within the 46,XY DSD undervirilization constellation that
      includes testicular dysgenesis. Graded PARTIAL because this is a
      category-level description rather than a partial-dysgenesis cohort finding.
- name: Decreased circulating anti-Mullerian hormone concentration
  category: Endocrine
  description: >-
    Reduced AMH reflects diminished surviving Sertoli-cell mass. Curated as a
    qualitative phenotype only — no partial-versus-complete AMH comparison with
    quotable values was located, so no threshold or discriminating cutoff is
    asserted.
  phenotype_term:
    preferred_term: Decreased circulating antimullerian hormone circulation
    term:
      id: HP:0031103
      label: Decreased circulating antimullerian hormone circulation
  evidence:
  - reference: PMID:35137906
    reference_title: "Leydig and Sertoli cell function in individuals with genital ambiguity, 46,XY karyotype, palpable gonads and normal testosterone secretion: a case-control study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AMH and inhibin B levels were significantly lower in cases than in controls
    explanation: >-
      The measured finding: AMH is significantly reduced in 46,XY DSD with genital
      ambiguity and palpable gonads. Graded PARTIAL because the cohort was partial
      androgen insensitivity, 5-alpha-reductase deficiency and idiopathic 46,XY
      DSD rather than partial gonadal dysgenesis specifically.
  - 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: >-
      associates with SOX9 to regulate the anti-Müllerian hormone expression,
      which lead to the regression of Müllerian structures.
    explanation: >-
      Supplies the mechanism behind the measured reduction - AMH is the
      Sertoli-derived output of the disrupted SF-1/SOX9 program.
- name: Adrenal insufficiency
  category: Endocrine
  subtype: NR5A1-related PGD
  description: >-
    Uncommon in NR5A1-related 46,XY DSD, which characteristically spares the
    adrenal, but not excluded — primary adrenal failure was the presentation in
    the first reported human NR5A1 case. Curated as a subtype-scoped phenotype so
    that "preserved adrenal function" is treated as an expectation to confirm
    rather than an assumption.
  phenotype_term:
    preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  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: >-
      NR5A1 mutations in humans was first described in a patient with 46,XY DSD,
      Müllerian structures, and primary adrenal failure
    explanation: Documents adrenal failure in NR5A1-related 46,XY DSD.
  - 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: >-
      More commonly, NR5A1 mutations happening in individuals with 46,XY DSD are
      associated with varying severity but without adrenal insufficiency
    explanation: >-
      Establishes that adrenal involvement is the exception, which is why this
      phenotype carries no frequency band and is scoped to the NR5A1 subtype.
- 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.
- name: Azoospermia
  category: Reproductive
  description: >-
    Absent sperm production, the usual finding when spermatogenesis is assessed in
    individuals raised male.
  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.
- name: Male infertility
  category: Reproductive
  description: >-
    Infertility is usual in individuals raised male, even when androgen production
    is adequate for virilization, because the tubular compartment is hypoplastic.
  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 infertility; the report does
      not itself use the word infertility, so support is graded partial.
- name: Hypergonadotropic hypogonadism
  category: Endocrine
  description: >-
    Where residual gonadal function is inadequate, FSH and LH rise because gonadal
    steroid and inhibin feedback are deficient.
  phenotype_term:
    preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  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: >-
      follicle stimulating hormone 53.31 mIU/mL (1.78 to 11.60)
    explanation: >-
      Markedly elevated FSH indicates primary gonadal failure. Graded PARTIAL
      because in this same patient testosterone was elevated rather than low - a
      compensated, partially functional gonad, which illustrates that the
      hypergonadotropic pattern in partial disease need not come with androgen
      deficiency.
- name: Delayed puberty
  category: Reproductive
  description: >-
    A minority of individuals raised female present in adolescence with delayed
    puberty rather than in infancy with atypical genitalia.
  phenotype_term:
    preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  frequency: OCCASIONAL
  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: >-
      The reported 18% in the female-assigned subgroup falls in the OCCASIONAL
      (5-29%) band. Note this is the proportion who *presented* with delayed
      puberty, not the proportion who develop it; the true prevalence of delayed
      puberty is likely higher, so this band is conservative.
- name: Hirsutism
  category: Integumentary
  description: >-
    Androgenic hair growth from residual pubertal Leydig function, characteristically
    distressing in individuals raised female.
  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.
- name: Gonadoblastoma
  category: Neoplasm
  description: >-
    The characteristic precursor neoplasm of Y-bearing dysgenetic gonads. It can
    arise very early — in one WT1-related case it was found in a gonadectomy
    specimen at one month of age.
  phenotype_term:
    preferred_term: Gonadoblastoma
    term:
      id: HP:0000150
      label: Gonadoblastoma
  frequency: OCCASIONAL
  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: >-
      The 8.8-19.7% range across the two partial subgroups falls in the OCCASIONAL
      (5-29%) band. Two caveats: the figure aggregates germ cell neoplasia in situ,
      gonadoblastoma and invasive tumour rather than gonadoblastoma alone, and it
      is prevalence found at gonadectomy in a referral registry rather than
      incidence in a retained gonad - the denominator problem this entry's
      gap_xy_pgd_gonad_retention_risk_benefit discussion treats as
      decision-critical.
