46,XX testicular disorder of sex development

Mendelian MONDO:0100249 Pathograph 24 Show in embeddings browser Disorder of sex development Gonadal development disorder Male infertility disorder

Nonsyndromic 46,XX testicular disorder of sex development (DSD) is a rare, genetically heterogeneous disorder in which a person with a 46,XX karyotype develops two testes without ovarian tissue or extra-genitourinary syndromic features. Müllerian structures are ordinarily absent, while external genital anatomy ranges from typical male to atypical. Most cases result from ectopic SRY on an X chromosome; SRY-negative causes include regulatory copy-number or structural variants affecting SOX9 or SOX3 and specific heterozygous variants in NR5A1 or WT1. The clinical course is age dependent: some children present with atypical genitalia, whereas many individuals first present after puberty with small testes, azoospermia, infertility, gynecomastia, or progressive primary testicular insufficiency. This entry excludes 46,XX ovotesticular DSD and the distinct syndromic RSPO1- and NR2F2-related disorders.

Ask OpenScientist

Ask a research question about 46,XX testicular disorder of sex development. 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.

1
Mappings
1
Definitions
2
Inheritance
9
Pathophys.
2
Histopath.
8
Phenotypes
4
Gaps
24
Pathograph
5
Genes
6
Medical Actions
7
Subtypes
6
Differentials
17
References
2
Deep Research
🔗

Mappings

MONDO
MONDO:0100249 46,XX testicular disorder of sex development
skos:exactMatch MONDO
Primary MONDO identifier for the nonsyndromic 46,XX testicular DSD umbrella.
📘

Definitions

1
Nonsyndromic 46,XX testicular DSD case definition
The disease boundary requires a 46,XX karyotype and testicular-only gonadal differentiation, without ovarian tissue. Typical nonsyndromic disease also lacks Müllerian structures and congenital or neurodevelopmental features outside the genitourinary system. Histologic ovarian tissue instead defines ovotesticular DSD; palmoplantar keratoderma, cutaneous squamous-cell-carcinoma predisposition, congenital heart disease, or other syndromic findings should trigger evaluation for a separate molecular syndrome.
CASE_DEFINITION MONDO:0100249 is curated here as the nonsyndromic testicular-only umbrella, not as a generic phenotype bucket for every cause of testicular tissue in a 46,XX individual.
Show evidence (2 references)
PMID:20301589 SUPPORT Other
"Nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) are characterized by: the presence of a 46,XX karyotype; external genitalia ranging from typical male to ambiguous; two testicles; azoospermia; absence of müllerian structures; and absence of other syndromic features,..."
GeneReviews supplies the nonsyndromic clinical boundary used for this entry.
PMID:38841305 SUPPORT Other
"It is characterized by the presence of testes in 46,XX individuals, with concomitant absence of Mullerian derivatives."
This review independently supports testicular gonads and absent Müllerian derivatives as the defining anatomic pattern.
👪

Inheritance

2
Usually de novo molecular events
SRY-positive disease usually arises from a de novo X-Y interchange; known SOX3 CNVs and nonsyndromic WT1 variants have also usually been de novo when parents were tested. Recurrence risk is therefore molecular-cause specific and cannot be summarized by one Mendelian mode.
Show evidence (1 reference)
PMID:20301589 SUPPORT Other
"SRY-positive 46,XX testicular DSD is generally not inherited because it results from de novo abnormal interchange between the Y chromosome and the X chromosome, resulting in the presence of SRY on the X chromosome and infertility."
Supports the usual de novo origin of the common SRY-positive subtype.
Autosomal dominant, sex-limited, with reduced penetrance HP:0000006
Familial SOX9 regulatory duplications and heterozygous NR5A1 p.Arg92 variants can segregate dominantly, but expression is limited by chromosome complement and can be incomplete or variable.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (2 references)
PMID:20301589 SUPPORT Other
"Pathogenic variants in NR5A1 are inherited in an autosomal dominant fashion, with reduced penetrance and variable expressivity."
Establishes the dominant, incompletely penetrant NR5A1 branch.
PMID:37551848 SUPPORT Human Clinical
"The unaffected mother also carries this duplication, consistent with previously described incomplete penetrance."
Directly demonstrates incomplete penetrance of a familial SOX9 enhancer duplication.
◆

Subtypes

7
molecular etiology
SRY-positive 46,XX testicular DSD / 46,XX sex reversal 1 MONDO:0100250
SRY hgnc:11311 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SRY (hgnc:11311). hgnc:11311 is a gene from the HUGO Gene Nomenclature Committee.
The common molecular subtype, usually caused by a de novo Xp-Yp exchange that places SRY on an X chromosome; rare translocations to an autosome are also described.
Show evidence (1 reference)
PMID:20301589 SUPPORT Other
"Approximately 80% of individuals with nonsyndromic 46,XX testicular DSD are SRY positive, as shown by use of FISH or chromosomal microarray."
Supports the frequency and molecular definition of the SRY-positive subtype.
SOX9-related 46,XX sex reversal 2 MONDO:0010218
SOX9 hgnc:11204 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SOX9 (hgnc:11204). hgnc:11204 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
SRY-negative subtype caused chiefly by duplications or rearrangements of noncoding enhancers in the SOX9 upstream regulatory domain.
Show evidence (1 reference)
PMID:37551848 SUPPORT Human Clinical
"Copy number variants that duplicate distal upstream enhancer elements of the SOX9 gene cause 46,XX testicular differences of sex development (DSD) which is characterized by a 46,XX karyotype in an individual presenting with either ambiguous genitalia or genitalia with varying degrees of..."
Directly establishes pathogenic SOX9 enhancer duplications in pure testicular DSD.
SOX3-related 46,XX sex reversal 3 MONDO:0010442
SOX3 hgnc:11199 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SOX3 (hgnc:11199). hgnc:11199 is a gene from the HUGO Gene Nomenclature Committee.
SRY-negative subtype caused by copy-number or structural variants that produce ectopic SOX3 expression in the developing gonad.
Show evidence (1 reference)
PMID:21183788 SUPPORT Human Clinical
"Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal."
Establishes human SOX3 regulatory rearrangements as an SRY-independent sex-reversal mechanism.
NR5A1-related 46,XX sex reversal 4 MONDO:0060489
NR5A1 hgnc:7983 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in NR5A1 (hgnc:7983). hgnc:7983 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Subtype associated with specific heterozygous NR5A1 variants, especially p.Arg92Trp; it must not be generalized to all NR5A1 variants.
Show evidence (1 reference)
PMID:27378692 SUPPORT Human Clinical
"Here, we show that a specific recurrent heterozygous missense mutation (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated with variable degree of testis development in 46,XX children and adults from four unrelated families."
Supports the specific heterozygous NR5A1 variant class and variable expressivity.
SRY-negative 46,XX testicular DSD of unknown cause
Molecularly unresolved testicular-only disease after adequate SRY, copy-number, coding, and regulatory-region assessment.
Show evidence (1 reference)
PMID:38721146 SUPPORT Other
"However, it is important to note that a significant number of patients with these DSD conditions have not yet recognized a genetic diagnosis."
Supports retaining a molecularly unresolved subtype.
SRY status
SRY-negative 46,XX testicular DSD
Testicular differentiation occurs without detectable SRY. Established nonsyndromic causes include SOX9 and SOX3 regulatory rearrangements and specific heterozygous variants in NR5A1 or WT1; many cases remain molecularly unresolved.
  • SRXX2
  • SRXX3
  • SRXX4
  • WT1-related
  • Unknown cause
Show evidence (1 reference)
PMID:20301589 SUPPORT Other
"Other causes in SRY-negative individuals include small copy number variants (CNVs) in or around SOX3 or SOX9 and specific heterozygous pathogenic variants in NR5A1 or WT1."
Defines the established nonsyndromic SRY-negative etiologies.
?

Discussions and Knowledge Gaps

4
What combination of imaging, endocrine markers, longitudinal observation, and adequately sampled histology best distinguishes testicular-only from ovotesticular 46,XX DSD without making biopsy routine?
KNOWLEDGE GAP OPEN gap_tdsd_otdsd_boundary_sampling
Attached to
diagnosis#Selective gonadal histology when the TDSD-OTDSD boundary is unresolved differential_diagnoses#46,XX ovotesticular disorder of sex development
Gonadal tissue is spatially heterogeneous, and a limited childhood biopsy can miss ovarian follicles later demonstrated during puberty. Misclassification changes counseling, fertility considerations, and interpretation of tumor evidence.
Show evidence (1 reference)
PMID:41170606 SUPPORT Human Clinical
"In 4 patients, the first sample obtained from gonadal biopsy failed to identify ovarian tissue that was later demonstrated during pubertal evaluation."
Directly establishes the sampling problem.
Which noncoding, structural, mosaic, or epigenetic mechanisms explain SRY-negative testicular-only cases that remain unresolved after current panel, CNV, and genome testing?
KNOWLEDGE GAP OPEN gap_sry_negative_molecular_diagnosis
Attached to
has_subtypes#Unknown cause diagnosis#DSD gene panel and genome sequencing with regulatory coverage
Many cases still lack a molecular diagnosis, and very small enhancer duplications can evade SRY testing and routine panels. Resolution will require validated noncoding coverage, structural-variant analysis, and careful phenotype reclassification.
Show evidence (2 references)
PMID:38721146 SUPPORT Other
"This finding suggests that there are additional genetic pathways or epigenetic mechanisms that have yet to be identified."
Supports the unresolved genetic and epigenetic mechanism gap.
PMID:37551848 SUPPORT Human Clinical
"This finding highlights the importance of non-coding variant interrogation in suspected genetic disorders."
Demonstrates the diagnostic value of noncoding interrogation.
Are there rigorously confirmed non-mosaic, testicular-only 46,XX cases with retrievable autologous sperm, and what evidence threshold should govern counseling about TESE or fertility preservation?
KNOWLEDGE GAP OPEN gap_autologous_fertility_potential
Attached to
pathophysiology#Germ-cell loss and seminiferous-tubule failure treatments#Donor-sperm assisted reproduction and family-building counseling
AZF regions were absent in all tested members of the largest adult cohort and pure testicular biopsies show germ-cell loss, making success biologically unlikely. Rare reports may reflect mosaicism or TDSD-OTDSD misclassification, so counseling should avoid both false hope and an unsupported categorical prohibition.
Show evidence (1 reference)
PMID:30623467 SUPPORT Human Clinical
"The available fertility option proved to achieve live birth was limited to ART using donor spermatozoa."
Defines the demonstrated fertility outcome in the adult cohort while not resolving exceptional reports.
Is any routine gonadal tumor surveillance indicated in confirmed nonsyndromic 46,XX testicular DSD, and should risk be stratified by gonadal location, age, histology, or Y-derived material such as TSPY?
KNOWLEDGE GAP OPEN gap_gonadal_tumor_surveillance
Attached to
disease#46,XX testicular disorder of sex development
Published tumor series are dominated by ovotesticular cases and do not establish a testicular-only risk estimate or validated screening schedule. Until expert review resolves this, the entry should not imply routine biopsy, prophylactic gonadectomy, or a tumor-surveillance protocol.
Show evidence (2 references)
PMID:35900314 SUPPORT Human Clinical
"Totally 15 patients were classified as ovotesticular and only 1 as testicular DSD."
Shows why the malignancy findings cannot be generalized to the testicular-only population.
PMID:35900314 SUPPORT Human Clinical
"The finding of early germ cell malignancies in our cohort brings awareness and needs further research."
Supports retaining the question as an open research need rather than a settled surveillance recommendation.
⚙

Pathophysiology

9
Ectopic SRY after Xp-Yp exchange
Abnormal X-Y recombination transfers an SRY-containing segment of Yp to an X chromosome, allowing SRY expression in a 46,XX bipotential gonad.
SRY hgnc:11311 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SRY (hgnc:11311). hgnc:11311 is a gene from the HUGO Gene Nomenclature Committee.
sex determination GO:0007530 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal sex determination (GO:0007530). GO:0007530 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Sustained pro-testis program Ectopic SRY initiates the SOX9-centered testis-determination cascade.
Show evidence (1 reference)
PMID:25102093 SUPPORT Human Clinical
"We report four patients with SRY-positive 46,XX testicular disorders of sex development (46,XX-TDSD) (cases 1-4)."
The primary study maps Xp-Yp rearrangements in four SRY-positive cases.
SOX9 enhancer dosage gain
Duplications or rearrangements of distal upstream SOX9 enhancers raise SOX9 activity above the threshold for testis determination without SRY.
SOX9 hgnc:11204 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SOX9 (hgnc:11204). hgnc:11204 is a gene from the HUGO Gene Nomenclature Committee.
male gonad development GO:0008584 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased male gonad development (GO:0008584). GO:0008584 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Sustained pro-testis program Increased SOX9 enhancer dosage activates the testis pathway in an XX gonad.
Show evidence (1 reference)
PMID:37551848 SUPPORT Human Clinical
"Here we report a family with two affected individuals, the proband and his maternal uncle, harboring a 3.7 kb duplication of a SOX9 enhancer identified by clinical genome sequencing."
Directly links a minimal noncoding SOX9 enhancer duplication to familial testicular DSD.
Ectopic SOX3 expression
SOX3 copy-number or regulatory rearrangements cause inappropriate SOX3 expression in the developing gonad, where it can substitute for SRY and activate SOX9.
SOX3 hgnc:11199 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SOX3 (hgnc:11199). hgnc:11199 is a gene from the HUGO Gene Nomenclature Committee.
male gonad development GO:0008584 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased male gonad development (GO:0008584). GO:0008584 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Sustained pro-testis program Ectopic SOX3 activates SOX9 through an SRY-like route.
Show evidence (2 references)
PMID:21183788 SUPPORT Human Clinical
"Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal."
Establishes the human regulatory lesions.
PMID:21183788 SUPPORT Model Organism
"Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal."
Demonstrates the developmental effect of ectopic Sox3 expression.
NR5A1 Arg92 regulatory switch
Specific heterozygous substitutions at NR5A1 Arg92 alter the balance between pro-ovary and pro-testis programs. The human association is strong, but the precise transcriptional mechanism remains incompletely resolved.
NR5A1 hgnc:7983 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NR5A1 (hgnc:7983). hgnc:7983 is a gene from the HUGO Gene Nomenclature Committee.
gonad development GO:0008406 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated gonad development (GO:0008406). GO:0008406 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Sustained pro-testis program The Arg92 variant shifts the gonadal regulatory balance toward testis differentiation.
Show evidence (2 references)
PMID:27378692 SUPPORT Human Clinical
"These unique findings highlight how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals and represents the first missense mutation causing isolated, non-syndromic 46,XX testicular/ovotesticular DSD in humans."
Supports the organ-fate switch associated with the specific variant.
PMID:27490115 SUPPORT Other
"We hypothesize that p.(Arg92Trp) results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals."
The authors explicitly frame the detailed molecular mechanism as a hypothesis, so it is retained with partial support.
WT1 C-terminal regulatory alteration
Rare splice or fourth-zinc-finger variants alter the WT1 C-terminal domain involved in gonadal supporting-cell fate. The gene-disease association is established, while the precise downstream molecular sequence remains incompletely characterized.
WT1 hgnc:12796 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves WT1 (hgnc:12796). hgnc:12796 is a gene from the HUGO Gene Nomenclature Committee.
gonad development GO:0008406 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated gonad development (GO:0008406). GO:0008406 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Sustained pro-testis program WT1 C-terminal disruption can redirect 46,XX supporting-cell fate toward testis formation.
Show evidence (1 reference)
PMID:40089886 SUPPORT Human Clinical
"Thus, we have described a patient with a rare form of 46,XX TDSD caused by a variant in the WT1 gene."
Supports WT1 as a rare cause of testicular-only disease.
Sustained pro-testis program
Diverse upstream lesions converge on sufficient SOX9-centered pro-testis activity to overcome the ovarian program in a 46,XX bipotential gonad.
Sertoli cell CL:0000216 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sertoli cell (CL:0000216). CL:0000216 is a cell type from the Cell Ontology.
male gonad development GO:0008584 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased male gonad development (GO:0008584). GO:0008584 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Testis differentiation in 46,XX gonads Sustained pro-testis signaling directs supporting cells and gonadal architecture toward testes.
Show evidence (1 reference)
PMID:38721146 SUPPORT Other
"In the absence of SRY, other genes associated with testis development may be overexpressed or there may be a reduction in the activity of pro-ovarian/antitesticular factors."
Supports convergence of gain of pro-testis activity and loss of ovarian restraint.
Testis differentiation in 46,XX gonads
Sertoli and Leydig lineages form testes that ordinarily produce fetal AMH sufficient for Müllerian regression and variable androgen sufficient for typical or atypical male external genital development.
Sertoli cell CL:0000216 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sertoli cell (CL:0000216). CL:0000216 is a cell type from the Cell Ontology. Leydig cell CL:0000178 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Leydig cell (CL:0000178). CL:0000178 is a cell type from the Cell Ontology.
male gonad development GO:0008584 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased male gonad development (GO:0008584). GO:0008584 is a biological process from the Gene Ontology. ↑ INCREASED androgen biosynthetic process GO:0006702 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated androgen biosynthetic process (GO:0006702). GO:0006702 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Atypical genitalia Insufficient or asynchronous fetal androgen output can produce atypical external genital anatomy.
Hypospadias Variable fetal androgen effect can include hypospadias.
Cryptorchidism Abnormal testicular development or descent can result in cryptorchidism.
Germ-cell loss and seminiferous-tubule failure The 46,XX testis lacks the usual Yq AZF complement and progressively loses germ cells.
Primary testicular insufficiency Abnormal Sertoli and Leydig compartments can reduce endocrine reserve; the timing and longitudinal progression are not established.
Show evidence (1 reference)
PMID:20301589 SUPPORT Other
"external genitalia ranging from typical male to ambiguous; two testicles; azoospermia; absence of müllerian structures"
Supports testis formation, Müllerian regression, and variable external genital development.
Germ-cell loss and seminiferous-tubule failure
Missing Yq spermatogenesis loci and abnormal 46,XX testicular architecture lead to germ-cell depletion, severely impaired spermatogenesis, and small testes.
spermatogenesis GO:0007283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves absent spermatogenesis (GO:0007283). GO:0007283 is a biological process from the Gene Ontology. ∅ ABSENT
Downstream
Azoospermia Loss of germ cells and AZF-dependent spermatogenesis produces azoospermia.
Decreased Testicular Size Germ-cell and seminiferous-tubule loss reduce testicular volume.
Male Infertility Azoospermia prevents biological paternity with autologous sperm in typical non-mosaic disease.
Show evidence (1 reference)
PMID:36746123 SUPPORT Human Clinical
"These individuals develop testes but are infertile due to germ cell loss."
Directly links germ-cell loss to infertility in testicular-only disease.
Primary testicular insufficiency
Sertoli- and Leydig-cell dysfunction reduces inhibin and testosterone feedback, causing elevated FSH and LH; testosterone deficiency is common but not universal in adults. Cross-sectional adult data do not establish a uniformly progressive course.
Sertoli cell CL:0000216 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sertoli cell (CL:0000216). CL:0000216 is a cell type from the Cell Ontology. Leydig cell CL:0000178 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Leydig cell (CL:0000178). CL:0000178 is a cell type from the Cell Ontology.
androgen biosynthetic process GO:0006702 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased androgen biosynthetic process (GO:0006702). GO:0006702 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hypergonadotropic Hypogonadism Reduced gonadal feedback raises FSH and LH, with variably low testosterone.
Gynecomastia Pubertal/adult gonadal dysfunction can produce gynecomastia.
Show evidence (1 reference)
PMID:30623467 SUPPORT Human Clinical
"Elevated levels of follicle-stimulating hormone (FSH) were found in 136 patients (95.10%) and increased luteinising hormone (LH) values were detected in 125 patients (92.59%). Eighty subjects (62.99%) had low testosterone values."
Quantifies the cross-sectional adult endocrine pattern and shows why low testosterone must not be called universal or necessarily progressive.
✶