  - 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: Directly documents very early gonadoblastoma in partial disease.
- name: Dysgerminoma
  category: Neoplasm
  description: >-
    Invasive seminomatous germ-cell tumor arising from precursor lesions in
    dysgenetic gonads.
  phenotype_term:
    preferred_term: Dysgerminoma
    term:
      id: HP:0100621
      label: Dysgerminoma
  evidence:
  - reference: PMID:39371651
    reference_title: "Germ Cell Tumors in 46, XY Gonadal Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three patients developed seminomatous cancers.
    explanation: >-
      Documents seminomatous tumors in 46,XY gonadal dysgenesis; in this small
      series the tumor cases were pure and mixed dysgenesis, so this is
      extrapolative for the partial form specifically.
- name: Steroid-resistant nephrotic syndrome
  category: Renal
  subtype: WT1-related PGD
  description: >-
    Present only in the WT1-related subtype, where the disorder of testicular
    development is accompanied by a progressive glomerulopathy that does not
    respond to steroids.
  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.
- name: Nephroblastoma
  category: Neoplasm
  subtype: WT1-related PGD
  description: >-
    Wilms tumor predisposition is specific to the WT1-related subtype and is the
    reason WT1 testing changes surveillance rather than only counseling.
  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.
- name: Peripheral neuropathy
  category: Neurologic
  subtype: DHH-related PGD
  description: >-
    Minifascicular polyneuropathy, specific to the biallelic DHH subtype, arising
    because DHH is also required for perineurial development in peripheral nerve.
  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.
biochemical:
- name: Follicle-stimulating hormone
  presence: INCREASED
  context: >-
    FSH is elevated when residual gonadal function is insufficient, reflecting
    loss of inhibin B and steroid feedback. FSH may be normal in individuals with
    well-preserved residual function, so a normal value does not exclude the
    diagnosis.
  biomarker_term:
    preferred_term: Follicle stimulating hormone
    term:
      id: CHEBI:81569
      label: Follicle stimulating hormone
  readouts:
  - target: Residual pubertal gonadal steroid capacity
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated FSH reports inadequate residual gonadal function; a normal FSH is
      compatible with preserved function.
    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: >-
        follicle stimulating hormone 53.31 mIU/mL (1.78 to 11.60)
      explanation: Elevated FSH reports failing gonadal feedback.
  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: >-
      follicle stimulating hormone 53.31 mIU/mL (1.78 to 11.60) and testosterone
      2.58 ng/mL (0–1.23) were elevated.
    explanation: Directly documents markedly elevated FSH in partial disease.
- name: Testosterone response to hCG stimulation
  presence: ABNORMAL
  context: >-
    Unlike complete gonadal dysgenesis, where the gonad cannot respond, the hCG
    stimulation test in partial disease measures genuinely variable residual
    Leydig-cell capacity. Its value is prognostic as well as diagnostic: the
    testosterone response predicts whether spontaneous puberty will occur.
  biomarker_term:
    preferred_term: testosterone
    term:
      id: CHEBI:17347
      label: testosterone
  readouts:
  - target: Residual pubertal gonadal steroid capacity
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      A preserved testosterone rise after hCG predicts spontaneous pubertal onset;
      a blunted response predicts the need for induction.
    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: >-
        testosterone response to human chorionic gonadotropin predicted onset of
        spontaneous puberty.
      explanation: Directly establishes the prognostic value of the hCG test.
  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: >-
      Labioscrotal gonads at presentation and testosterone response to human
      chorionic gonadotropin predicted onset of spontaneous puberty.
    explanation: Directly supports use of the hCG-stimulated testosterone response.
- name: Anti-Müllerian hormone
  presence: DECREASED
  context: >-
    AMH is a Sertoli-cell product, so it is expected to index surviving
    Sertoli-cell mass and therefore the degree of testicular differentiation.
    Caveat on the evidence: no partial-versus-complete AMH comparison with
    quotable numbers was found for this entry, so the widely repeated clinical
    expectation that AMH is low-but-detectable in partial disease (versus
    undetectable in the complete form) is stated here as an inference from the
    mechanism, not as an evidenced discriminator. Interpret an individual AMH
    against age- and sex-appropriate assay ranges rather than as a categorical
    partial/complete test.
  readouts:
  - target: Partial fetal AMH secretion
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      AMH indexes surviving Sertoli-cell mass and therefore the degree of
      testicular differentiation.
    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: >-
        associates with SOX9 to regulate the anti-Müllerian hormone expression,
        which lead to the regression of Müllerian structures.
      explanation: >-
        Supports AMH as the Sertoli-derived signal whose level reflects the
        testicular program; this source states the mechanism rather than reporting
        a measured AMH value.
  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: >-
      SF-1 binds to and activates testis-specific enhancer of SOX9 core (TESCO),
      and associates with SOX9 to regulate the anti-Müllerian hormone expression
    explanation: >-
      Establishes the SF-1/SOX9 control of AMH; graded PARTIAL because the source
      does not report a quantitative AMH level in the partial phenotype.
  - reference: PMID:35137906
    reference_title: "Leydig and Sertoli cell function in individuals with genital ambiguity, 46,XY karyotype, palpable gonads and normal testosterone secretion: a case-control study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AMH and inhibin B levels were significantly lower in cases than in controls
    explanation: >-
      Case-control confirmation that AMH is reduced in 46,XY DSD with genital
      ambiguity and palpable gonads. Graded PARTIAL because the cohort was partial
      androgen insensitivity, 5-alpha-reductase deficiency and idiopathic 46,XY
      DSD rather than partial gonadal dysgenesis specifically.
- name: Inhibin B
  presence: DECREASED
  context: >-
    Inhibin B is the other Sertoli-cell product used alongside AMH to gauge
    gonadal reserve. It is reduced in 46,XY DSD with genital ambiguity, and has
    been proposed as the more discriminating of the two between DSD categories.
    As with AMH, no partial-gonadal-dysgenesis-specific reference values were
    located, so this record is qualitative.
  readouts:
  - target: Incomplete testicular differentiation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Low inhibin B indexes reduced functional Sertoli-cell mass and therefore the
      degree of testicular differentiation failure.
    evidence:
    - reference: PMID:35137906
      reference_title: "Leydig and Sertoli cell function in individuals with genital ambiguity, 46,XY karyotype, palpable gonads and normal testosterone secretion: a case-control study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        AMH and inhibin B levels were significantly lower in cases than in
        controls
      explanation: >-
        Supports reduced Sertoli-cell output in 46,XY DSD with ambiguous genitalia;
        extrapolative to partial gonadal dysgenesis specifically.
  evidence:
  - reference: PMID:35137906
    reference_title: "Leydig and Sertoli cell function in individuals with genital ambiguity, 46,XY karyotype, palpable gonads and normal testosterone secretion: a case-control study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we can speculate that inhibin B levels may be used to differentiate among
      DSD cases.
    explanation: >-
      The authors' own hedged proposal ("speculate") that inhibin B discriminates
      between DSD categories - recorded as a hypothesis, not established practice.
genetic:
- name: NR5A1
  gene_term:
    preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  association: >-
    Causal heterozygous loss-of-function variant; the most frequently identified
    cause of the partial phenotype specifically
  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.
  - 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.
- name: OTX2
  gene_term:
    preferred_term: OTX2
    term:
      id: hgnc:8522
      label: OTX2
  association: >-
    Proposed penetrance modifier co-inherited from the non-transmitting parent in
    an NR5A1 splice-variant family
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  notes: >-
    Named in the top-level Digenic inheritance block. The modifier role is the
    authors' hypothesis for the family's incomplete penetrance, not a demonstrated
    interaction.
  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: >-
      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 hedged wording ("possibly modulated") is why this is a PARTIAL modifier
      record rather than a causative one.
- name: PROP1
  gene_term:
    preferred_term: PROP1
    term:
      id: hgnc:9455
      label: PROP1
  association: >-
    Proposed penetrance modifier co-inherited from the non-transmitting parent in
    an NR5A1 splice-variant family
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  notes: >-
    Named in the top-level Digenic inheritance block; same evidential caveat as
    the OTX2 record.
  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: >-
      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: >-
      Supports a proposed oligogenic modifier contribution in the second proband
      of the same family.
- 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.
  - 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.
- 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: >-
    A genotype-severity correlation is classically described (missense and
    intron-9 splice variants giving severe dysgenesis; nonsense variants and
    deletions giving haploinsufficiency with milder dysgenesis and later
    nephropathy), but it should not be relied on: the one case cited here is a
    whole-gene deletion that nevertheless produced severe partial dysgenesis,
    gonadoblastoma at one month, and bilateral Wilms tumour at nine months, and
    the authors present it explicitly as a counterexample.
  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.
  - 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: >-
      Nonsense mutations and deletions only lead to WT1 haploinsufficiency and,
      hence, to less severe gonadal dysgenesis and late-onset nephropathy.
    explanation: >-
      This states the classically described genotype-severity correlation, but it
      is the paper's BACKGROUND framing of prior belief, not its finding - graded
      PARTIAL for that reason and paired with the refuting conclusion below.
  - reference: PMID:25613702
    reference_title: "WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case report."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case description illustrates that a WT1 deletion might be associated
      with a more severe phenotype than previously thought.
    explanation: >-
      The paper's own conclusion refutes the deletion-equals-milder-disease rule
      quoted above, so the correlation must not be used to reassure about a
      deletion genotype.
- name: DHX37
  gene_term:
    preferred_term: DHX37
    term:
      id: hgnc:17210
      label: DHX37
  association: >-
    Causal heterozygous variant, recurrently p.(Arg308Gln); in a subset acts
    together with an NR5A1 variant in a digenic model
  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.