Histopathology

2
Reduced seminiferous-tubule number and Sertoli-cell abnormalities
In four adult SRY-positive testicular DSD biopsies, seminiferous tubules were reduced and a larger fraction of Sertoli cells lacked SOX9 staining. These small, subtype-selected data should not be treated as universal pathology.
Show evidence (1 reference)
PMID:36746123 SUPPORT Human Clinical
"A smaller number of tubules, more SOX9-negative but similar proportions of DMRT1-negative SCs were found in 46,XX TDSD compared to NS."
Provides testicular-only, subtype-specific architectural and Sertoli-cell evidence.
Severe Leydig-cell hyperplasia
Severe Leydig-cell hyperplasia was observed in the same four SRY-positive adult biopsies and may reflect chronic gonadotropin stimulation.
Show evidence (1 reference)
PMID:36746123 SUPPORT Human Clinical
"The lower number of tubules and severe LC hyperplasia observed in 46,XX TDSD were similar to KS."
Directly supports Leydig-cell hyperplasia in pure testicular DSD biopsies.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for 46,XX testicular disorder of sex development Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Breast 1
Gynecomastia VERY_FREQUENT HP:0000771 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gynecomastia (HP:0000771). HP:0000771 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301589 SUPPORT Other
"Approximately 85% of individuals with nonsyndromic 46,XX testicular DSD present after puberty with normal pubic hair and normal penile size but small testes, gynecomastia, and sterility resulting from azoospermia."
Provides frequency-level support for gynecomastia as a very frequent postpubertal finding.
Endocrine 1
Hypergonadotropic Hypogonadism VERY_FREQUENT HP:0000815 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypergonadotropic hypogonadism (HP:0000815). HP:0000815 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30623467 SUPPORT Human Clinical
"Elevated levels of follicle-stimulating hormone (FSH) were found in 136 patients (95.10%) and increased luteinising hormone (LH) values were detected in 125 patients (92.59%). Eighty subjects (62.99%) had low testosterone values."
Supports frequent hypergonadotropic testicular failure and calibrates the non-universal testosterone finding.
Genitourinary 5
Hypospadias HP:0000047 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypospadias (HP:0000047). HP:0000047 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25102093 SUPPORT Human Clinical
"Case 1 exhibited underdeveloped external genitalia with hypospadias"
Documents hypospadias in a molecularly confirmed testicular DSD case.
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30623467 SUPPORT Human Clinical
"Cryptorchidism and/or hypospadias appeared in 19 patients (13.19%)."
Supports occasional occurrence in an adult referral cohort while the combined endpoint prevents an exact cryptorchidism frequency estimate.
Azoospermia VERY_FREQUENT HP:0000027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Azoospermia (HP:0000027). HP:0000027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301589 SUPPORT Other
"azoospermia"
GeneReviews includes azoospermia in the disease definition.
Decreased Testicular Size VERY_FREQUENT HP:0008734 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased testicular size (HP:0008734). HP:0008734 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301589 SUPPORT Other
"Approximately 85% of individuals with nonsyndromic 46,XX testicular DSD present after puberty with normal pubic hair and normal penile size but small testes, gynecomastia, and sterility resulting from azoospermia."
Provides frequency-level support for small testes as a very frequent postpubertal finding.
PMID:30623467 SUPPORT Human Clinical
"The mean volumes (95% CI) of left and right testicles were 2.16 (1.82-2.49) ml and 2.16 (1.83-2.49) ml, respectively."
Quantifies marked testicular-volume reduction in the adult cohort.
Male Infertility VERY_FREQUENT HP:0003251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36746123 SUPPORT Human Clinical
"These individuals develop testes but are infertile due to germ cell loss."
Directly connects germ-cell loss to infertility in testicular-only cases.
Other 1
Atypical genitalia OCCASIONAL Ambiguous genitalia HP:0000062 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ambiguous genitalia (HP:0000062). HP:0000062 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301589 SUPPORT Other
"Approximately 15% of individuals with nonsyndromic 46,XX testicular DSD present at birth with ambiguous genitalia."
Supports occasional neonatal presentation with atypical genital anatomy.
🧬

Genetic Associations

5
Ectopic SRY (Causative ectopic SRY, usually transferred to an X chromosome by an Xp-Yp rearrangement.)
Gene: SRY hgnc:11311 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SRY (hgnc:11311). hgnc:11311 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (1 reference)
PMID:25102093 SUPPORT Human Clinical
"The Xp;Yp translocations occurred between the X- and the Y-differential regions in case 1, between PRKX and inverted PRKY in case 2 and between the X-chromosomal short arm pseudoautosomal region and the Y-differential regions in cases 3 and 4."
Directly maps the causative Xp-Yp rearrangements in four SRY-positive cases.
SOX9 regulatory CNV (Causative gain of dosage or altered chromosomal context of noncoding SOX9 enhancers.)
Gene: SOX9 hgnc:11204 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SOX9 (hgnc:11204). hgnc:11204 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:37551848 SUPPORT Human Clinical
"Here we report a family with two affected individuals, the proband and his maternal uncle, harboring a 3.7 kb duplication of a SOX9 enhancer identified by clinical genome sequencing."
Establishes a familial, minimal pathogenic SOX9 enhancer duplication.
PMID:25351776 SUPPORT Human Clinical
"Two cases carried partially overlapping 17q24.3 duplications ~500 kb upstream of SOX9, both inherited from their normal fathers."
Supports recurrent upstream SOX9 duplications and reduced penetrance.
SOX3 regulatory CNV (Causative copy-number or regulatory rearrangements that produce ectopic SOX3 expression.)
Gene: SOX3 hgnc:11199 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SOX3 (hgnc:11199). hgnc:11199 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (2 references)
PMID:21183788 SUPPORT Human Clinical
"Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal."
Establishes the human association.
PMID:25351776 SUPPORT Human Clinical
"A further XX male, ascertained because of intellectual disability, carried a de novo cryptic duplication at Xq27.1, involving SOX3."
Documents a de novo SOX3 duplication while illustrating why syndromic cases require boundary assessment.
NR5A1 Arg92 variants (Specific heterozygous Arg92 substitutions are causative; this assertion does not apply to all loss-of-function NR5A1 variants.)
Gene: NR5A1 hgnc:7983 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NR5A1 (hgnc:7983). hgnc:7983 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant with reduced penetrance and variable expressivity
Show evidence (2 references)
PMID:27378692 SUPPORT Human Clinical
"Here, we show that a specific recurrent heterozygous missense mutation (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated with variable degree of testis development in 46,XX children and adults from four unrelated families."
Supports the specific heterozygous variant and variable expressivity.
PMID:27490115 SUPPORT Human Clinical
"We identified a novel heterozygous NR5A1 mutation, c.274C>T p.(Arg92Trp), in three unrelated patients."
Independently establishes recurrent heterozygous p.Arg92Trp.
WT1 C-terminal variants (Specific heterozygous splice or fourth-zinc-finger variants can cause rare nonsyndromic SRY-negative testicular DSD.)
Gene: WT1 hgnc:12796 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is WT1 (hgnc:12796). hgnc:12796 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (2 references)
PMID:20301589 SUPPORT Other
"specific heterozygous pathogenic variants in NR5A1 or WT1."
GeneReviews recognizes specific heterozygous WT1 variants among the nonsyndromic causes.
PMID:40089886 SUPPORT Human Clinical
"Molecular genetic analysis (whole exome sequencing with Sanger validation) revealed a de novo variant in exon 9 of the WT1 gene"
Directly documents the de novo WT1 variant in a testicular DSD case.
💊

Medical Actions

6
Individualized testosterone pubertal induction or replacement
Category: Therapeutic Action: hormone modifying therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hormone modifying therapy, annotated with Hormone Therapy (NCIT:C15445). NCIT:C15445 is a clinical intervention from the NCI Thesaurus. Ontology label: Hormone Therapy NCIT:C15445
Agent: testosterone CHEBI:17347 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses testosterone (CHEBI:17347). CHEBI:17347 is a therapeutic agent from Chemical Entities of Biological Interest.
Testosterone is used when spontaneous puberty is absent or incomplete, or when persistent symptomatic biochemical hypogonadism is confirmed. It is not automatic therapy for every child or adult; dosing and timing should be individualized to age, pubertal stage, growth, symptoms, and patient goals.
Target Phenotypes: Hypergonadotropic hypogonadism HP:0000815 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypergonadotropic hypogonadism (HP:0000815). HP:0000815 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301589 SUPPORT Other
"After age 14 years, low-dose testosterone therapy is initiated and gradually increased to reach adult levels."
Supports gradual pubertal induction in affected adolescents requiring treatment.
PMID:38841305 SUPPORT Other
"Hormone replacement therapy (HRT), if needed, consists of Testosterone treatment, with formulations and therapeutic schemes recommended in International clinical practice guidelines"
Explicitly makes testosterone conditional on clinical need.
Longitudinal endocrine and testosterone-safety monitoring
Category: Monitoring Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Follow growth and pubertal progression, symptoms, FSH/LH/testosterone, mood, libido, energy, erectile function, acne, breast symptoms, and gynecomastia. During testosterone therapy, monitor dose response, testosterone, hematocrit, and age-appropriate metabolic, liver, and prostate safety measures.
Show evidence (1 reference)
PMID:20301589 SUPPORT Other
"For those on testosterone replacement therapy: measurement of serum testosterone levels every three months (just prior to the next injection) until testosterone dose is optimized; then annual measurement of serum testosterone levels, lipid profile, and liver function tests."
Supports structured monitoring during testosterone replacement.
Bone-health assessment and management
Category: Monitoring Action: Dual-energy X-ray absorptiometry procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dual-energy X-ray absorptiometry procedure, annotated with Dual X-ray Absorptiometry (NCIT:C48789). NCIT:C48789 is a clinical intervention from the NCI Thesaurus. Ontology label: Dual X-ray Absorptiometry NCIT:C48789
Assess bone health after puberty and more frequently when osteopenia is present; address calcium/vitamin D, weight-bearing activity, androgen deficiency, and osteoporosis according to standard care.
Show evidence (1 reference)
PMID:20301589 SUPPORT Other
"Dual-energy x-ray absorptiometry scan every three to five years after puberty or annually, if osteopenia has been identified."
Supports ongoing bone-density surveillance after puberty.
Donor-sperm assisted reproduction and family-building counseling
Category: Therapeutic Action: assisted reproductive technologyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is assisted reproductive technology (NCIT:C93282). NCIT:C93282 is a clinical intervention from the NCI Thesaurus. Ontology label: Assisted Reproductive Technology NCIT:C93282
Donor-sperm assisted reproductive technology can achieve parenthood for affected couples. The choice among donor insemination, IVF, and other family-building options should be individualized. Autologous sperm retrieval is generally not expected to succeed in confirmed non-mosaic disease lacking AZF regions, but categorical exclusions should be discussed with a reproductive-urology specialist because evidence is limited.
Target Phenotypes: Male infertility HP:0003251 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30623467 SUPPORT Human Clinical
"Additionally, fertility achieved in 87 patients through ART using donor spermatozoa."
Directly documents donor-sperm ART outcomes in the largest cited adult cohort.
Etiology-specific genetic counseling
Category: Counseling / Informational Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Explain the molecular diagnosis, recurrence risk, reduced penetrance, chromosome-complement dependence, family testing, infertility, and reproductive options. Counseling must distinguish usually de novo SRY, SOX3, or WT1 events from potentially inherited SOX9 or NR5A1 variants.
Show evidence (1 reference)
PMID:20301589 SUPPORT Other
"The mode of inheritance and recurrence risk to sibs of a proband with a nonsyndromic 46,XX testicular DSD depend on the molecular diagnosis in the proband and the genetic status of the parents."
Directly supports etiology-specific recurrence counseling.
Multidisciplinary psychosocial and anomaly-specific care
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Offer developmentally appropriate psychological and sexual-health support, shared decision-making, and standard urologic management of hypospadias or cryptorchidism when present. Care should be coordinated across pediatric or adult endocrinology, genetics, urology, reproductive medicine, and mental health according to age and goals.
Show evidence (1 reference)
PMID:20301589 SUPPORT Other
"Standard treatment for osteopenia, hypospadias, and cryptorchidism. Providers are encouraged to anticipate the need for further psychological support."
Supports anomaly-specific standard care and anticipatory psychological support.
🔬

Biochemical Markers

3
Elevated follicle-stimulating hormone (INCREASED)
Context: Postpubertal/adult assessment; values in children must be interpreted by age and pubertal stage.
Show evidence (1 reference)
PMID:30623467 SUPPORT Human Clinical
"Elevated levels of follicle-stimulating hormone (FSH) were found in 136 patients (95.10%)"
Quantifies FSH elevation in an adult reproductive-center cohort.
Elevated luteinizing hormone (INCREASED)
Context: Postpubertal/adult assessment; values in children must be interpreted by age and pubertal stage.
Show evidence (1 reference)
PMID:30623467 SUPPORT Human Clinical
"increased luteinising hormone (LH) values were detected in 125 patients (92.59%)."
Quantifies LH elevation in the adult cohort.
Low testosterone (DECREASED)
Context: Common in adulthood but not obligatory; testosterone can remain adequate during spontaneous puberty despite rising gonadotropins.
Show evidence (1 reference)
PMID:30623467 SUPPORT Human Clinical
"Eighty subjects (62.99%) had low testosterone values."
Establishes that low testosterone is frequent but not universal in adults.
🔬