- name: DHH
  gene_term:
    preferred_term: DHH
    term:
      id: hgnc:2865
      label: DHH
  association: >-
    Causal biallelic loss-of-function variant, classically with minifascicular
    polyneuropathy
  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.
- name: SRY
  gene_term:
    preferred_term: SRY
    term:
      id: hgnc:11311
      label: SRY
  association: >-
    Y-linked variant, definitively causal for 46,XY gonadal dysgenesis as a class
    but of unclassified relationship to the partial entity specifically; listed
    here as part of the testis-determination network rather than as an evidenced
    partial-phenotype cause
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  notes: >-
    No SRY subtype is asserted for this entry. In the largest partial cohort SRY
    defects were characteristic of complete rather than partial disease, and in
    the adult sequencing series all three SRY carriers had complete dysgenesis.
    Partial presentations attributable to residual SRY activity, or to somatic
    mosaicism for an SRY variant (gene-level mosaicism - the karyotype remains
    nonmosaic 46,XY, so this does not conflict with the case definition), are
    plausible and are described in review literature, but no case with quotable
    primary evidence was identified, so the claim is deliberately not made.
  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: >-
      with common gene defects in SRY and WT1 in CGD and NR5A1 in PGD.
    explanation: >-
      Places SRY on the complete side of the complete/partial contrast; retained
      to document the network membership, not to assert a partial subtype.
  - 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: >-
      Pathogenic variants were found in sex-determining region Y (SRY; n = 3)
    explanation: >-
      In this series the three SRY carriers fell in the complete-gonadal-dysgenesis
      group, which is why SRY is not given a partial subtype here.
- name: SOX9
  gene_term:
    preferred_term: SOX9
    term:
      id: hgnc:11204
      label: SOX9
  association: >-
    Deletion affecting upstream testis-specific enhancer sequence, causal for
    46,XY sex reversal but of unclassified relationship to the partial entity;
    the published 46,XY enhancer-deletion phenotype is complete, so SOX9 is
    recorded here as a gene of the wider testis-determination network rather than
    as a partial-phenotype cause
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  notes: >-
    No partial-phenotype SOX9 enhancer case is currently published: the reported
    46,XY deletion cases are described as sex reversal and belong to the complete
    entry (MONDO:0010765). This record is retained only because SOX9 dosage is
    part of the attenuated pro-testis network modeled here; no PGD subtype is
    asserted. Coding SOX9 loss with campomelic dysplasia is a separate syndromic
    entity.
  evidence:
  - reference: PMID:30552336
    reference_title: Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      loss of one copy in 46,XY DSD patients
    explanation: >-
      Establishes heterozygous enhancer loss as the 46,XY mechanism. Graded
      PARTIAL because the phenotype this paper reports for 46,XY enhancer
      deletion is sex reversal, not a graded partial phenotype.
  - reference: PMID:30552336
    reference_title: Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SOX9 enhancers that, when duplicated or deleted, result in 46,XX or 46,XY
      sex reversal, respectively.
    explanation: >-
      Records that the published 46,XY enhancer-deletion outcome is sex reversal,
      which argues against assigning this lesion a partial-phenotype subtype in
      this entry.
- name: ZFPM2
  gene_term:
    preferred_term: ZFPM2
    term:
      id: hgnc:16700
      label: ZFPM2
  association: >-
    Candidate causal missense variant impairing the FOG2-GATA4 interaction;
    reported zygosity is mixed (one patient heterozygous, the other carrying a
    heterozygous plus a homozygous variant)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Evidence rests on two reported patients; gene-disease validity for the partial
    phenotype specifically is not established, and the source does not separate
    partial from complete presentations. The complete-form entry declined to
    promote ZFPM2 on gene-validity grounds; it is retained here only as a
    provisional subtype, explicitly flagged as emerging.
  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: >-
      Provides functional support for the FOG2-GATA4 mechanism in two patients;
      the small n and lack of partial/complete separation keep this PARTIAL.
environmental: []
histopathology:
- name: Dysgenetic testis with hypoplastic seminiferous tubules
  description: >-
    The defining histology of partial disease. Unlike the homogeneous fibrous
    streak tissue of complete gonadal dysgenesis, the gonad contains recognizable
    seminiferous tubules that are hypoplastic and disorganized. Establishing this
    distinction on the gonadectomy specimen is what confirms partial rather than
    complete disease.
  diagnostic: true
  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: >-
      hypoplastic seminiferous tubules seen under the microscope, consistent with
      the dysplastic testicular tissue.
    explanation: Directly documents the hypoplastic-tubule histology.
- name: Gonadoblastoma and germ cell neoplasia in situ in dysgenetic gonads
  description: >-
    Resected gonads may harbor precursor lesions or invasive tumor. Because
    neoplasia can be focal, a limited biopsy with benign histology is not a
    reliable exclusion test.
  diagnostic: false
  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: HUMAN_CLINICAL
    snippet: >-
      pre-invasive tumors such as germ cell neoplasia in situ (GCNIS) or
      gonadoblastoma, which is commonly observed in complete or partial dysgenesis
    explanation: Directly supports precursor lesions in partial dysgenesis.
  - 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: HUMAN_CLINICAL
    snippet: >-
      Tissue samples had been previously taken laparoscopically with benign
      histology.
    explanation: >-
      Illustrates that a limited laparoscopic biopsy reported as benign can precede
      a later tumour. Graded PARTIAL and flagged for provenance: this patient in
      the cited series had complete androgen insensitivity, not partial gonadal
      dysgenesis, so the sampling-limitation principle transfers but the tumour
      substrate and risk are not those of a dysgenetic gonad.
imaging_findings:
- name: Variable or absent Müllerian structures
  modality: MRI
  diagnostic: false
  description: >-
    Because AMH output is partial, Müllerian derivatives may be absent,
    rudimentary, or present. Imaging must therefore establish rather than assume
    the internal anatomy — the opposite of the expectation in complete 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: >-
      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.
  - 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: >-
      The discordant ultrasound finding from the same case, documenting a
      rudimentary Müllerian remnant.
- name: Inguinal or intra-abdominal dysgenetic gonads
  modality: ULTRASOUND
  diagnostic: false
  description: >-
    Gonads are frequently undescended and identifiable in the inguinal canal or
    abdomen. Gonadal position matters beyond localization: labioscrotal position
    predicts residual function and lower tumor risk.
  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.
diagnosis:
- name: Integrated clinical, endocrine, and karyotypic assessment
  description: >-
    Assess external genital anatomy, gonadal palpability and position, family
    history, and syndromic features (renal, neurological), alongside
    age-appropriate FSH, LH, testosterone, and AMH. Confirm a nonmosaic 46,XY
    karyotype, since 45,X/46,XY mixed gonadal dysgenesis is the principal
    chromosomal mimic.
  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.
- name: hCG stimulation test for residual Leydig-cell function
  description: >-
    Human chorionic gonadotropin stimulation quantifies residual Leydig-cell
    testosterone capacity. In partial gonadal dysgenesis this is not merely a
    diagnostic discriminator against androgen-synthesis defects but a prognostic
    test, since the response predicts spontaneous puberty and therefore informs
    gonad-retention and sex-of-rearing discussions.
  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
    snippet: >-
      testosterone response to human chorionic gonadotropin predicted onset of
      spontaneous puberty.
    explanation: Directly supports the prognostic use of the hCG test.
- name: Abdominopelvic imaging for gonadal position and Müllerian anatomy
  description: >-
    Ultrasound, supplemented by MRI where indeterminate, locates the gonads and
    establishes whether Müllerian derivatives are present — which, unlike in
    complete disease, cannot be assumed.
  diagnosis_term:
    preferred_term: Ultrasound
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  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: >-
      All patients with 46, XY DSD should undergo abdominopelvic ultrasonography
      by a trained radiologist.
    explanation: Directly supports ultrasound in the diagnostic workup.
- name: Broad molecular testing including WT1
  description: >-
    Stepwise copy-number analysis followed by a DSD gene panel or exome/genome
    sequencing. WT1 deserves specific emphasis: it should be tested promptly in
    46,XY gonadal dysgenesis even when no renal abnormality has been found,
    because a positive result triggers nephropathy and Wilms tumor surveillance.
    A negative result does not exclude the clinical diagnosis, since roughly half
    of cases remain molecularly unexplained.
  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.
  - 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.
  - 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.
- name: Gonadal histopathology to confirm partial rather than complete dysgenesis
  description: >-
    Histological demonstration of hypoplastic seminiferous tubules — as opposed to
    homogeneous fibrous streak tissue — establishes the partial phenotype and
    should be accompanied by assessment for gonadoblastoma and germ cell neoplasia
    in situ.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  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 supports histology as the confirmatory test for partial disease.
differential_diagnoses:
- name: 46,XY complete gonadal dysgenesis
  description: >-
    The principal contrast. In the complete form, testis determination fails
    entirely: gonads are bilateral fibrous streaks, fetal AMH and androgen are
    absent, external genitalia are typically female, Müllerian structures uniformly
    persist with a uterus, and there is no residual gonadal function to drive
    spontaneous puberty or unwanted virilization. Gonadal histology and evidence of
    any residual fetal or pubertal testicular hormone output distinguish the two.
    Tumor risk is higher in the complete form.
  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.
  - 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.
- name: 45,X/46,XY mixed gonadal dysgenesis
  description: >-
    Mixed gonadal dysgenesis presents with similarly ambiguous genitalia and is
    the single most important mimic, but it is a sex-chromosome DSD. The
    distinction is made by formal karyotype with adequate cell counts, NOT by
    gonadal asymmetry: an asymmetric pair (a dysgenetic testis on one side and a
    streak on the other) is classically described in mixed gonadal dysgenesis but
    occurs in 46,XY partial gonadal dysgenesis too, so it does not separate the
    two.
  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.