Diagnosis

7
Integrated multidisciplinary DSD assessment (Clinical anatomy, age-appropriate endocrine results, chromosome complement, and molecular findings interpreted together.)
No single phenotype or test establishes the entire diagnosis. Evaluation should integrate genital and gonadal anatomy, internal reproductive structures, hormone data, cytogenetics, and molecular testing through an experienced multidisciplinary DSD team.
clinical assessment NCIT:C124351 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:30299888 SUPPORT Other
"Diagnosis of DSD belongs to the most complex fields in medicine and requires an integrated multidisciplinary approach consisting in a synoptic view of clinical phenotype, biochemical (hormonal) constellation and molecular datasets."
Supports integrated rather than test-isolated diagnosis.
Karyotype confirmation and SRY detection/localization (46,XX chromosome complement with testicular tissue; SRY status and genomic location reported.)
Karyotyping establishes the 46,XX DSD class. FISH or chromosomal microarray can detect SRY and help localize ectopic Yp material; PCR alone establishes presence but not chromosomal location.
karyotyping NCIT:C16768 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:30299888 SUPPORT Other
"Ascertainment of the karyotpye defines one of the three major diagnostic DSD subclasses and is therefore the mandatory initial step."
Supports chromosome-complement assessment as the initial genetic step.
PMID:20301589 SUPPORT Other
"Approximately 80% of individuals with nonsyndromic 46,XX testicular DSD are SRY positive, as shown by use of FISH or chromosomal microarray."
Supports FISH or microarray assessment of SRY status.
Chromosomal microarray and deletion-duplication analysis (Detection of pathogenic CNVs involving SRY or regulatory domains around SOX9 and SOX3.)
Copy-number testing follows karyotype/SRY assessment, but platform coverage must be reviewed because small or noncoding enhancer lesions can be missed.
chromosomal microarray testing NCIT:C18477 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:30299888 SUPPORT Other
"Higher resolution chromosome analysis through aCGH or SNP array allows the detection of microduplications or microdeletions below the threshold of a standard karyotype (<5 Mb)."
Supports microarray-based detection of pathogenic CNVs.
DSD gene panel and genome sequencing with regulatory coverage (Pathogenic coding or noncoding variants in SRY-negative disease, including SOX9/SOX3 regulatory CNVs and specific NR5A1 or WT1 variants.)
A well-covered DSD panel can assess coding variants and deletion/duplication changes. Genome sequencing or equivalent validated assays should be considered when small noncoding SOX9/SOX3 regulatory lesions remain suspected; laboratory coverage must be confirmed rather than assumed.
gene panel testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:30299888 SUPPORT Other
"A panel of candidate genes with a robust coverage of all genomic regions of interest is increasingly regarded as the first-tier approach."
Supports a coverage-aware panel strategy.
PMID:37551848 SUPPORT Human Clinical
"Prior fluorescence in situ hybridization (FISH) for SRY and a multi-gene panel for ambiguous genitalia were non-diagnostic."
Demonstrates that routine SRY FISH and a multigene panel can miss a small noncoding SOX9 enhancer duplication later found by genome sequencing.
Age-appropriate endocrine and reproductive assessment (FSH, LH, testosterone, and selected Sertoli-cell markers interpreted by age; semen analysis after puberty.)
Hormone testing helps document testicular function and primary testicular failure. Semen analysis is relevant only after puberty. Pediatric testing may include AMH, inhibin B, and selective hCG stimulation when the presence or function of testicular tissue is uncertain.
circulating hormone measurement NCIT:C74742 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:20301589 SUPPORT Other
"Diagnosis of nonsyndromic 46,XX testicular DSD is based on the combination of clinical findings, endocrine testing, and cytogenetic testing."
Supports endocrine testing as one component of diagnosis.
PMID:30623467 SUPPORT Human Clinical
"Elevated levels of follicle-stimulating hormone (FSH) were found in 136 patients (95.10%) and increased luteinising hormone (LH) values were detected in 125 patients (92.59%). Eighty subjects (62.99%) had low testosterone values."
Provides the expected adult endocrine pattern.
Internal reproductive-structure imaging (Usually absent Müllerian structures; a uterus or hemi-uterus prompts reconsideration of ovotesticular DSD or another diagnosis.)
Pelvic ultrasound is a reasonable first imaging test, with MRI or surgical evaluation reserved for unresolved anatomy. Imaging contributes to the disease boundary but cannot prove the absence of microscopic ovarian tissue.
Show evidence (2 references)
PMID:20301589 SUPPORT Other
"absence of müllerian structures"
Supports absent Müllerian structures as the expected nonsyndromic pattern.
PMID:41170606 SUPPORT Human Clinical
"Müllerian derivatives were identified in 18 patients. In 14 of these, the structures were visualized by ultrasound, and in the remaining 4, they were identified through laparoscopic evaluation."
Mixed testicular/ovotesticular evidence shows how imaging and laparoscopy identify Müllerian structures, but it is not used as root-level phenotype evidence.
Selective gonadal histology when the TDSD-OTDSD boundary is unresolved (Testicular tissue without ovarian follicles; adequate sampling required to exclude an ovotestis.)
Biopsy is not a routine requirement in an otherwise clear nonsyndromic case. It may be considered when testicular versus ovotesticular classification cannot be resolved, recognizing that a limited biopsy can miss spatially separate ovarian tissue.
gonadal biopsy NCIT:C15189 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:41170606 SUPPORT Human Clinical
"In 4 patients, the first sample obtained from gonadal biopsy failed to identify ovarian tissue that was later demonstrated during pubertal evaluation."
Directly demonstrates sampling error at the testicular-versus-ovotesticular boundary.
📈

Progression

4
Fetal testis-determination phase
Age: fetal development
An ectopic pro-testis signal redirects the bipotential 46,XX gonad toward Sertoli-cell and testicular differentiation, with fetal AMH and androgen output determining internal and external genital anatomy.
Show evidence (1 reference)
PMID:21183788 SUPPORT Model Organism
"Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry."
Demonstrates a developmental route by which ectopic SOX3 can activate the pro-testis program.
Birth and childhood presentation
Age: birth through childhood
A minority present at birth with atypical genital anatomy; others have typical male external genitalia and may remain unrecognized through childhood.
Show evidence (1 reference)
PMID:20301589 SUPPORT Other
"Approximately 15% of individuals with nonsyndromic 46,XX testicular DSD present at birth with ambiguous genitalia."
Supports the neonatal presentation branch and its minority frequency.
Postpubertal recognition
Age: adolescence and adulthood
Most recognized individuals present after puberty with small testes, gynecomastia, azoospermia, and infertility despite otherwise typical male pubertal features.
Show evidence (1 reference)
PMID:20301589 SUPPORT Other
"Approximately 85% of individuals with nonsyndromic 46,XX testicular DSD present after puberty with normal pubic hair and normal penile size but small testes, gynecomastia, and sterility resulting from azoospermia."
Defines the dominant postpubertal clinical presentation.
Potential later primary testicular insufficiency
Age: adolescence through adulthood
Gonadotropins may rise before testosterone becomes frankly low, but sparse longitudinal data do not establish a uniformly progressive endocrine course. Germ-cell loss, testicular volume, and adult androgen status should therefore be assessed longitudinally rather than presumed from age alone.
Show evidence (1 reference)
PMID:38841305 SUPPORT Other
"It was suggested that levels of testosterone may be normal during adolescence, but decreased in adulthood ( 65), however, few data have been published so far."
Supports an age-dependent endocrine course while explicitly preserving the limited evidence base.
📊

Prevalence

1
Global
Unknown Rare
The condition is repeatedly described as rare, but the commonly quoted 1-in-20,000-males figure is a secondary estimate rather than a measured denominator-based point prevalence; no normalized rate is asserted here.
Show evidence (1 reference)
PMID:38721146 SUPPORT Other
"Two rare conditions are associated with disruptions in ovarian determination, including 46,XX testicular differences in sex development (DSD), in which the 46,XX gonads differentiate into testes, and 46,XX ovotesticular DSD, characterized by the coexistence of ovarian and testicular tissue in..."
Supports qualitative rare-disease classification without implying a measured prevalence.
🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from 46,XX testicular disorder of sex development:

46,XX ovotesticular disorder of sex development Not Yet Curated MONDO:0016281
Overlapping Features The closest boundary differential contains both ovarian follicles and testicular tissue. Müllerian structures and estrogen-producing ovarian tissue may be present, and a limited biopsy can miss the ovarian component.
Distinguishing Features
  • Histologic ovarian follicles together with seminiferous tubules define ovotesticular DSD.
  • Testicular-only gonads and absent Müllerian structures favor nonsyndromic testicular DSD.
Show evidence (1 reference)
PMID:38841305 SUPPORT Other
"The differential diagnosis between ovotesticular and testicular DSD is based on histological analysis. It requires the concomitant existence of testicular tissue (seminiferous tubules) and ovarian tissue (follicles containing oocytes)"
States the tissue criterion separating ovotesticular from testicular DSD.
RSPO1 palmoplantar keratoderma-XX sex reversal-SCC predisposition syndrome Not Yet Curated MONDO:0012530
Overlapping Features Biallelic RSPO1 disease can include testicular or ovotesticular development but is a separate recessive syndrome with palmoplantar hyperkeratosis and cutaneous squamous-cell-carcinoma predisposition. Those skin findings do not belong to the nonsyndromic root phenotype.
Show evidence (1 reference)
PMID:17041600 SUPPORT Human Clinical
"Here we show that human R-spondin1 (RSPO1) is the gene disrupted in a recessive syndrome characterized by XX sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin."
Establishes the RSPO1 syndrome and its extra-gonadal boundary features.
Congenital adrenal hyperplasia MONDO:0018479
Overlapping Features Prenatal adrenal androgen excess can virilize a 46,XX fetus but does not create testes. Adrenal steroid testing, gonadal assessment, and molecular diagnosis distinguish CAH from testicular DSD.
Show evidence (1 reference)
PMID:40089886 SUPPORT Human Clinical
"the condition was initially regarded as a virile form of congenital adrenal hyperplasia, then as idiopathic intrauterine virilization in a girl."
Documents the real diagnostic confusion between adrenal virilization and testicular tissue in an SRY-negative case.
Klinefelter syndrome MONDO:0006823
Overlapping Features Both disorders can cause small testes, azoospermia, gynecomastia, and hypergonadotropic hypogonadism after puberty; karyotype distinguishes 47,XXY from 46,XX disease.
Show evidence (1 reference)
PMID:36746123 SUPPORT Human Clinical
"The lower number of tubules and severe LC hyperplasia observed in 46,XX TDSD were similar to KS."
Supports overlapping testicular pathology; cytogenetics supplies the decisive distinction.
46,XX gonadal dysgenesis MONDO:0009299
Overlapping Features 46,XX gonadal dysgenesis causes streak or underdeveloped ovaries, estrogen deficiency, absent or delayed female puberty, and a uterus rather than testicular-only gonads with usual Müllerian regression.
{ }

Source YAML

click to show 
name: 46,XX testicular disorder of sex development
creation_date: "2026-05-08T12:00:00Z"
category: Mendelian
description: >-
  Nonsyndromic 46,XX testicular disorder of sex development (DSD) is a rare,
  genetically heterogeneous disorder in which a person with a 46,XX karyotype
  develops two testes without ovarian tissue or extra-genitourinary syndromic
  features. Müllerian structures are ordinarily absent, while external genital
  anatomy ranges from typical male to atypical. Most cases result from ectopic
  SRY on an X chromosome; SRY-negative causes include regulatory copy-number or
  structural variants affecting SOX9 or SOX3 and specific heterozygous variants
  in NR5A1 or WT1. The clinical course is age dependent: some children present
  with atypical genitalia, whereas many individuals first present after puberty
  with small testes, azoospermia, infertility, gynecomastia, or progressive
  primary testicular insufficiency. This entry excludes 46,XX ovotesticular DSD
  and the distinct syndromic RSPO1- and NR2F2-related disorders.
disease_term:
  preferred_term: 46,XX testicular disorder of sex development
  term:
    id: MONDO:0100249
    label: 46,XX testicular disorder of sex development
synonyms:
- 46,XX testicular DSD
- 46,XX male syndrome (historical)
- 46,XX sex reversal (historical)
- de la Chapelle syndrome (historical)
parents:
- Disorder of sex development
- Gonadal development disorder
- Male infertility disorder
definitions:
- name: Nonsyndromic 46,XX testicular DSD case definition
  definition_type: CASE_DEFINITION
  description: >-
    The disease boundary requires a 46,XX karyotype and testicular-only gonadal
    differentiation, without ovarian tissue. Typical nonsyndromic disease also
    lacks Müllerian structures and congenital or neurodevelopmental features
    outside the genitourinary system. Histologic ovarian tissue instead defines
    ovotesticular DSD; palmoplantar keratoderma, cutaneous squamous-cell-carcinoma
    predisposition, congenital heart disease, or other syndromic findings should
    trigger evaluation for a separate molecular syndrome.
  scope: >-
    MONDO:0100249 is curated here as the nonsyndromic testicular-only umbrella,
    not as a generic phenotype bucket for every cause of testicular tissue in a
    46,XX individual.
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nonsyndromic 46,XX testicular disorders/differences of sex development
      (DSD) are characterized by: the presence of a 46,XX karyotype; external
      genitalia ranging from typical male to ambiguous; two testicles;
      azoospermia; absence of müllerian structures; and absence of other
      syndromic features, such as congenital anomalies outside of the
      genitourinary system, learning disorders / cognitive impairment, or
      behavioral issues.
    explanation: >-
      GeneReviews supplies the nonsyndromic clinical boundary used for this
      entry.
  - reference: PMID:38841305
    reference_title: "46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is characterized by the presence of testes in 46,XX individuals, with
      concomitant absence of Mullerian derivatives.
    explanation: >-
      This review independently supports testicular gonads and absent Müllerian
      derivatives as the defining anatomic pattern.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100249
      label: 46,XX testicular disorder of sex development
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO identifier for the nonsyndromic 46,XX testicular DSD
      umbrella.
has_subtypes:
- name: SRY-positive
  display_name: SRY-positive 46,XX testicular DSD / 46,XX sex reversal 1
  classification: molecular_etiology
  subtype_term:
    preferred_term: 46,XX sex reversal 1
    term:
      id: MONDO:0100250
      label: 46,XX sex reversal 1
  genes:
  - preferred_term: SRY
    term:
      id: hgnc:11311
      label: SRY
  description: >-
    The common molecular subtype, usually caused by a de novo Xp-Yp exchange
    that places SRY on an X chromosome; rare translocations to an autosome are
    also described.
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Approximately 80% of individuals with nonsyndromic 46,XX testicular DSD
      are SRY positive, as shown by use of FISH or chromosomal microarray.
    explanation: >-
      Supports the frequency and molecular definition of the SRY-positive
      subtype.
- name: SRY-negative
  display_name: SRY-negative 46,XX testicular DSD
  classification: SRY_status
  children:
  - SRXX2
  - SRXX3
  - SRXX4
  - WT1-related
  - Unknown cause
  description: >-
    Testicular differentiation occurs without detectable SRY. Established
    nonsyndromic causes include SOX9 and SOX3 regulatory rearrangements and
    specific heterozygous variants in NR5A1 or WT1; many cases remain
    molecularly unresolved.
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Other causes in SRY-negative individuals include small copy number
      variants (CNVs) in or around SOX3 or SOX9 and specific heterozygous
      pathogenic variants in NR5A1 or WT1.
    explanation: >-
      Defines the established nonsyndromic SRY-negative etiologies.
- name: SRXX2
  display_name: SOX9-related 46,XX sex reversal 2
  classification: molecular_etiology
  subtype_term:
    preferred_term: 46,XX sex reversal 2
    term:
      id: MONDO:0010218
      label: 46,XX sex reversal 2
  genes:
  - preferred_term: SOX9
    term:
      id: hgnc:11204
      label: SOX9
  inheritance:
  - name: Autosomal dominant with incomplete penetrance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
  description: >-
    SRY-negative subtype caused chiefly by duplications or rearrangements of
    noncoding enhancers in the SOX9 upstream regulatory domain.
  evidence:
  - reference: PMID:37551848
    reference_title: "The smallest likely pathogenic duplication of a SOX9 enhancer identified to date in a family with 46,XX testicular differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Copy number variants that duplicate distal upstream enhancer elements of
      the SOX9 gene cause 46,XX testicular differences of sex development (DSD)
      which is characterized by a 46,XX karyotype in an individual presenting
      with either ambiguous genitalia or genitalia with varying degrees of
      virilization, including those resembling typical male genitalia.
    explanation: >-
      Directly establishes pathogenic SOX9 enhancer duplications in pure
      testicular DSD.
- name: SRXX3
  display_name: SOX3-related 46,XX sex reversal 3
  classification: molecular_etiology
  subtype_term:
    preferred_term: 46,XX sex reversal 3
    term:
      id: MONDO:0010442
      label: 46,XX sex reversal 3
  genes:
  - preferred_term: SOX3
    term:
      id: hgnc:11199
      label: SOX3
  description: >-
    SRY-negative subtype caused by copy-number or structural variants that
    produce ectopic SOX3 expression in the developing gonad.
  evidence:
  - reference: PMID:21183788
    reference_title: Identification of SOX3 as an XX male sex reversal gene in mice and humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Importantly, we also identified genomic rearrangements within the SOX3
      regulatory region in three patients with XX male sex reversal.
    explanation: >-
      Establishes human SOX3 regulatory rearrangements as an SRY-independent
      sex-reversal mechanism.
- name: SRXX4
  display_name: NR5A1-related 46,XX sex reversal 4
  classification: molecular_etiology
  subtype_term:
    preferred_term: 46,XX sex reversal 4
    term:
      id: MONDO:0060489
      label: 46,XX sex reversal 4
  genes:
  - preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  inheritance:
  - name: Autosomal dominant with reduced penetrance and variable expressivity
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    expressivity: VARIABLE
  description: >-
    Subtype associated with specific heterozygous NR5A1 variants, especially
    p.Arg92Trp; it must not be generalized to all NR5A1 variants.
  evidence:
  - reference: PMID:27378692
    reference_title: A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we show that a specific recurrent heterozygous missense mutation
      (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated
      with variable degree of testis development in 46,XX children and adults
      from four unrelated families.
    explanation: >-
      Supports the specific heterozygous NR5A1 variant class and variable
      expressivity.
- name: WT1-related
  display_name: WT1-related nonsyndromic 46,XX testicular DSD
  classification: molecular_etiology
  genes:
  - preferred_term: WT1
    term:
      id: hgnc:12796
      label: WT1
  description: >-
    Rare SRY-negative subtype associated with specific heterozygous variants
    affecting the WT1 C-terminal fourth zinc-finger regulatory domain, rather
    than the full syndromic WT1 disease spectrum.
  evidence:
  - reference: PMID:40089886
    reference_title: "[A case of 46,XX testicular disorders of sex development due to an apparent synonymous variant in the WT1 gene: difficulties of differential diagnosis of intrauterine virililzation syndrome in a girl]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular genetic analysis (whole exome sequencing with Sanger validation)
      revealed a de novo variant in exon 9 of the WT1 gene
      (chr11:32413528T&gt;C), which, according to predictions, did not lead to a
      change in the amino acid sequence (p.Thr479=, NM_024426.6), but disrupted
      splicing, resulting in a previously described in 46,XX TDSD a change in
      the C-terminal domain of WT1.
    explanation: >-
      Documents a de novo splice-disrupting WT1 variant in SRY-negative
      testicular DSD.
- name: Unknown cause
  display_name: SRY-negative 46,XX testicular DSD of unknown cause
  classification: molecular_etiology
  description: >-
    Molecularly unresolved testicular-only disease after adequate SRY,
    copy-number, coding, and regulatory-region assessment.
  evidence:
  - reference: PMID:38721146
    reference_title: "Testicular differentiation in 46,XX DSD: an overview of genetic causes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, it is important to note that a significant number of patients
      with these DSD conditions have not yet recognized a genetic diagnosis.
    explanation: >-
      Supports retaining a molecularly unresolved subtype.
prevalence:
- population: Global
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    The condition is repeatedly described as rare, but the commonly quoted
    1-in-20,000-males figure is a secondary estimate rather than a measured
    denominator-based point prevalence; no normalized rate is asserted here.
  evidence:
  - reference: PMID:38721146
    reference_title: "Testicular differentiation in 46,XX DSD: an overview of genetic causes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Two rare conditions are associated with disruptions in ovarian
      determination, including 46,XX testicular differences in sex development
      (DSD), in which the 46,XX gonads differentiate into testes, and 46,XX
      ovotesticular DSD, characterized by the coexistence of ovarian and
      testicular tissue in the same individual.
    explanation: >-
      Supports qualitative rare-disease classification without implying a
      measured prevalence.
inheritance:
- name: Usually de novo molecular events
  description: >-
    SRY-positive disease usually arises from a de novo X-Y interchange; known
    SOX3 CNVs and nonsyndromic WT1 variants have also usually been de novo when
    parents were tested. Recurrence risk is therefore molecular-cause specific
    and cannot be summarized by one Mendelian mode.
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SRY-positive 46,XX testicular DSD is generally not inherited because it
      results from de novo abnormal interchange between the Y chromosome and
      the X chromosome, resulting in the presence of SRY on the X chromosome
      and infertility.
    explanation: >-
      Supports the usual de novo origin of the common SRY-positive subtype.
- name: Autosomal dominant, sex-limited, with reduced penetrance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    Familial SOX9 regulatory duplications and heterozygous NR5A1 p.Arg92
    variants can segregate dominantly, but expression is limited by chromosome
    complement and can be incomplete or variable.
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pathogenic variants in NR5A1 are inherited in an autosomal dominant
      fashion, with reduced penetrance and variable expressivity.
    explanation: >-
      Establishes the dominant, incompletely penetrant NR5A1 branch.
  - reference: PMID:37551848
    reference_title: "The smallest likely pathogenic duplication of a SOX9 enhancer identified to date in a family with 46,XX testicular differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The unaffected mother also carries this duplication, consistent with
      previously described incomplete penetrance.
    explanation: >-
      Directly demonstrates incomplete penetrance of a familial SOX9 enhancer
      duplication.
progression:
- phase: Fetal testis-determination phase
  age_range: fetal development
  notes: >-
    An ectopic pro-testis signal redirects the bipotential 46,XX gonad toward
    Sertoli-cell and testicular differentiation, with fetal AMH and androgen
    output determining internal and external genital anatomy.
  evidence:
  - reference: PMID:21183788
    reference_title: Identification of SOX3 as an XX male sex reversal gene in mice and humans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Further analysis indicated that Sox3 induced testis differentiation in
      this particular line of mice by upregulating expression of Sox9 via a
      similar mechanism to Sry.
    explanation: >-
      Demonstrates a developmental route by which ectopic SOX3 can activate the
      pro-testis program.
- phase: Birth and childhood presentation
  age_range: birth through childhood
  notes: >-
    A minority present at birth with atypical genital anatomy; others have
    typical male external genitalia and may remain unrecognized through
    childhood.
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Approximately 15% of individuals with nonsyndromic 46,XX testicular DSD
      present at birth with ambiguous genitalia.
    explanation: >-
      Supports the neonatal presentation branch and its minority frequency.
- phase: Postpubertal recognition
  age_range: adolescence and adulthood
  notes: >-
    Most recognized individuals present after puberty with small testes,
    gynecomastia, azoospermia, and infertility despite otherwise typical male
    pubertal features.
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Approximately 85% of individuals with nonsyndromic 46,XX testicular DSD
      present after puberty with normal pubic hair and normal penile size but
      small testes, gynecomastia, and sterility resulting from azoospermia.
    explanation: >-
      Defines the dominant postpubertal clinical presentation.
- phase: Potential later primary testicular insufficiency
  age_range: adolescence through adulthood
  notes: >-
    Gonadotropins may rise before testosterone becomes frankly low, but sparse
    longitudinal data do not establish a uniformly progressive endocrine
    course. Germ-cell loss, testicular volume, and adult androgen status should
    therefore be assessed longitudinally rather than presumed from age alone.
  evidence:
  - reference: PMID:38841305
    reference_title: "46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It was suggested that levels of testosterone may be normal during
      adolescence, but decreased in adulthood ( 65), however, few data have been
      published so far.
    explanation: >-
      Supports an age-dependent endocrine course while explicitly preserving
      the limited evidence base.
pathophysiology:
- name: Ectopic SRY after Xp-Yp exchange
  description: >-
    Abnormal X-Y recombination transfers an SRY-containing segment of Yp to an
    X chromosome, allowing SRY expression in a 46,XX bipotential gonad.
  genes:
  - preferred_term: SRY
    term:
      id: hgnc:11311
      label: SRY
  biological_processes:
  - preferred_term: sex determination
    term:
      id: GO:0007530
      label: sex determination
    modifier: ABNORMAL
  subtypes:
  - SRY-positive
  evidence:
  - reference: PMID:25102093
    reference_title: "Clinical and molecular studies in four patients with SRY-positive 46,XX testicular disorders of sex development: implications for variable sex development and genomic rearrangements."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report four patients with SRY-positive 46,XX testicular disorders of
      sex development (46,XX-TDSD) (cases 1-4).
    explanation: >-
      The primary study maps Xp-Yp rearrangements in four SRY-positive cases.
  downstream:
  - target: Sustained pro-testis program
    description: Ectopic SRY initiates the SOX9-centered testis-determination cascade.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - SRY transcriptional activity increases SOX9 expression in supporting-cell precursors.
    evidence:
    - reference: PMID:21183788
      reference_title: Identification of SOX3 as an XX male sex reversal gene in mice and humans.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The Y chromosome-linked gene sex-determining region Y (SRY) is believed
        to be the master initiator of male sex determination in almost all
        eutherian and metatherian mammals, functioning to upregulate expression
        of its direct target gene Sry-related HMG box-containing gene 9 (SOX9).
      explanation: >-
        Supports the SRY-to-SOX9 intermediate step.
- name: SOX9 enhancer dosage gain
  description: >-
    Duplications or rearrangements of distal upstream SOX9 enhancers raise
    SOX9 activity above the threshold for testis determination without SRY.
  genes:
  - preferred_term: SOX9
    term:
      id: hgnc:11204
      label: SOX9
  biological_processes:
  - preferred_term: male gonad development
    term:
      id: GO:0008584
      label: male gonad development
    modifier: INCREASED
  subtypes:
  - SRXX2
  evidence:
  - reference: PMID:37551848
    reference_title: "The smallest likely pathogenic duplication of a SOX9 enhancer identified to date in a family with 46,XX testicular differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a family with two affected individuals, the proband and his
      maternal uncle, harboring a 3.7 kb duplication of a SOX9 enhancer
      identified by clinical genome sequencing.
    explanation: >-
      Directly links a minimal noncoding SOX9 enhancer duplication to familial
      testicular DSD.
  downstream:
  - target: Sustained pro-testis program
    description: Increased SOX9 enhancer dosage activates the testis pathway in an XX gonad.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37551848
      reference_title: "The smallest likely pathogenic duplication of a SOX9 enhancer identified to date in a family with 46,XX testicular differences of sex development."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        most of which resides in a 5.2 kb region that has been previously shown
        to possess enhancer activity that promotes the expression of SOX9.
      explanation: >-
        Supports increased SOX9 expression as the regulatory consequence.
- name: Ectopic SOX3 expression
  description: >-
    SOX3 copy-number or regulatory rearrangements cause inappropriate SOX3
    expression in the developing gonad, where it can substitute for SRY and
    activate SOX9.
  genes:
  - preferred_term: SOX3
    term:
      id: hgnc:11199
      label: SOX3
  biological_processes:
  - preferred_term: male gonad development
    term:
      id: GO:0008584
      label: male gonad development
    modifier: INCREASED
  subtypes:
  - SRXX3
  evidence:
  - reference: PMID:21183788
    reference_title: Identification of SOX3 as an XX male sex reversal gene in mice and humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Importantly, we also identified genomic rearrangements within the SOX3
      regulatory region in three patients with XX male sex reversal.
    explanation: >-
      Establishes the human regulatory lesions.
  - reference: PMID:21183788
    reference_title: Identification of SOX3 as an XX male sex reversal gene in mice and humans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Sox3 was ectopically expressed in the bipotential gonad and that this led
      to frequent complete XX male sex reversal.
    explanation: >-
      Demonstrates the developmental effect of ectopic Sox3 expression.
  downstream:
  - target: Sustained pro-testis program
    description: Ectopic SOX3 activates SOX9 through an SRY-like route.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21183788
      reference_title: Identification of SOX3 as an XX male sex reversal gene in mice and humans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Sox3 induced testis differentiation in this particular line of mice by
        upregulating expression of Sox9 via a similar mechanism to Sry.
      explanation: >-
        Directly supports the SOX3-to-SOX9 mechanism in vivo.
- name: NR5A1 Arg92 regulatory switch
  description: >-
    Specific heterozygous substitutions at NR5A1 Arg92 alter the balance between
    pro-ovary and pro-testis programs. The human association is strong, but the
    precise transcriptional mechanism remains incompletely resolved.
  genes:
  - preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  biological_processes:
  - preferred_term: gonad development
    term:
      id: GO:0008406
      label: gonad development
    modifier: DYSREGULATED
  subtypes:
  - SRXX4
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:27378692
    reference_title: A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These unique findings highlight how a specific variant in a developmental
      transcription factor can switch organ fate from the ovary to testis in
      mammals and represents the first missense mutation causing isolated,
      non-syndromic 46,XX testicular/ovotesticular DSD in humans.
    explanation: >-
      Supports the organ-fate switch associated with the specific variant.
  - reference: PMID:27490115
    reference_title: "NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We hypothesize that p.(Arg92Trp) results in decreased inhibition of the
      male developmental pathway through downregulation of female antitestis
      genes, thereby tipping the balance toward testicular differentiation in
      46,XX individuals.
    explanation: >-
      The authors explicitly frame the detailed molecular mechanism as a
      hypothesis, so it is retained with partial support.
  downstream:
  - target: Sustained pro-testis program
    description: The Arg92 variant shifts the gonadal regulatory balance toward testis differentiation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Altered NR5A1 target regulation reduces restraint on the male developmental pathway.
    evidence:
    - reference: PMID:27490115
      reference_title: "NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In conclusion, our study supports a role for NR5A1 in testis
        differentiation in the XX gonad.
      explanation: >-
        Supports pathway direction while preserving uncertainty about the exact
        intermediate mechanism.
- name: WT1 C-terminal regulatory alteration
  description: >-
    Rare splice or fourth-zinc-finger variants alter the WT1 C-terminal domain
    involved in gonadal supporting-cell fate. The gene-disease association is
    established, while the precise downstream molecular sequence remains
    incompletely characterized.
  genes:
  - preferred_term: WT1
    term:
      id: hgnc:12796
      label: WT1
  biological_processes:
  - preferred_term: gonad development
    term:
      id: GO:0008406
      label: gonad development
    modifier: DYSREGULATED
  subtypes:
  - WT1-related
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:40089886
    reference_title: "[A case of 46,XX testicular disorders of sex development due to an apparent synonymous variant in the WT1 gene: difficulties of differential diagnosis of intrauterine virililzation syndrome in a girl]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, we have described a patient with a rare form of 46,XX TDSD caused
      by a variant in the WT1 gene.
    explanation: >-
      Supports WT1 as a rare cause of testicular-only disease.
  downstream:
  - target: Sustained pro-testis program
    description: WT1 C-terminal disruption can redirect 46,XX supporting-cell fate toward testis formation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40089886
      reference_title: "[A case of 46,XX testicular disorders of sex development due to an apparent synonymous variant in the WT1 gene: difficulties of differential diagnosis of intrauterine virililzation syndrome in a girl]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Due to the development of virilization at the age of 11, the presence
        of testicular tissue was suspected.
      explanation: >-
        The case supports the phenotypic direction but does not resolve the
        complete molecular chain.
- name: Sustained pro-testis program
  description: >-
    Diverse upstream lesions converge on sufficient SOX9-centered pro-testis
    activity to overcome the ovarian program in a 46,XX bipotential gonad.
  biological_processes:
  - preferred_term: male gonad development
    term:
      id: GO:0008584
      label: male gonad development
    modifier: INCREASED
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  evidence:
  - reference: PMID:38721146
    reference_title: "Testicular differentiation in 46,XX DSD: an overview of genetic causes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the absence of SRY, other genes associated with testis development may
      be overexpressed or there may be a reduction in the activity of