- name: Partial androgen insensitivity syndrome
  description: >-
    PAIS produces overlapping genital ambiguity but the gonads are normally
    differentiated testes: AMH is normal or high, Müllerian structures are absent,
    and testosterone is normal or elevated with a normal or exaggerated hCG
    response. In practice the two are readily conflated, and cohorts often carry a
    combined "partially virilized 46,XY DSD" label until molecular testing
    resolves them.
  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.
- name: 46,XY androgen synthesis disorders
  description: >-
    5-alpha-reductase 2 deficiency, 17-beta-hydroxysteroid dehydrogenase 3
    deficiency, and steroidogenic block disorders cause undervirilization despite
    differentiated testes. Normal AMH with a characteristic steroid-precursor
    profile after hCG distinguishes them from failure of testis determination.
  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.
- name: Ovotesticular disorder of sex development
  description: >-
    Ovotesticular DSD also produces ambiguous genitalia in a dysgenetic-appearing
    gonadal setting, but is defined by the presence of both ovarian follicular and
    testicular tubular tissue in the same individual. Only careful histological
    examination of the whole gonad separates it from partial 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: >-
      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.
- 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.
treatments:
- name: Individualized gonadal management (retention versus gonadectomy)
  action_category: THERAPEUTIC
  description: >-
    Gonadal management in partial disease is materially different from the
    complete form, where nonfunctional gonads are removed without a functional
    trade-off. Here the gonads may carry genuine endocrine value, so the decision
    balances tumor risk against retained function and must be individualized.
    Factors favoring retention include labioscrotal gonad position, a preserved
    hCG-stimulated testosterone response, and male sex of rearing, all of which
    associate with both lower tumor risk and a real prospect of spontaneous
    puberty. Factors favoring gonadectomy include intra-abdominal position, absent
    residual function, female sex of rearing (where retained gonads risk unwanted
    virilization in 42%), and a WT1 genotype. There is no validated surveillance
    protocol for retained gonads — imaging and tumor markers are unreliable — so
    retention entails accepting an unmonitorable residual risk, which should be
    disclosed. Decisions should be made by an experienced multidisciplinary team
    with developmentally appropriate patient participation.
  treatment_term:
    preferred_term: orchiectomy
    term:
      id: NCIT:C15288
      label: Orchiectomy
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Dysgenetic Y-bearing germ-cell niche
    treatment_effect: INHIBITS
    description: Gonadectomy removes the tumor-susceptible Y-bearing dysgenetic tissue.
    evidence:
    - reference: PMID:32352694
      reference_title: WT1 Disorder.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Prevent whenever possible gonadoblastoma by prophylactic gonadectomy in
        those with a disorder of testicular development.
      explanation: Supports prophylactic gonadectomy as the tumor-prevention intervention.
  target_phenotypes:
  - preferred_term: Gonadoblastoma
    term:
      id: HP:0000150
      label: Gonadoblastoma
  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: >-
      Many PGD patients with preserved gonads have the potential to develop
      puberty spontaneously, though further study is needed to determine the risk
      of developing gonadal tumors.
    explanation: >-
      Directly supports the retention-versus-removal trade-off and the unresolved
      tumor risk that makes it a judgment rather than a protocol.
  - 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 patient underwent bilateral orchiectomy at age 12 years and was given a
      feminizing hormonal treatment of 0.5 mg/day of estradiol valerate tablets.
    explanation: >-
      A worked example of gonadectomy chosen in an individual raised female who was
      virilizing.
- name: Sex-steroid replacement concordant with sex of rearing
  action_category: THERAPEUTIC
  description: >-
    Replacement is needed when residual gonadal function is inadequate or after
    gonadectomy, and the steroid chosen follows the sex of rearing rather than the
    karyotype. Individuals raised female receive estrogen (with progestogen if an
    endometrium-bearing uterus is present); individuals raised male receive
    testosterone. Two features are distinctive to partial disease. First,
    replacement is often only partially required, since residual function may carry
    a patient part of the way through puberty. Second, in individuals raised female
    with retained gonads, estrogen may be given specifically to counter unwanted
    endogenous virilization — a therapeutic problem that does not arise in the
    complete form. Induction should be individualized and multidisciplinary; regimen
    detail is extrapolated from broader congenital gonadal-hormone-deficiency
    guidance rather than from partial-dysgenesis-specific trials.
  treatment_term:
    preferred_term: Hormone Replacement Therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: estradiol
      term:
        id: CHEBI:23965
        label: estradiol
    - preferred_term: testosterone
      term:
        id: CHEBI:17347
        label: testosterone
  target_mechanisms:
  - target: Residual pubertal gonadal steroid capacity
    treatment_effect: BYPASSES
    description: >-
      Exogenous sex steroid supplements or replaces inadequate residual gonadal
      output.
    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
      snippet: >-
        recommendations for puberty induction with oestrogen or testosterone.
      explanation: Supports sex-steroid induction for gonadal hormone deficiency.
  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
    snippet: >-
      Puberty induction should be individualised but considered at 11 years in
      girls
    explanation: Supports individualized, timely pubertal induction.