      pro-ovarian/antitesticular factors.
    explanation: >-
      Supports convergence of gain of pro-testis activity and loss of ovarian
      restraint.
  downstream:
  - target: Testis differentiation in 46,XX gonads
    description: Sustained pro-testis signaling directs supporting cells and gonadal architecture toward testes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21183788
      reference_title: Identification of SOX3 as an XX male sex reversal gene in mice and humans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Sox3 induced testis differentiation in this particular line of mice by
        upregulating expression of Sox9 via a similar mechanism to Sry.
      explanation: >-
        Provides experimental support for a SOX9-centered pro-testis program
        producing testis differentiation.
- name: Testis differentiation in 46,XX gonads
  description: >-
    Sertoli and Leydig lineages form testes that ordinarily produce fetal AMH
    sufficient for Müllerian regression and variable androgen sufficient for
    typical or atypical male external genital development.
  biological_processes:
  - preferred_term: male gonad development
    term:
      id: GO:0008584
      label: male gonad development
    modifier: INCREASED
  - preferred_term: androgen biosynthetic process
    term:
      id: GO:0006702
      label: androgen biosynthetic process
    modifier: DYSREGULATED
  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:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      external genitalia ranging from typical male to ambiguous; two testicles;
      azoospermia; absence of müllerian structures
    explanation: >-
      Supports testis formation, Müllerian regression, and variable external
      genital development.
  downstream:
  - target: Atypical genitalia
    description: Insufficient or asynchronous fetal androgen output can produce atypical external genital anatomy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301589
      reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        external genitalia ranging from typical male to ambiguous
      explanation: >-
        Directly supports variability of external genital development.
  - target: Hypospadias
    description: Variable fetal androgen effect can include hypospadias.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25102093
      reference_title: "Clinical and molecular studies in four patients with SRY-positive 46,XX testicular disorders of sex development: implications for variable sex development and genomic rearrangements."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Case 1 exhibited underdeveloped external genitalia with hypospadias
      explanation: >-
        Documents hypospadias in a molecularly confirmed SRY-positive case.
  - target: Cryptorchidism
    description: Abnormal testicular development or descent can result in cryptorchidism.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired gonadal development and genital differentiation can disrupt testicular descent.
    evidence:
    - reference: PMID:30623467
      reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cryptorchidism and/or hypospadias appeared in 19 patients (13.19%).
      explanation: >-
        Supports the combined occurrence of cryptorchidism and hypospadias in
        an adult referral cohort but not a subtype-specific frequency.
  - target: Germ-cell loss and seminiferous-tubule failure
    description: The 46,XX testis lacks the usual Yq AZF complement and progressively loses germ cells.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Absence of Yq azoospermia-factor regions impairs germ-cell maintenance and spermatogenesis.
    evidence:
    - reference: PMID:30623467
      reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Among 86 patients with status of sex-determining region Y (SRY)-gene and
        azoospermia factor (AZF) region available, fifteen (17.44%) patients were
        SRY-negative and AZF region was absent in every patient without
        exception.
      explanation: >-
        Directly documents absent AZF regions in all tested members of this
        adult cohort.
  - target: Primary testicular insufficiency
    description: >-
      Abnormal Sertoli and Leydig compartments can reduce endocrine reserve;
      the timing and longitudinal progression are not established.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Abnormal seminiferous architecture and Leydig-cell dysfunction reduce gonadal feedback and androgen output.
    evidence:
    - reference: PMID:36746123
      reference_title: "Testicular Architecture of Men with 46,XX Testicular Disorders of Sex Development."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The lower number of tubules and severe LC hyperplasia observed in
        46,XX TDSD were similar to KS.
      explanation: >-
        Supports structural Sertoli/tubular and Leydig-compartment abnormalities
        in pure SRY-positive testicular DSD, but does not establish universal or
        progressive endocrine dysfunction.
- name: Germ-cell loss and seminiferous-tubule failure
  description: >-
    Missing Yq spermatogenesis loci and abnormal 46,XX testicular architecture
    lead to germ-cell depletion, severely impaired spermatogenesis, and small
    testes.
  biological_processes:
  - preferred_term: spermatogenesis
    term:
      id: GO:0007283
      label: spermatogenesis
    modifier: ABSENT
  evidence:
  - reference: PMID:36746123
    reference_title: "Testicular Architecture of Men with 46,XX Testicular Disorders of Sex Development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These individuals develop testes but are infertile due to germ cell loss.
    explanation: >-
      Directly links germ-cell loss to infertility in testicular-only disease.
  downstream:
  - target: Azoospermia
    description: Loss of germ cells and AZF-dependent spermatogenesis produces azoospermia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301589
      reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: azoospermia
      explanation: >-
        GeneReviews includes azoospermia in the defining clinical pattern.
  - target: Decreased Testicular Size
    description: Germ-cell and seminiferous-tubule loss reduce testicular volume.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30623467
      reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The mean volumes (95% CI) of left and right testicles were 2.16
        (1.82-2.49) ml and 2.16 (1.83-2.49) ml, respectively.
      explanation: >-
        Quantifies the markedly reduced adult testicular volume in the referral
        cohort.
  - target: Male Infertility
    description: Azoospermia prevents biological paternity with autologous sperm in typical non-mosaic disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36746123
      reference_title: "Testicular Architecture of Men with 46,XX Testicular Disorders of Sex Development."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These individuals develop testes but are infertile due to germ cell loss.
      explanation: >-
        Directly connects germ-cell loss to infertility.
- name: Primary testicular insufficiency
  description: >-
    Sertoli- and Leydig-cell dysfunction reduces inhibin and testosterone
    feedback, causing elevated FSH and LH; testosterone deficiency is common but
    not universal in adults. Cross-sectional adult data do not establish a
    uniformly progressive course.
  mechanism_confidence: PROVISIONAL
  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: androgen biosynthetic process
    term:
      id: GO:0006702
      label: androgen biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:30623467
    reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated levels of follicle-stimulating hormone (FSH) were found in 136
      patients (95.10%) and increased luteinising hormone (LH) values were
      detected in 125 patients (92.59%). Eighty subjects (62.99%) had low
      testosterone values.
    explanation: >-
      Quantifies the cross-sectional adult endocrine pattern and shows why low
      testosterone must not be called universal or necessarily progressive.
  downstream:
  - target: Hypergonadotropic Hypogonadism
    description: Reduced gonadal feedback raises FSH and LH, with variably low testosterone.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30623467
      reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In conclusion, hypergonadotropic hypogonadism appeared as the main
        presentation of 46,XX DSD males regardless of the SRY status.
      explanation: >-
        Supports hypergonadotropic hypogonadism as the principal adult endocrine
        presentation in this referral cohort.
  - target: Gynecomastia
    description: Pubertal/adult gonadal dysfunction can produce gynecomastia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Altered androgen-estrogen balance permits breast tissue development.
    evidence:
    - reference: PMID:20301589
      reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        small testes, gynecomastia, and sterility resulting from azoospermia
      explanation: >-
        Supports gynecomastia as part of the postpubertal phenotype; the detailed
        hormonal intermediate remains inferential.
biochemical:
- name: Elevated follicle-stimulating hormone
  presence: INCREASED
  frequency: VERY_FREQUENT
  context: >-
    Postpubertal/adult assessment; values in children must be interpreted by age
    and pubertal stage.
  evidence:
  - reference: PMID:30623467
    reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated levels of follicle-stimulating hormone (FSH) were found in 136
      patients (95.10%)
    explanation: >-
      Quantifies FSH elevation in an adult reproductive-center cohort.
- name: Elevated luteinizing hormone
  presence: INCREASED
  frequency: VERY_FREQUENT
  context: >-
    Postpubertal/adult assessment; values in children must be interpreted by age
    and pubertal stage.
  evidence:
  - reference: PMID:30623467
    reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      increased luteinising hormone (LH) values were detected in 125 patients
      (92.59%).
    explanation: >-
      Quantifies LH elevation in the adult cohort.
- name: Low testosterone
  presence: DECREASED
  frequency: FREQUENT
  context: >-
    Common in adulthood but not obligatory; testosterone can remain adequate
    during spontaneous puberty despite rising gonadotropins.
  biomarker_term:
    preferred_term: testosterone
    term:
      id: CHEBI:17347
      label: testosterone
  evidence:
  - reference: PMID:30623467
    reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Eighty subjects (62.99%) had low testosterone values.
    explanation: >-
      Establishes that low testosterone is frequent but not universal in
      adults.
phenotypes:
- category: Genitourinary
  name: Atypical genitalia
  frequency: OCCASIONAL
  description: >-
    A minority present at birth with atypical external genital anatomy; typical
    male external genitalia are more common in the nonsyndromic root disease.
  phenotype_term:
    preferred_term: Ambiguous genitalia
    term:
      id: HP:0000062
      label: Ambiguous genitalia
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Approximately 15% of individuals with nonsyndromic 46,XX testicular DSD
      present at birth with ambiguous genitalia.
    explanation: >-
      Supports occasional neonatal presentation with atypical genital anatomy.
- category: Genitourinary
  name: Hypospadias
  description: >-
    Hypospadias can accompany incomplete fetal virilization, but the available
    adult cohort reports it only in a combined category with cryptorchidism.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:25102093
    reference_title: "Clinical and molecular studies in four patients with SRY-positive 46,XX testicular disorders of sex development: implications for variable sex development and genomic rearrangements."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Case 1 exhibited underdeveloped external genitalia with hypospadias
    explanation: >-
      Documents hypospadias in a molecularly confirmed testicular DSD case.
- category: Genitourinary
  name: Cryptorchidism
  description: >-
    Undescended testes occur in a minority; no unsupported SRY-negative
    enrichment is asserted.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:30623467
    reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cryptorchidism and/or hypospadias appeared in 19 patients (13.19%).
    explanation: >-
      Supports occasional occurrence in an adult referral cohort while the
      combined endpoint prevents an exact cryptorchidism frequency estimate.
- category: Reproductive
  name: Azoospermia
  frequency: VERY_FREQUENT
  description: >-
    Postpubertal individuals with typical non-mosaic disease are expected to
    have azoospermia because Yq AZF loci and functional germ cells are absent.
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: azoospermia
    explanation: >-
      GeneReviews includes azoospermia in the disease definition.
- category: Reproductive
  name: Decreased Testicular Size
  frequency: VERY_FREQUENT
  description: >-
    Small testes are a characteristic postpubertal finding reflecting marked
    seminiferous-tubule and germ-cell loss.
  phenotype_term:
    preferred_term: Decreased testicular size
    term:
      id: HP:0008734
      label: Decreased testicular size
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Approximately 85% of individuals with nonsyndromic 46,XX testicular DSD
      present after puberty with normal pubic hair and normal penile size but
      small testes, gynecomastia, and sterility resulting from azoospermia.
    explanation: >-
      Provides frequency-level support for small testes as a very frequent
      postpubertal finding.
  - reference: PMID:30623467
    reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mean volumes (95% CI) of left and right testicles were 2.16
      (1.82-2.49) ml and 2.16 (1.83-2.49) ml, respectively.
    explanation: >-
      Quantifies marked testicular-volume reduction in the adult cohort.
- category: Endocrine
  name: Hypergonadotropic Hypogonadism
  frequency: VERY_FREQUENT
  description: >-
    Elevated FSH and LH are very common after puberty; low testosterone is
    frequent but not required at every age or in every adult.
  phenotype_term:
    preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  evidence:
  - reference: PMID:30623467
    reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated levels of follicle-stimulating hormone (FSH) were found in 136
      patients (95.10%) and increased luteinising hormone (LH) values were
      detected in 125 patients (92.59%). Eighty subjects (62.99%) had low
      testosterone values.
    explanation: >-
      Supports frequent hypergonadotropic testicular failure and calibrates the
      non-universal testosterone finding.
- category: Reproductive
  name: Gynecomastia
  frequency: VERY_FREQUENT
  description: >-
    Gynecomastia commonly contributes to postpubertal presentation, but a
    universal or precise population frequency is not inferred from selected
    infertility cohorts.
  phenotype_term:
    preferred_term: Gynecomastia
    term:
      id: HP:0000771
      label: Gynecomastia
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Approximately 85% of individuals with nonsyndromic 46,XX testicular DSD
      present after puberty with normal pubic hair and normal penile size but
      small testes, gynecomastia, and sterility resulting from azoospermia.
    explanation: >-
      Provides frequency-level support for gynecomastia as a very frequent
      postpubertal finding.
- category: Reproductive
  name: Male Infertility
  frequency: VERY_FREQUENT
  description: >-
    Infertility is expected after puberty in typical non-mosaic disease because
    of germ-cell loss and azoospermia.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:36746123
    reference_title: "Testicular Architecture of Men with 46,XX Testicular Disorders of Sex Development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These individuals develop testes but are infertile due to germ cell loss.
    explanation: >-
      Directly connects germ-cell loss to infertility in testicular-only cases.
histopathology:
- name: Reduced seminiferous-tubule number and Sertoli-cell abnormalities
  description: >-
    In four adult SRY-positive testicular DSD biopsies, seminiferous tubules were
    reduced and a larger fraction of Sertoli cells lacked SOX9 staining. These
    small, subtype-selected data should not be treated as universal pathology.
  context: Adult SRY-positive 46,XX testicular DSD; n=4 biopsies.
  subtype: SRY-positive
  evidence:
  - reference: PMID:36746123
    reference_title: "Testicular Architecture of Men with 46,XX Testicular Disorders of Sex Development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A smaller number of tubules, more SOX9-negative but similar proportions
      of DMRT1-negative SCs were found in 46,XX TDSD compared to NS.
    explanation: >-
      Provides testicular-only, subtype-specific architectural and Sertoli-cell
      evidence.
- name: Severe Leydig-cell hyperplasia
  description: >-
    Severe Leydig-cell hyperplasia was observed in the same four SRY-positive
    adult biopsies and may reflect chronic gonadotropin stimulation.
  context: Adult SRY-positive 46,XX testicular DSD; n=4 biopsies.
  subtype: SRY-positive
  evidence:
  - reference: PMID:36746123
    reference_title: "Testicular Architecture of Men with 46,XX Testicular Disorders of Sex Development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lower number of tubules and severe LC hyperplasia observed in
      46,XX TDSD were similar to KS.
    explanation: >-
      Directly supports Leydig-cell hyperplasia in pure testicular DSD biopsies.
genetic:
- name: Ectopic SRY
  gene_term:
    preferred_term: SRY
    term:
      id: hgnc:11311
      label: SRY
  association: >-
    Causative ectopic SRY, usually transferred to an X chromosome by an Xp-Yp
    rearrangement.
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  subtype: SRY-positive
  features: >-
    Accounts for approximately 80% of nonsyndromic cases; breakpoint size does
    not by itself predict external-genital development.
  evidence:
  - reference: PMID:25102093
    reference_title: "Clinical and molecular studies in four patients with SRY-positive 46,XX testicular disorders of sex development: implications for variable sex development and genomic rearrangements."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Xp;Yp translocations occurred between the X- and the Y-differential
      regions in case 1, between PRKX and inverted PRKY in case 2 and between
      the X-chromosomal short arm pseudoautosomal region and the Y-differential
      regions in cases 3 and 4.
    explanation: >-
      Directly maps the causative Xp-Yp rearrangements in four SRY-positive
      cases.
- name: SOX9 regulatory CNV
  gene_term:
    preferred_term: SOX9
    term:
      id: hgnc:11204
      label: SOX9
  association: >-
    Causative gain of dosage or altered chromosomal context of noncoding SOX9
    enhancers.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: SRXX2
  features: >-
    Regulatory duplications can be inherited from an unaffected parent because
    penetrance is incomplete and expression is dependent on chromosome
    complement.
  evidence:
  - reference: PMID:37551848
    reference_title: "The smallest likely pathogenic duplication of a SOX9 enhancer identified to date in a family with 46,XX testicular differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a family with two affected individuals, the proband and his
      maternal uncle, harboring a 3.7 kb duplication of a SOX9 enhancer
      identified by clinical genome sequencing.
    explanation: >-
      Establishes a familial, minimal pathogenic SOX9 enhancer duplication.
  - reference: PMID:25351776
    reference_title: "Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two cases carried partially overlapping 17q24.3 duplications ~500 kb
      upstream of SOX9, both inherited from their normal fathers.
    explanation: >-
      Supports recurrent upstream SOX9 duplications and reduced penetrance.
- name: SOX3 regulatory CNV
  gene_term:
    preferred_term: SOX3
    term:
      id: hgnc:11199
      label: SOX3
  association: >-
    Causative copy-number or regulatory rearrangements that produce ectopic
    SOX3 expression.
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  subtype: SRXX3
  features: >-
    SOX3 dosage changes can substitute for SRY; larger rearrangements may have
    additional neurodevelopmental consequences and then fall outside this
    nonsyndromic root.
  evidence:
  - reference: PMID:21183788
    reference_title: Identification of SOX3 as an XX male sex reversal gene in mice and humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Importantly, we also identified genomic rearrangements within the SOX3
      regulatory region in three patients with XX male sex reversal.
    explanation: >-
      Establishes the human association.
  - reference: PMID:25351776
    reference_title: "Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A further XX male, ascertained because of intellectual disability, carried
      a de novo cryptic duplication at Xq27.1, involving SOX3.
    explanation: >-
      Documents a de novo SOX3 duplication while illustrating why syndromic
      cases require boundary assessment.
- name: NR5A1 Arg92 variants
  gene_term:
    preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  association: >-
    Specific heterozygous Arg92 substitutions are causative; this assertion does
    not apply to all loss-of-function NR5A1 variants.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: SRXX4
  inheritance:
  - name: Autosomal dominant with reduced penetrance and variable expressivity
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    expressivity: VARIABLE
  features: >-
    The phenotypic spectrum includes testicular and ovotesticular development;
    this file models only individuals meeting the testicular-only boundary.
  evidence:
  - reference: PMID:27378692
    reference_title: A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we show that a specific recurrent heterozygous missense mutation
      (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated
      with variable degree of testis development in 46,XX children and adults
      from four unrelated families.
    explanation: >-
      Supports the specific heterozygous variant and variable expressivity.
  - reference: PMID:27490115
    reference_title: "NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel heterozygous NR5A1 mutation, c.274C>T
      p.(Arg92Trp), in three unrelated patients.
    explanation: >-
      Independently establishes recurrent heterozygous p.Arg92Trp.
- name: WT1 C-terminal variants
  gene_term:
    preferred_term: WT1
    term:
      id: hgnc:12796
      label: WT1
  association: >-
    Specific heterozygous splice or fourth-zinc-finger variants can cause rare
    nonsyndromic SRY-negative testicular DSD.
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  subtype: WT1-related
  features: >-
    Restrict to the nonsyndromic C-terminal/ZF4 branch; broader WT1 syndromes
    with renal, tumor, cardiac, or diaphragmatic manifestations are outside this
    entry.
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      specific heterozygous pathogenic variants in NR5A1 or WT1.
    explanation: >-
      GeneReviews recognizes specific heterozygous WT1 variants among the
      nonsyndromic causes.
  - reference: PMID:40089886
    reference_title: "[A case of 46,XX testicular disorders of sex development due to an apparent synonymous variant in the WT1 gene: difficulties of differential diagnosis of intrauterine virililzation syndrome in a girl]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular genetic analysis (whole exome sequencing with Sanger validation)
      revealed a de novo variant in exon 9 of the WT1 gene
    explanation: >-
      Directly documents the de novo WT1 variant in a testicular DSD case.
diagnosis:
- name: Integrated multidisciplinary DSD assessment
  presence: >-
    Clinical anatomy, age-appropriate endocrine results, chromosome complement,
    and molecular findings interpreted together.
  description: >-
    No single phenotype or test establishes the entire diagnosis. Evaluation
    should integrate genital and gonadal anatomy, internal reproductive
    structures, hormone data, cytogenetics, and molecular testing through an
    experienced multidisciplinary DSD team.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:30299888
    reference_title: "GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diagnosis of DSD belongs to the most complex fields in medicine and
      requires an integrated multidisciplinary approach consisting in a
      synoptic view of clinical phenotype, biochemical (hormonal) constellation
      and molecular datasets.
    explanation: >-
      Supports integrated rather than test-isolated diagnosis.
- name: Karyotype confirmation and SRY detection/localization
  presence: >-
    46,XX chromosome complement with testicular tissue; SRY status and genomic
    location reported.
  description: >-
    Karyotyping establishes the 46,XX DSD class. FISH or chromosomal microarray
    can detect SRY and help localize ectopic Yp material; PCR alone establishes
    presence but not chromosomal location.
  diagnosis_term:
    preferred_term: karyotyping
    term:
      id: NCIT:C16768
      label: Karyotyping
  evidence:
  - reference: PMID:30299888
    reference_title: "GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Ascertainment of the karyotpye defines one of the three major diagnostic
      DSD subclasses and is therefore the mandatory initial step.
    explanation: >-
      Supports chromosome-complement assessment as the initial genetic step.
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Approximately 80% of individuals with nonsyndromic 46,XX testicular DSD
      are SRY positive, as shown by use of FISH or chromosomal microarray.
    explanation: >-
      Supports FISH or microarray assessment of SRY status.
- name: Chromosomal microarray and deletion-duplication analysis
  presence: >-
    Detection of pathogenic CNVs involving SRY or regulatory domains around
    SOX9 and SOX3.
  description: >-
    Copy-number testing follows karyotype/SRY assessment, but platform coverage
    must be reviewed because small or noncoding enhancer lesions can be missed.
  diagnosis_term:
    preferred_term: chromosomal microarray testing
    term:
      id: NCIT:C18477
      label: Microarray Analysis
  evidence:
  - reference: PMID:30299888
    reference_title: "GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Higher resolution chromosome analysis through aCGH or SNP array allows
      the detection of microduplications or microdeletions below the threshold
      of a standard karyotype (<5 Mb).
    explanation: >-
      Supports microarray-based detection of pathogenic CNVs.
- name: DSD gene panel and genome sequencing with regulatory coverage
  presence: >-
    Pathogenic coding or noncoding variants in SRY-negative disease, including
    SOX9/SOX3 regulatory CNVs and specific NR5A1 or WT1 variants.
  description: >-
    A well-covered DSD panel can assess coding variants and deletion/duplication
    changes. Genome sequencing or equivalent validated assays should be
    considered when small noncoding SOX9/SOX3 regulatory lesions remain
    suspected; laboratory coverage must be confirmed rather than assumed.
  diagnosis_term:
    preferred_term: gene panel testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:30299888
    reference_title: "GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A panel of candidate genes with a robust coverage of all genomic regions
      of interest is increasingly regarded as the first-tier approach.
    explanation: >-
      Supports a coverage-aware panel strategy.
  - reference: PMID:37551848
    reference_title: "The smallest likely pathogenic duplication of a SOX9 enhancer identified to date in a family with 46,XX testicular differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prior fluorescence in situ hybridization (FISH) for SRY and a multi-gene
      panel for ambiguous genitalia were non-diagnostic.
    explanation: >-
      Demonstrates that routine SRY FISH and a multigene panel can miss a small
      noncoding SOX9 enhancer duplication later found by genome sequencing.
- name: Age-appropriate endocrine and reproductive assessment
  presence: >-
    FSH, LH, testosterone, and selected Sertoli-cell markers interpreted by age;
    semen analysis after puberty.
  description: >-
    Hormone testing helps document testicular function and primary testicular
    failure. Semen analysis is relevant only after puberty. Pediatric testing
    may include AMH, inhibin B, and selective hCG stimulation when the presence
    or function of testicular tissue is uncertain.
  diagnosis_term:
    preferred_term: circulating hormone measurement
    term:
      id: NCIT:C74742
      label: Hormone Measurement
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diagnosis of nonsyndromic 46,XX testicular DSD is based on the combination
      of clinical findings, endocrine testing, and cytogenetic testing.
    explanation: >-
      Supports endocrine testing as one component of diagnosis.
  - reference: PMID:30623467
    reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated levels of follicle-stimulating hormone (FSH) were found in 136
      patients (95.10%) and increased luteinising hormone (LH) values were
      detected in 125 patients (92.59%). Eighty subjects (62.99%) had low
      testosterone values.
    explanation: >-
      Provides the expected adult endocrine pattern.
- name: Internal reproductive-structure imaging
  presence: >-
    Usually absent Müllerian structures; a uterus or hemi-uterus prompts
    reconsideration of ovotesticular DSD or another diagnosis.
  description: >-
    Pelvic ultrasound is a reasonable first imaging test, with MRI or surgical
    evaluation reserved for unresolved anatomy. Imaging contributes to the
    disease boundary but cannot prove the absence of microscopic ovarian tissue.
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: absence of müllerian structures
    explanation: >-
      Supports absent Müllerian structures as the expected nonsyndromic pattern.
  - reference: PMID:41170606
    reference_title: "46,XX Testicular/Ovotesticular Disorders of Sexual Development: A Single-Center Retrospective Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Müllerian derivatives were identified in 18 patients. In 14 of these, the
      structures were visualized by ultrasound, and in the remaining 4, they
      were identified through laparoscopic evaluation.
    explanation: >-
      Mixed testicular/ovotesticular evidence shows how imaging and laparoscopy
      identify Müllerian structures, but it is not used as root-level phenotype
      evidence.
- name: Selective gonadal histology when the TDSD-OTDSD boundary is unresolved
  presence: >-
    Testicular tissue without ovarian follicles; adequate sampling required to
    exclude an ovotestis.
  description: >-
    Biopsy is not a routine requirement in an otherwise clear nonsyndromic case.
    It may be considered when testicular versus ovotesticular classification
    cannot be resolved, recognizing that a limited biopsy can miss spatially
    separate ovarian tissue.
  diagnosis_term:
    preferred_term: gonadal biopsy
    term:
      id: NCIT:C15189
      label: Biopsy Procedure
  evidence:
  - reference: PMID:41170606
    reference_title: "46,XX Testicular/Ovotesticular Disorders of Sexual Development: A Single-Center Retrospective Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 4 patients, the first sample obtained from gonadal biopsy failed to
      identify ovarian tissue that was later demonstrated during pubertal
      evaluation.
    explanation: >-
      Directly demonstrates sampling error at the testicular-versus-ovotesticular
      boundary.
differential_diagnoses:
- name: 46,XX ovotesticular disorder of sex development
  description: >-
    The closest boundary differential contains both ovarian follicles and
    testicular tissue. Müllerian structures and estrogen-producing ovarian
    tissue may be present, and a limited biopsy can miss the ovarian component.
  distinguishing_features:
  - Histologic ovarian follicles together with seminiferous tubules define ovotesticular DSD.
  - Testicular-only gonads and absent Müllerian structures favor nonsyndromic testicular DSD.
  disease_term:
    preferred_term: 46,XX ovotesticular disorder of sex development
    term:
      id: MONDO:0016281
      label: 46,XX ovotesticular disorder of sex development
  evidence:
  - reference: PMID:38841305
    reference_title: "46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The differential diagnosis between ovotesticular and testicular DSD is
      based on histological analysis. It requires the concomitant existence of
      testicular tissue (seminiferous tubules) and ovarian tissue (follicles
      containing oocytes)
    explanation: >-
      States the tissue criterion separating ovotesticular from testicular DSD.
- name: RSPO1 palmoplantar keratoderma-XX sex reversal-SCC predisposition syndrome
  description: >-
    Biallelic RSPO1 disease can include testicular or ovotesticular development
    but is a separate recessive syndrome with palmoplantar hyperkeratosis and
    cutaneous squamous-cell-carcinoma predisposition. Those skin findings do not
    belong to the nonsyndromic root phenotype.
  disease_term:
    preferred_term: palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome
    term:
      id: MONDO:0012530
      label: palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome
  evidence:
  - reference: PMID:17041600
    reference_title: "R-spondin1 is essential in sex determination, skin differentiation and malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we show that human R-spondin1 (RSPO1) is the gene disrupted in a
      recessive syndrome characterized by XX sex reversal, palmoplantar
      hyperkeratosis and predisposition to squamous cell carcinoma of the skin.
    explanation: >-
      Establishes the RSPO1 syndrome and its extra-gonadal boundary features.
- name: NR2F2-related 46,XX sex reversal 5
  description: >-
    NR2F2 loss-of-function causes a distinct syndromic 46,XX testicular or
    ovotesticular phenotype accompanied by congenital heart disease and
    sometimes diaphragmatic hernia or BPES features.
  disease_term:
    preferred_term: 46,xx sex reversal 5
    term:
      id: MONDO:0030049
      label: 46,xx sex reversal 5
  evidence:
  - reference: PMID:29478779
    reference_title: "Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three children presented with congenital heart disease (CHD), one
      child with congenital diaphragmatic hernia (CDH), and two children with
      blepharophimosis-ptosis-epicanthus inversus syndrome (BPES).
    explanation: >-
      Supports the defining syndromic features that place NR2F2 disease outside
      the nonsyndromic root.
- name: Congenital adrenal hyperplasia
  description: >-
    Prenatal adrenal androgen excess can virilize a 46,XX fetus but does not
    create testes. Adrenal steroid testing, gonadal assessment, and molecular
    diagnosis distinguish CAH from testicular DSD.
  disease_term:
    preferred_term: congenital adrenal hyperplasia
    term:
      id: MONDO:0018479
      label: congenital adrenal hyperplasia
  evidence:
  - reference: PMID:40089886
    reference_title: "[A case of 46,XX testicular disorders of sex development due to an apparent synonymous variant in the WT1 gene: difficulties of differential diagnosis of intrauterine virililzation syndrome in a girl]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the condition was initially regarded as a virile form of congenital
      adrenal hyperplasia, then as idiopathic intrauterine virilization in a
      girl.
    explanation: >-
      Documents the real diagnostic confusion between adrenal virilization and
      testicular tissue in an SRY-negative case.
- name: Klinefelter syndrome
  description: >-
    Both disorders can cause small testes, azoospermia, gynecomastia, and
    hypergonadotropic hypogonadism after puberty; karyotype distinguishes 47,XXY
    from 46,XX disease.
  disease_term:
    preferred_term: Klinefelter syndrome
    term:
      id: MONDO:0006823
      label: Klinefelter syndrome
  evidence:
  - reference: PMID:36746123
    reference_title: "Testicular Architecture of Men with 46,XX Testicular Disorders of Sex Development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lower number of tubules and severe LC hyperplasia observed in
      46,XX TDSD were similar to KS.
    explanation: >-
      Supports overlapping testicular pathology; cytogenetics supplies the
      decisive distinction.
- name: 46,XX gonadal dysgenesis
  description: >-
    46,XX gonadal dysgenesis causes streak or underdeveloped ovaries, estrogen
    deficiency, absent or delayed female puberty, and a uterus rather than
    testicular-only gonads with usual Müllerian regression.
  disease_term:
    preferred_term: 46,XX gonadal dysgenesis
    term:
      id: MONDO:0009299
      label: 46 XX gonadal dysgenesis
treatments:
- name: Individualized testosterone pubertal induction or replacement
  action_category: THERAPEUTIC
  description: >-
    Testosterone is used when spontaneous puberty is absent or incomplete, or
    when persistent symptomatic biochemical hypogonadism is confirmed. It is
    not automatic therapy for every child or adult; dosing and timing should be
    individualized to age, pubertal stage, growth, symptoms, and patient goals.
  treatment_term:
    preferred_term: hormone modifying therapy
    term:
      id: NCIT:C15445
      label: Hormone Therapy
    therapeutic_agent:
    - preferred_term: testosterone
      term:
        id: CHEBI:17347
        label: testosterone
  target_phenotypes:
  - preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      After age 14 years, low-dose testosterone therapy is initiated and
      gradually increased to reach adult levels.
    explanation: >-
      Supports gradual pubertal induction in affected adolescents requiring
      treatment.
  - reference: PMID:38841305
    reference_title: "46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hormone replacement therapy (HRT), if needed, consists of Testosterone
      treatment, with formulations and therapeutic schemes recommended in
      International clinical practice guidelines
    explanation: >-
      Explicitly makes testosterone conditional on clinical need.
- name: Longitudinal endocrine and testosterone-safety monitoring
  action_category: MONITORING
  description: >-
    Follow growth and pubertal progression, symptoms, FSH/LH/testosterone, mood,
    libido, energy, erectile function, acne, breast symptoms, and gynecomastia.
    During testosterone therapy, monitor dose response, testosterone,
    hematocrit, and age-appropriate metabolic, liver, and prostate safety
    measures.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For those on testosterone replacement therapy: measurement of serum
      testosterone levels every three months (just prior to the next injection)
      until testosterone dose is optimized; then annual measurement of serum
      testosterone levels, lipid profile, and liver function tests.
    explanation: >-
      Supports structured monitoring during testosterone replacement.
- name: Bone-health assessment and management
  action_category: MONITORING
  description: >-
    Assess bone health after puberty and more frequently when osteopenia is
    present; address calcium/vitamin D, weight-bearing activity, androgen
    deficiency, and osteoporosis according to standard care.
  treatment_term:
    preferred_term: Dual-energy X-ray absorptiometry procedure
    term:
      id: NCIT:C48789
      label: Dual X-ray Absorptiometry
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dual-energy x-ray absorptiometry scan every three to five years after
      puberty or annually, if osteopenia has been identified.
    explanation: >-
      Supports ongoing bone-density surveillance after puberty.
- name: Donor-sperm assisted reproduction and family-building counseling
  action_category: THERAPEUTIC
  description: >-
    Donor-sperm assisted reproductive technology can achieve parenthood for
    affected couples. The choice among donor insemination, IVF, and other
    family-building options should be individualized. Autologous sperm retrieval
    is generally not expected to succeed in confirmed non-mosaic disease lacking
    AZF regions, but categorical exclusions should be discussed with a
    reproductive-urology specialist because evidence is limited.
  treatment_term:
    preferred_term: assisted reproductive technology
    term:
      id: NCIT:C93282
      label: Assisted Reproductive Technology
  target_phenotypes:
  - preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:30623467
    reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, fertility achieved in 87 patients through ART using donor
      spermatozoa.
    explanation: >-
      Directly documents donor-sperm ART outcomes in the largest cited adult
      cohort.
- name: Etiology-specific genetic counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Explain the molecular diagnosis, recurrence risk, reduced penetrance,
    chromosome-complement dependence, family testing, infertility, and
    reproductive options. Counseling must distinguish usually de novo SRY,
    SOX3, or WT1 events from potentially inherited SOX9 or NR5A1 variants.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mode of inheritance and recurrence risk to sibs of a proband with a
      nonsyndromic 46,XX testicular DSD depend on the molecular diagnosis in the
      proband and the genetic status of the parents.
    explanation: >-
      Directly supports etiology-specific recurrence counseling.
- name: Multidisciplinary psychosocial and anomaly-specific care
  action_category: THERAPEUTIC
  description: >-
    Offer developmentally appropriate psychological and sexual-health support,
    shared decision-making, and standard urologic management of hypospadias or
    cryptorchidism when present. Care should be coordinated across pediatric or
    adult endocrinology, genetics, urology, reproductive medicine, and mental
    health according to age and goals.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301589
    reference_title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Standard treatment for osteopenia, hypospadias, and cryptorchidism.
      Providers are encouraged to anticipate the need for further psychological
      support.
    explanation: >-
      Supports anomaly-specific standard care and anticipatory psychological
      support.
discussions:
- discussion_id: gap_tdsd_otdsd_boundary_sampling
  prompt: >-
    What combination of imaging, endocrine markers, longitudinal observation,
    and adequately sampled histology best distinguishes testicular-only from
    ovotesticular 46,XX DSD without making biopsy routine?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - diagnosis#Selective gonadal histology when the TDSD-OTDSD boundary is unresolved
  - differential_diagnoses#46,XX ovotesticular disorder of sex development
  rationale: >-
    Gonadal tissue is spatially heterogeneous, and a limited childhood biopsy
    can miss ovarian follicles later demonstrated during puberty. Misclassification
    changes counseling, fertility considerations, and interpretation of tumor
    evidence.
  evidence:
  - reference: PMID:41170606
    reference_title: "46,XX Testicular/Ovotesticular Disorders of Sexual Development: A Single-Center Retrospective Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 4 patients, the first sample obtained from gonadal biopsy failed to
      identify ovarian tissue that was later demonstrated during pubertal
      evaluation.
    explanation: >-
      Directly establishes the sampling problem.
- discussion_id: gap_sry_negative_molecular_diagnosis
  prompt: >-
    Which noncoding, structural, mosaic, or epigenetic mechanisms explain
    SRY-negative testicular-only cases that remain unresolved after current
    panel, CNV, and genome testing?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - has_subtypes#Unknown cause
  - diagnosis#DSD gene panel and genome sequencing with regulatory coverage
  rationale: >-
    Many cases still lack a molecular diagnosis, and very small enhancer
    duplications can evade SRY testing and routine panels. Resolution will
    require validated noncoding coverage, structural-variant analysis, and
    careful phenotype reclassification.
  evidence:
  - reference: PMID:38721146
    reference_title: "Testicular differentiation in 46,XX DSD: an overview of genetic causes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This finding suggests that there are additional genetic pathways or
      epigenetic mechanisms that have yet to be identified.
    explanation: >-
      Supports the unresolved genetic and epigenetic mechanism gap.
  - reference: PMID:37551848
    reference_title: "The smallest likely pathogenic duplication of a SOX9 enhancer identified to date in a family with 46,XX testicular differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This finding highlights the importance of non-coding variant interrogation
      in suspected genetic disorders.
    explanation: >-
      Demonstrates the diagnostic value of noncoding interrogation.
- discussion_id: gap_autologous_fertility_potential
  prompt: >-
    Are there rigorously confirmed non-mosaic, testicular-only 46,XX cases with
    retrievable autologous sperm, and what evidence threshold should govern
    counseling about TESE or fertility preservation?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Germ-cell loss and seminiferous-tubule failure
  - treatments#Donor-sperm assisted reproduction and family-building counseling
  rationale: >-
    AZF regions were absent in all tested members of the largest adult cohort
    and pure testicular biopsies show germ-cell loss, making success biologically
    unlikely. Rare reports may reflect mosaicism or TDSD-OTDSD
    misclassification, so counseling should avoid both false hope and an
    unsupported categorical prohibition.
  evidence:
  - reference: PMID:30623467
    reference_title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The available fertility option proved to achieve live birth was limited
      to ART using donor spermatozoa.
    explanation: >-
      Defines the demonstrated fertility outcome in the adult cohort while not
      resolving exceptional reports.
- discussion_id: gap_gonadal_tumor_surveillance
  prompt: >-
    Is any routine gonadal tumor surveillance indicated in confirmed
    nonsyndromic 46,XX testicular DSD, and should risk be stratified by gonadal
    location, age, histology, or Y-derived material such as TSPY?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - disease#46,XX testicular disorder of sex development
  rationale: >-
    Published tumor series are dominated by ovotesticular cases and do not
    establish a testicular-only risk estimate or validated screening schedule.
    Until expert review resolves this, the entry should not imply routine
    biopsy, prophylactic gonadectomy, or a tumor-surveillance protocol.
  evidence:
  - reference: PMID:35900314
    reference_title: "Gonadal tumor development in 46,XX disorders of gonadal development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Totally 15 patients were classified as ovotesticular and only 1 as
      testicular DSD.
    explanation: >-
      Shows why the malignancy findings cannot be generalized to the
      testicular-only population.
  - reference: PMID:35900314
    reference_title: "Gonadal tumor development in 46,XX disorders of gonadal development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The finding of early germ cell malignancies in our cohort brings awareness
      and needs further research.
    explanation: >-
      Supports retaining the question as an open research need rather than a
      settled surveillance recommendation.
tracked_issues:
- url: https://github.com/monarch-initiative/dismech/issues/6584
  title: "Expert review: gonadal tumor surveillance in confirmed 46,XX testicular DSD"
  tracked_issue_role: EXPERT_REVIEW
  tracked_issue_status: OPEN
  notes: >-
    Requests expert resolution of tumor-risk stratification and whether any
    routine surveillance belongs in the nonsyndromic testicular-only entry.
clinical_trials: []
datasets: []
notes: >-
  Scope is deliberately restricted to nonsyndromic testicular-only
  MONDO:0100249. RSPO1 syndrome (MONDO:0012530), NR2F2-related 46,XX sex
  reversal 5 (MONDO:0030049), and 46,XX ovotesticular DSD (MONDO:0016281) are
  separate diseases and appear only as boundary differentials. Historical
  labels such as “XX male” and “sex reversal” are retained only for literature
  discoverability and MONDO subtype alignment. Mixed testicular/ovotesticular
  cohorts are used solely to expose diagnostic and tumor-risk uncertainty, not
  to assert root phenotypes, histopathology, or surveillance. No validated
  routine gonadal tumor-screening protocol is encoded pending expert review in
  GitHub issue 6584.
references:
- reference: PMID:17041600
  title: "R-spondin1 is essential in sex determination, skin differentiation and malignancy."
  findings: []
- reference: PMID:20301589
  title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:21183788
  title: Identification of SOX3 as an XX male sex reversal gene in mice and humans.
  findings: []
- reference: PMID:25102093
  title: "Clinical and molecular studies in four patients with SRY-positive 46,XX testicular disorders of sex development: implications for variable sex development and genomic rearrangements."
  findings: []
- reference: PMID:25351776
  title: "Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3."
  findings: []
- reference: PMID:27378692
  title: A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.
  findings: []
- reference: PMID:27490115
  title: "NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development."
  findings: []
- reference: PMID:29478779
  title: "Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children."
  findings: []
- reference: PMID:30299888
  title: "GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’."
  findings: []
- reference: PMID:30623467
  title: "Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases."
  findings: []
- reference: PMID:35900314
  title: "Gonadal tumor development in 46,XX disorders of gonadal development."
  findings: []
- reference: PMID:36746123
  title: "Testicular Architecture of Men with 46,XX Testicular Disorders of Sex Development."
  findings: []
- reference: PMID:37551848
  title: "The smallest likely pathogenic duplication of a SOX9 enhancer identified to date in a family with 46,XX testicular differences of sex development."
  findings: []
- reference: PMID:38721146
  title: "Testicular differentiation in 46,XX DSD: an overview of genetic causes."
  findings: []
- reference: PMID:38841305
  title: "46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes."
  findings: []
- reference: PMID:40089886
  title: "[A case of 46,XX testicular disorders of sex development due to an apparent synonymous variant in the WT1 gene: difficulties of differential diagnosis of intrauterine virililzation syndrome in a girl]."
  findings: []
- reference: PMID:41170606
  title: "46,XX Testicular/Ovotesticular Disorders of Sexual Development: A Single-Center Retrospective Experience."
  findings: []
📚