  - 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 patient recovered well after surgery and hormonal treatment and had a
      regression in hirsutism and clitoromegaly.
    explanation: >-
      Documents estrogen replacement reversing virilization in an individual raised
      female.
- name: Genital reconstructive surgery
  action_category: THERAPEUTIC
  description: >-
    Hypospadias repair and orchidopexy may be undertaken in individuals raised
    male; genitoplasty may be considered in those raised female. This is the most
    contested aspect of care: the field has moved away from early corrective
    surgery toward deferral, careful diagnosis, family education, and
    individualized decisions by a multidisciplinary team, with long-term outcome
    data remaining conflicting. Orchidopexy has an additional rationale here beyond
    cosmesis and fertility, since a palpable scrotal gonad is more amenable to
    examination and is associated with lower tumor risk.
  treatment_term:
    preferred_term: orchiopexy
    term:
      id: NCIT:C111066
      label: Orchiopexy
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:23276787
    reference_title: Review and management of 46,XY disorders of sex development.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The focus of treatment has shifted from early gender assignment and
      corrective surgery to careful diagnosis, proper education of patients and
      their families, and individualized treatment by a multi-disciplinary team.
    explanation: Directly supports the shift away from early corrective surgery.
  - reference: PMID:23276787
    reference_title: Review and management of 46,XY disorders of sex development.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Conflicting data on long-term outcomes of these individuals have been
      reported in the literature.
    explanation: Supports genuine outcome uncertainty rather than a settled surgical standard.
- name: Renal surveillance and Wilms tumor monitoring
  action_category: MONITORING
  description: >-
    Applies specifically to the WT1-related subtype. Monitor for proteinuria every
    six months to age ten and yearly thereafter, and screen for Wilms tumor every
    three months to age seven. Critically, the glomerulopathy must NOT be treated
    with immunosuppressants, which are ineffective and potentially toxic;
    renin-angiotensin-aldosterone system inhibition is the preferred approach.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:32352694
    reference_title: WT1 Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    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
    explanation: Directly supplies the surveillance schedule for the WT1 subtype.
  - reference: PMID:32352694
    reference_title: WT1 Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Avoid treating glomerulopathy with immunosuppressants, as they are not
      effective and potentially toxic.
    explanation: >-
      A GeneReviews agents-to-avoid warning that materially changes management in
      this subtype.
- name: Long-term endocrine, growth, and developmental follow-up
  action_category: MONITORING
  description: >-
    Follow-up should continue well past pubertal completion. Gonadotropins drift
    upward over years even in individuals who virilized spontaneously, so
    periodic FSH, LH, and testosterone assessment is needed to detect emerging
    androgen deficiency and start replacement. Growth prognosis is generally good
    and does not itself require intervention. A long-term series also found
    cognitive impairment in a minority and recommended screening for learning
    disabilities; that observation comes from a single small cohort and should be
    treated as a prompt to remain alert rather than an established disease
    feature.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  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 last evaluation, FSH was high or high-normal in 8/10; LH was high or
      high-normal in 5/10; testosterone was decreased in one.
    explanation: >-
      Documents late gonadotropin elevation and emerging androgen deficiency,
      justifying ongoing endocrine surveillance.
  - 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: >-
      Though additional studies are required, screening for learning disabilities
      is advisable.
    explanation: >-
      The authors' own hedged recommendation from a 10-patient series; graded
      PARTIAL because the cognitive finding is not an established feature of the
      disease.
- name: Gene-specific genetic counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Counseling must be gene-specific. NR5A1 families require explicit discussion of
    markedly incomplete penetrance (<50%) and intrafamilial variability, so an
    unaffected carrier parent or sibling is expected rather than surprising. MAP3K1
    identification should prompt DSD evaluation of female siblings. WT1 findings
    convert counseling into active surveillance. Digenic DHX37/NR5A1 findings
    complicate simple recurrence arithmetic. DHH families should be counseled about
    later neuropathy.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  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: >-
      Identification of a MAP3K1 variant should prompt an evaluation for DSD in
      female siblings of the proband.
    explanation: Supplies a gene-specific cascade-testing recommendation.
  - 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
    explanation: Supports the penetrance counseling point for NR5A1 families.
- name: Psychosocial support, disclosure, and sex-of-rearing counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Partial gonadal dysgenesis raises sex-of-rearing questions more acutely than
    the complete form, because the genital phenotype is genuinely intermediate and
    endogenous puberty may not match the assigned sex. Sex reassignment later in
    life occurs in a meaningful minority. Care should include staged,
    developmentally appropriate disclosure, psychological and peer support, support
    for autonomy and gender identity, and fertility and sexual-health counseling.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  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: >-
      Sex was reassigned in 16.1% and 5.3% of individuals with PGDf and PGDm,
      respectively.
    explanation: >-
      Quantifies later sex reassignment, supporting the need for autonomy-centered
      counseling.