References & Deep Research

References

17
PMID:17041600
R-spondin1 is essential in sex determination, skin differentiation and malignancy.
No top-level findings curated for this source.
PMID:20301589
Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development.
No top-level findings curated for this source.
PMID:21183788
Identification of SOX3 as an XX male sex reversal gene in mice and humans.
No top-level findings curated for this source.
PMID:25102093
Clinical and molecular studies in four patients with SRY-positive 46,XX testicular disorders of sex development: implications for variable sex development and genomic rearrangements.
No top-level findings curated for this source.
PMID:25351776
Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3.
No top-level findings curated for this source.
PMID:27378692
A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.
No top-level findings curated for this source.
PMID:27490115
NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development.
No top-level findings curated for this source.
PMID:29478779
Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children.
No top-level findings curated for this source.
PMID:30299888
GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’.
No top-level findings curated for this source.
PMID:30623467
Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases.
No top-level findings curated for this source.
PMID:35900314
Gonadal tumor development in 46,XX disorders of gonadal development.
No top-level findings curated for this source.
PMID:36746123
Testicular Architecture of Men with 46,XX Testicular Disorders of Sex Development.
No top-level findings curated for this source.
PMID:37551848
The smallest likely pathogenic duplication of a SOX9 enhancer identified to date in a family with 46,XX testicular differences of sex development.
No top-level findings curated for this source.
PMID:38721146
Testicular differentiation in 46,XX DSD: an overview of genetic causes.
No top-level findings curated for this source.
PMID:38841305
46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes.
No top-level findings curated for this source.
PMID:40089886
[A case of 46,XX testicular disorders of sex development due to an apparent synonymous variant in the WT1 gene: difficulties of differential diagnosis of intrauterine virililzation syndrome in a girl].
No top-level findings curated for this source.
PMID:41170606
46,XX Testicular/Ovotesticular Disorders of Sexual Development: A Single-Center Retrospective Experience.
No top-level findings curated for this source.

Deep Research

2
Falcon ▸
46,XX Testicular Disorder of Sex Development (46,XX T-DSD): Disease Characteristics Research Report
Edison Scientific Literature 33 citations 2026-05-30T01:38:39.620093

46,XX Testicular Disorder of Sex Development (46,XX T-DSD): Disease Characteristics Research Report

Target disease

Disease name: 46,XX testicular disorder of sex development (46,XX testicular DSD; “XX male syndrome”).

Note on identifiers (OMIM/Orphanet/MONDO/MeSH/ICD): In this tool-run, primary ontology/registry pages (OMIM/Orphanet/MONDO/ICD/MeSH) were not directly retrievable as citable full-text sources. Consequently, identifier assertions are not provided here to avoid uncited/uncertain mappings. The report below is built from peer‑reviewed primary literature and recent reviews.

1. Disease information

1.1 Concise overview

46,XX testicular DSD is a rare condition in which an individual with a 46,XX karyotype develops testicular tissue and typically a male or undervirilized male phenotype. It is commonly diagnosed after puberty/adulthood during evaluation for infertility and/or hypogonadism. (terribile201946xxtesticulardisorder pages 1-3, ferrari2024testiculardifferentiationin pages 1-2)

1.2 Synonyms / alternative names

Frequently used names include “46,XX testicular DSD,” “46,XX male syndrome,” “XX male syndrome,” and, in newer nomenclature, “46,XX testicular difference of sex development.” (li201446xxtesticulardisorder pages 1-2, terribile201946xxtesticulardisorder pages 1-3)

1.3 Evidence source type

Most evidence for this condition derives from aggregated case series and systematic reviews (adult infertility presentations) plus single‑center pediatric cohorts for early/ambiguous genitalia presentations, and mechanistic inference from human genetics and animal models. (terribile201946xxtesticulardisorder pages 1-3, gong2025retrospectiveanalysisof pages 1-2, ferrari2024testiculardifferentiationin pages 2-4)

2. Etiology

2.1 Primary causal factors (genetic/mechanistic)

The disease is primarily genetic and arises from dysregulation of the early gonadal sex‑determination network, which can be conceptualized as competition between: - a pro‑testis pathway centered on SRY → SOX9 activation and reinforcement; and - a pro‑ovary/anti‑testis pathway centered on RSPO1/WNT4/β‑catenin (CTNNB1) and FOXL2. (ferrari2024testiculardifferentiationin pages 2-4, abalı2024diagnosisandmanagement pages 1-2)

A. SRY translocation (most common)

A large fraction of 46,XX testicular DSD is due to translocation of Y‑chromosomal material including SRY (typically to Xp or an autosome), which triggers testis determination despite an XX karyotype. Reviews commonly report ~80–90% SRY‑positive. (terribile201946xxtesticulardisorder pages 7-9, terribile201946xxtesticulardisorder pages 1-3)

Direct abstract quote (systematic review context): “The patients generally have normal external genitalia and discover their pathology in adulthood because of infertility… The sex-determining region Y (SRY) gene was detected in 51/57 cases.” (Terribile 2019, Medicina; published 2019-07; URL https://doi.org/10.3390/medicina55070371) (terribile201946xxtesticulardisorder pages 1-3)

B. SRY‑negative mechanisms (minority, heterogeneous)

SRY‑negative 46,XX testicular/ovotesticular DSD is attributed to (i) gain of function/overexpression of pro‑testis genes or (ii) loss of function of pro‑ovary/anti‑testis genes, though many cases remain unsolved. (ferrari2024testiculardifferentiationin pages 2-4, abalı2024diagnosisandmanagement pages 1-2)

Direct abstract quotes supporting these two broad categories: - “SRY-negative 46,XX males show overexpression of pro-testis genes, such as SOX9 and SOX3, or failure of pro-ovarian genes, such as WNT4 and RSPO1, which induces testis differentiation…” (Wei 2022, BMC Med Genomics; published 2022-09; URL https://doi.org/10.1186/s12920-022-01347-0) (wei2022duplicationofsox3 pages 1-3) - “Genes associated with 46,XX T/OT-DSD include translocations of the SRY; copy number variants in NR2F2, NR0B1, SOX3, SOX9, SOX10, and FGF9, and sequence variants in NR5A1, NR2F2, RSPO1, SOX9, WNT2B, WNT4, and WT1.” (Abalı & Guran 2024, Front Endocrinol; published 2024-05; URL https://doi.org/10.3389/fendo.2024.1354759) (abalı2024diagnosisandmanagement pages 1-2)

C. Copy-number variants / structural variation affecting SOX genes

SRY‑negative cases can result from structural variants affecting gene dosage/regulatory architecture of SOX genes (e.g., SOX3 duplication). A reported SRY‑negative case had a 1.4 Mb duplication involving SOX3, with a recommendation to screen SOX3 in SRY‑negative XX males. (wei2022duplicationofsox3 pages 1-3)

D. NR5A1 (SF‑1) recurrent variant as a molecular “switch”

A key non‑SRY mechanism is the recurrent NR5A1 p.Arg92Trp variant, which has been identified in multiple unrelated 46,XX (ovo)testicular DSD individuals after excluding SRY translocation and CNVs. (baetens2017nr5a1isa pages 1-2, bashamboo2016arecurrentp.arg92trp pages 1-3)

Direct abstract quote: “A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.” (Bashamboo 2016, Hum Mol Genet; published 2016-07; URL https://doi.org/10.1093/hmg/ddw186) (bashamboo2016arecurrentp.arg92trp pages 1-3)

Mechanistic interpretation from a Genetics in Medicine study: the variant is hypothesized to bias fate by “decreased inhibition of the male developmental pathway through downregulation of female antitestis genes,” tipping the balance toward testicular differentiation in 46,XX individuals. (Baetens 2017, Genet Med; published 2017-04; URL https://doi.org/10.1038/gim.2016.118) (baetens2017nr5a1isa pages 1-2)

2.2 Risk factors

Genetic risk factor: presence of SRY translocation or pathogenic variants/CNVs in the sex‑determination network genes noted above is causal rather than merely predisposing. (terribile201946xxtesticulardisorder pages 7-9, abalı2024diagnosisandmanagement pages 1-2)

Environmental risk factors: For 46,XX testicular DSD specifically, the dominant causes are genetic; exogenous androgen exposure more strongly pertains to other 46,XX DSD categories (e.g., CAH or maternal androgen exposure), rather than XX testicular differentiation. (abalı2024diagnosisandmanagement pages 1-2)

2.3 Protective factors / gene–environment interactions

No specific protective factors or gene–environment interactions are established for XX testicular DSD in the sources retrieved here.

3. Phenotypes

3.1 Core phenotype spectrum (with suggested HPO terms)

Phenotype is variable, ranging from typical male external genitalia to ambiguous genitalia, often with gonadal dysgenesis and infertility.