  - 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
    snippet: >-
      Psychological aspects of puberty and fertility issues are especially
      important to address in individuals with sex development disorders
    explanation: Supports psychosocial and fertility-focused support.
clinical_trials: []
datasets: []
discussions:
- discussion_id: gap_xy_pgd_gonad_retention_risk_benefit
  prompt: >-
    In 46,XY partial gonadal dysgenesis with functionally significant residual
    testicular tissue, what is the age-stratified gonadal tumor risk for a
    retained gonad (as opposed to the prevalence found at gonadectomy), how much
    does labioscrotal position and hCG responsiveness modify it, and is any
    surveillance strategy sensitive enough to make gonad retention safe?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    Published tumor figures are prevalence-at-gonadectomy in referral cohorts, not
    incidence in retained gonads, and are therefore the wrong denominator for the
    decision clinicians actually face. Because partial disease — unlike complete
    disease — offers a genuine functional reason to retain gonads, this denominator
    problem is decision-critical rather than academic. No validated surveillance
    protocol exists, and imaging and tumor markers are known to miss lesions.
  attaches_to:
  - pathophysiology#Gonadal germ-cell neoplasia risk
  - pathophysiology#Residual pubertal gonadal steroid capacity
  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
    snippet: >-
      though further study is needed to determine the risk of developing gonadal
      tumors.
    explanation: The cohort's own authors identify this precise gap.
  - 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: HUMAN_CLINICAL
    snippet: >-
      the limitation of tumor markers and US or MRI/CT to detect them and missing
      guidelines for surveillance.
    explanation: Directly documents the absence of a reliable surveillance strategy.
- discussion_id: gap_xy_pgd_molecular_yield
  prompt: >-
    What accounts for the roughly half of 46,XY partial gonadal dysgenesis cases
    that remain molecularly unexplained after panel and exome testing — non-coding
    regulatory variation, oligogenic burden, mosaicism confined to the gonad, or
    genes not yet implicated?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    Diagnostic yield has plateaued near 40-50% despite broad sequencing. The
    documented digenic DHX37/NR5A1 cases and the dosage-sensitive SOX9 enhancer
    architecture both suggest that single-gene coding analysis is structurally
    unable to capture the remainder.
  attaches_to:
  - pathophysiology#Attenuated pro-testis network activation
  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:37240737
    reference_title: "DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      approximately 50% of all cases remain elusive.
    explanation: Directly quantifies the unexplained fraction.
  - 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
    explanation: Confirms the plateaued diagnostic yield in a large contemporary cohort.
  - reference: PMID:35249806
    reference_title: Genetics of 46,XY gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      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.
    explanation: >-
      An expert review independently confirms that established testis-determining
      genes account for only a minority of cases.
- 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: >-
    NR5A1 is the gene most characteristically implicated in 46,XY partial gonadal
    dysgenesis, so the fidelity of its animal models directly determines how much
    mechanistic weight mouse data can carry for this disease. A direct
    human-versus-mouse comparison of the identical p.R92W allele found the gonadal
    consequence to be species-divergent: disruption of male gonadal development in
    both, but ovary-to-testis conversion only in humans. This means the
    NR5A1-dependent sex-determination network is not fully conserved, and murine
    rescue or knockout results should not be treated as directly predictive of
    the human partial phenotype's severity or threshold behavior. Evidence exists
    in the model; what is uncertain is its translational validity.
  attaches_to:
  - pathophysiology#Attenuated pro-testis network activation
  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.
  - 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: >-
      Our findings provide novel insights into the conservation and divergence in
      the molecular networks
    explanation: >-
      The authors frame the result explicitly in terms of network conservation
      versus divergence, which is the translational-validity question this
      record tracks.
references:
- reference: PMID:20301714
  title: Nonsyndromic Disorders of Testicular Development Overview.
  tags:
  - GeneReviews
  findings: []
- 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: []
- 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: []
- 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: []
- 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: []
- 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: []
- 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: []
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.

  Subtype-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;
    they remain in the complete-form entry.
  - SRY and SOX9 get no subtype here, despite being canonical testis-determination
    genes, because every located citation reports the 46,XY phenotype as complete
    (sex reversal). They are kept as `genetic:` records with that limitation
    stated. Asserting partial subtypes for them would have meant reusing the
    complete-form entry's own evidence, which cannot support both.
  - WT1 IS given a subtype here, although the complete-form entry treats syndromic
    WT1 disease as outside its root. The divergence is deliberate: WT1-related
    partial dysgenesis is well documented, and the renal/Wilms surveillance and
    the immunosuppressant warning are management-critical, so the subtype earns
    its place with its extra-gonadal features scoped to it.
  - ZFPM2 IS given a subtype here, although the complete-form entry declined it on
    gene-validity grounds. It is retained only as provisional/emerging and is
    flagged as such in both the subtype and the `genetic:` record; if a
    gene-validity review rejects ZFPM2, this subtype should go with it.

  45,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.

  Known 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. This entry is also a natural member of the
  Gonadal_Dysgenesis and Digenic_and_Oligogenic_Disorders groupings; adding it
  there is left as a separate change so this PR stays scoped to one new file.

📚