Commonly reported features include: - Azoospermia / infertility (HP:0000027 Azoospermia; HP:0000789 Infertility) (li201446xxtesticulardisorder pages 1-2, terribile201946xxtesticulardisorder pages 1-3) - Hypergonadotropic hypogonadism / primary testicular failure (HP:0000044 Hypogonadotropic hypogonadism is not appropriate; consider HP:0000044?; better: HP:0000035 Hypergonadotropic hypogonadism; HP:0000035; and lab: increased LH/FSH) (terribile201946xxtesticulardisorder pages 7-9, li201446xxtesticulardisorder pages 1-2) - Small testes / microorchidism (HP:0000028 Microorchidism; HP:0000007 Cryptorchidism) (terribile201946xxtesticulardisorder pages 7-9, li201446xxtesticulardisorder pages 1-2) - Hypospadias (HP:0000047 Hypospadias) (terribile201946xxtesticulardisorder pages 7-9, li201446xxtesticulardisorder pages 1-2) - Gynecomastia (HP:0000774 Gynecomastia) (terribile201946xxtesticulardisorder pages 7-9, li201446xxtesticulardisorder pages 1-2) - Residual Müllerian structures / prostatic utricle (subset, especially SRY-negative/undervirilized) (HP:0000132 Abnormality of uterus / persistent Müllerian structures; note this is phenotype-dependent) (wei2022duplicationofsox3 pages 1-3, terribile201946xxtesticulardisorder pages 9-11)

Direct abstract quote summarizing the common adult presentation pattern: “The patients generally have normal external genitalia and discover their pathology in adulthood because of infertility.” (Terribile 2019; URL https://doi.org/10.3390/medicina55070371) (terribile201946xxtesticulardisorder pages 1-3)

3.2 Age of onset and progression

  • Congenital onset at gonadal differentiation (fetal), but ascertainment is often later.
  • Ferrari et al. summarize that ~80% have typical male genitalia at birth with diagnosis often after puberty due to gynecomastia/hypogonadism/infertility. (ferrari2024testiculardifferentiationin pages 1-2)
  • A subset presents in infancy/childhood with ambiguous genitalia; in a pediatric cohort the median age at first presentation was 18 months. (gong2025retrospectiveanalysisof pages 1-2)

3.3 Frequency / statistics from published cohorts

From an adult systematic review (selected phenotypes across published cases): - cryptorchidism (~15%) and anterior hypospadias (~10%) were cited as non‑rare genital findings; hypergonadotropic hypogonadism was common. (terribile201946xxtesticulardisorder pages 7-9)

Pediatric single‑center cohort (46,XX testicular/ovotesticular DSD; n=52): - median age at presentation: 18 months - SRY in peripheral blood: 4/52; SRY in tissue (tested n=8): 0/8 - gonadal biopsy performed: 47/52; most frequent pathology: bilateral seminiferous tubules 17/47 - tumor marker: OCT3/4 positive 2/16 by immunohistochemistry; no tumors observed in biopsies - male‑reared adolescents: puberty onset ~12 ± 0.87 years; basal LH 6.44 ± 4.19 IU/L, FSH 13.18 ± 10.22 IU/L, testosterone 3.40 ± 1.63 nmol/L (gong2025retrospectiveanalysisof pages 1-2)

4. Genetic / molecular information

4.1 Causal genes and variant classes (evidence-based list)

Evidence-supported genes implicated in 46,XX testicular/ovotesticular DSD across the retrieved 2024 review literature include: - SRY (usually via translocation) (terribile201946xxtesticulardisorder pages 7-9, abalı2024diagnosisandmanagement pages 1-2) - NR5A1 (SF-1) sequence variants (notably p.Arg92Trp) (baetens2017nr5a1isa pages 1-2, bashamboo2016arecurrentp.arg92trp pages 1-3) - SOX9 / SOX3 / SOX10 CNVs/structural variants causing overexpression/positional effects (wei2022duplicationofsox3 pages 1-3, abalı2024diagnosisandmanagement pages 1-2) - RSPO1, WNT4 loss-of-function in the pro-ovary pathway (ferrari2024testiculardifferentiationin pages 2-4, abalı2024diagnosisandmanagement pages 1-2) - Other genes named in reviews: NR2F2, NR0B1, FGF9, WT1, WNT2B (abalı2024diagnosisandmanagement pages 1-2)

4.2 Mechanistic chain (current understanding)

A simplified causal chain: 1. Primary genetic change: (a) SRY translocation or (b) SRY-independent activation of SOX9 (via SOX gene dosage/NR5A1 changes) or (c) impaired ovarian-maintenance signaling (RSPO1/WNT4/β‑catenin/FOXL2). (ferrari2024testiculardifferentiationin pages 2-4, abalı2024diagnosisandmanagement pages 1-2, baetens2017nr5a1isa pages 1-2) 2. Cell fate shift in fetal bipotential gonad: increased Sertoli-lineage program (SOX9/FGF9/PGD2 reinforcement) and/or reduced granulosa/ovary program. (ferrari2024testiculardifferentiationin pages 2-4, hattori2023nuclearreceptorgene pages 1-3) 3. Testicular tissue differentiation (often dysgenetic) → androgen/AMH signaling patterns that shape internal/external genital development. 4. Postnatal outcomes: variable genital phenotype; progressive primary testicular failure leading to hypergonadotropic hypogonadism and infertility/azoospermia. (terribile201946xxtesticulardisorder pages 7-9, li201446xxtesticulardisorder pages 1-2)

4.3 Variant interpretation and “unknowns”

A substantial fraction of SRY-negative cases remain without a molecular diagnosis, suggesting unrecognized genetic/epigenetic mechanisms. Ferrari 2024 emphasizes that “a significant number of patients… have not yet recognized a genetic diagnosis.” (Ferrari 2024; URL https://doi.org/10.3389/fendo.2024.1385901) (ferrari2024testiculardifferentiationin pages 1-2)

5. Environmental information

Environmental causes are not a primary driver for 46,XX testicular DSD in the retrieved literature. Reviews of non‑CAH 46,XX DSD focus mainly on genetic etiologies and distinguish androgen‑excess disorders (CAH, aromatase deficiency, glucocorticoid resistance) from testicular/ovotesticular differentiation disorders. (abalı2024diagnosisandmanagement pages 1-2)

6. Mechanism / pathophysiology

6.1 Pathways (suggested pathway/ontology anchors)

Key antagonistic modules: - Pro-testis module: SRY → SOX9; reinforced by FGF9 and PGD2; includes NR5A1 as a core gonadal regulator. (ferrari2024testiculardifferentiationin pages 2-4, hattori2023nuclearreceptorgene pages 1-3) - Pro-ovary/anti-testis module: RSPO1/WNT4 → β‑catenin (CTNNB1); FOXL2 required for ovarian development/maintenance. (ferrari2024testiculardifferentiationin pages 2-4)

Suggested GO biological process terms (examples for knowledge base annotation): - GO:0007530 sex determination - GO:0007281 germ cell development - GO:0007548 sex differentiation - GO:0001701 in utero embryonic development

Suggested Cell Ontology (CL) terms: - CL:0000011 Sertoli cell - CL:0000178 Leydig cell - CL:0002338 granulosa cell

6.2 Tumor biology / surveillance markers

In a pediatric cohort (n=52), gonadal biopsy showed no tumors, but OCT3/4 positivity (a germ‑cell tumor risk marker) was observed in 2/16 tested by immunohistochemistry, suggesting the need for individualized tumor-risk assessment in some cases. (gong2025retrospectiveanalysisof pages 1-2)

7. Anatomical structures affected

7.1 Primary organs and structures

  • Gonads (testes/ovotestes, often dysgenetic) (UBERON:0000473 testis; UBERON:0000992 ovary—coexistence in OT‑DSD)
  • Internal genital tract may include variable Müllerian remnants (uterus/fallopian tubes) in some SRY-negative/ambiguous presentations. (terribile201946xxtesticulardisorder pages 9-11, wei2022duplicationofsox3 pages 1-3)
  • External genitalia range from typical male to ambiguous (hypospadias, micropenis). (terribile201946xxtesticulardisorder pages 7-9, gong2025retrospectiveanalysisof pages 1-2)

8. Temporal development (natural history)

While gonadal fate is determined prenatally, ascertainment is typically: - Adolescence/adulthood due to infertility/hypogonadism/gynecomastia in those with typical male genitalia. (terribile201946xxtesticulardisorder pages 1-3, ferrari2024testiculardifferentiationin pages 1-2) - Infancy/childhood in those with ambiguous genitalia/hypospadias/cryptorchidism. (gong2025retrospectiveanalysisof pages 1-2)

A typical trajectory includes progressive testicular dysfunction with hypergonadotropic hypogonadism and infertility/azoospermia. (terribile201946xxtesticulardisorder pages 7-9, li201446xxtesticulardisorder pages 1-2)

9. Inheritance and population

9.1 Epidemiology

  • Incidence is commonly cited as ~1:20,000–25,000 newborn males. (luo2026raresrynegative46xx pages 4-5, terribile201946xxtesticulardisorder pages 1-3, ferrari2024testiculardifferentiationin pages 1-2)
  • Ferrari 2024 further reports it accounts for ~2% of male infertility. (ferrari2024testiculardifferentiationin pages 1-2)

9.2 Inheritance pattern

Most SRY+ cases are typically sporadic de novo chromosomal rearrangements (SRY translocation during paternal meiosis) rather than classical Mendelian inheritance. (terribile201946xxtesticulardisorder pages 7-9)

Some SRY-negative genetic causes can follow Mendelian inheritance patterns depending on the gene (e.g., recessive RSPO1/WNT4-related syndromes versus de novo CNVs), but inheritance details vary by molecular diagnosis and were not comprehensively quantifiable from the retrieved excerpts. (abalı2024diagnosisandmanagement pages 14-14, abalı2024diagnosisandmanagement pages 1-2)

10. Diagnostics

10.1 Core diagnostic approach (real-world implementation)

Clinical and endocrine evaluation plus mandatory cytogenetic/genetic workup is standard: - Semen analysis and karyotype are emphasized as key initial tests in adults presenting with infertility. (terribile201946xxtesticulardisorder pages 9-11, terribile201946xxtesticulardisorder pages 1-3) - SRY detection via PCR and/or FISH is used to classify SRY+ vs SRY− cases and can guide downstream testing. (terribile201946xxtesticulardisorder pages 9-11, li201446xxtesticulardisorder pages 1-2) - Abdominal/pelvic ultrasound is used to evaluate for residual Müllerian structures. (terribile201946xxtesticulardisorder pages 9-11, terribile201946xxtesticulardisorder pages 1-3)

10.2 Recommended genetic testing workflow (DSD best practice)

A widely cited expert position paper (EU COST DSDnet) supports a stepwise approach: - “Ascertainment of the karyotpye defines one of the three major diagnostic DSD subclasses and is therefore the mandatory initial step.” (Audí 2018, Eur J Endocrinol; published 2018-10; URL https://doi.org/10.1530/eje-18-0256) (audı2018geneticsinendocrinology pages 1-6) - After karyotype: molecular testing for monogenic causes and/or CNVs; panels are increasingly used early; WES/WGS are transitioning into routine and also enable novel-gene discovery but require cautious interpretation. (audı2018geneticsinendocrinology pages 6-9, audı2018geneticsinendocrinology pages 1-6)

A newborn-focused review also emphasizes modern implementation choices: - targeted NGS gene panels for coverage/limited incidental findings; escalation to WES/WGS for complex cases; and that trio WES can increase diagnostic yield. (ibba2022differencesofsex pages 18-21)

10.3 Differential diagnosis

Key distinctions: - 46,XX DSD due to androgen excess (e.g., CAH) typically has normal ovarian development and differs mechanistically from XX testicular differentiation. (abalı2024diagnosisandmanagement pages 1-2) - Ovotesticular DSD (46,XX OT‑DSD) overlaps substantially and may be part of the same mechanistic spectrum; Ferrari 2024 cites OT‑DSD as rare (~1:100,000 births) and most often 46,XX (65–90%). (ferrari2024testiculardifferentiationin pages 2-4)

11. Outcome / prognosis

11.1 Survival and mortality

No disease-specific mortality signal is emphasized in the retrieved excerpts; the major morbidity is reproductive/endocrine.

11.2 Morbidity and functional outcomes

  • Fertility: azoospermia is common; fertility is typically severely impaired. (li201446xxtesticulardisorder pages 1-2, terribile201946xxtesticulardisorder pages 1-3)
  • Endocrine: progressive testicular failure and hypergonadotropic hypogonadism are common, requiring monitoring and sometimes hormone therapy. (terribile201946xxtesticulardisorder pages 7-9, gong2025retrospectiveanalysisof pages 1-2)
  • Psychosocial/quality of life: DSD care guidelines emphasize multidisciplinary management, but validated QoL measures specific to 46,XX T‑DSD were not extractable from the retrieved sources.

12. Treatment

12.1 Management principles (current practice)

There are no disease‑modifying molecular therapies in routine clinical care; management is supportive and individualized.

Infertility counseling / assisted reproduction: - “Testicular sperm extraction is not recommended, and adoption or in vitro fertilization with a sperm donor are fertility options.” (Terribile 2019; URL https://doi.org/10.3390/medicina55070371) (terribile201946xxtesticulardisorder pages 7-9)

Endocrine management: - monitor for puberty/testosterone insufficiency and hypergonadotropic hypogonadism; in pediatric cohorts, early gonadectomy in female-reared children prevents spontaneous puberty and can necessitate sex-hormone replacement planning. (gong2025retrospectiveanalysisof pages 1-2)

Surgical management (when indicated): - repair of hypospadias/cryptorchidism; management of Müllerian remnants/prostatic utricle in specific anatomic presentations; endoscopic evaluation was recommended preoperatively for detecting prostatic utricle in SRY‑negative cases. (wei2022duplicationofsox3 pages 1-3)

Tumor-risk assessment: - individualized; pediatric series found no tumors on biopsy but OCT3/4 positivity in a minority. (gong2025retrospectiveanalysisof pages 1-2)

Suggested MAXO terms (examples for knowledge base mapping): - MAXO:0000058 hormone replacement therapy - MAXO:0001176 genetic counseling - MAXO:0001020 orchidopexy - MAXO:0001095 hypospadias repair - MAXO:0000931 gonadectomy (select cases)

12.2 Clinical trials

A clinicaltrials.gov search identified no interventional trials specifically targeting 46,XX testicular DSD; retrieved trials were not disease‑specific (e.g., decision-support for parents of children with rare disease). (NCT01875640 retrieved, but not specific to 46,XX T‑DSD; tool output)

13. Prevention

Primary prevention is not currently feasible for most cases because many are de novo chromosomal rearrangements. Secondary/tertiary prevention focuses on: - early recognition of ambiguous genitalia presentations; - timely genetic diagnosis to guide anticipatory endocrine follow-up and fertility counseling. (audı2018geneticsinendocrinology pages 6-9, audı2018geneticsinendocrinology pages 1-6)

14. Other species / natural disease

A naturally occurring XX DSD subtype exists in dogs that is phenotypically similar to the human SRY‑negative XX DSD spectrum. In one study: - “This is a naturally occurring disorder in humans (Homo sapiens) and dogs (C. familiaris). Phenotypes in the canine XX DSD model are strikingly similar to those of the human XX DSD subtype.” (Meyers‑Wallen 2017, PLoS ONE; published 2017-10; URL https://doi.org/10.1371/journal.pone.0186331) ()

The same study identified a variant upstream of SOX9 and found embryonic gonads had RSPO1 downregulation, proposing upstream lesions causing “epigenomic gonadal mosaicism.” ()

(Note: was introduced via paper_search results but not previously listed in gathered evidence; therefore it is not citable unless present in context IDs. It is not in the citable list above, so it is not used further.)

15. Model organisms

Ferrari 2024 anchors gene-network understanding using mammalian developmental genetics, describing early gonadal ridge formation genes and downstream testis/ovary antagonism. (ferrari2024testiculardifferentiationin pages 2-4)

Beyond descriptive models, the canine XX DSD model provides a naturally occurring system to study SRY‑negative XX testicular/ovotesticular development and the RSPO1/WNT axis. (; not citable here, see note above)

Summary table

The following table provides a compact synthesis of key facts (names, incidence, SRY distribution, presentation, and management).

Item Evidence-based details Key sources (pqac ids)
Disease names / synonyms 46,XX testicular disorder of sex development; 46,XX testicular DSD; 46,XX male syndrome; XX male syndrome; 46,XX testicular difference of sex development (li201446xxtesticulardisorder pages 1-2, terribile201946xxtesticulardisorder pages 1-3, grinspon2016disordersofsex pages 1-2)
Epidemiology Rare condition with reported incidence about 1:20,000-25,000 male newborns; estimated to account for ~2% of male infertility. A pediatric testicular/ovotesticular DSD series cited ~1:100,000 births for the broader childhood TDSD/OTDSD grouping (luo2026raresrynegative46xx pages 4-5, terribile201946xxtesticulardisorder pages 1-3, ferrari2024testiculardifferentiationin pages 1-2, gong2025retrospectiveanalysisof pages 1-2)
SRY-positive vs SRY-negative Literature commonly reports ~80-90% SRY-positive and ~10-20% SRY-negative among 46,XX testicular DSD cases. In one systematic review, SRY was detected in 51/57 cases, usually on Xp. In a pediatric 52-case TDSD/OTDSD series, SRY-negative cases predominated; only 4/52 had SRY in peripheral blood and 0/8 tissue samples were SRY-positive (terribile201946xxtesticulardisorder pages 7-9, li201446xxtesticulardisorder pages 1-2, terribile201946xxtesticulardisorder pages 1-3, gong2025retrospectiveanalysisof pages 1-2, wei2022duplicationofsox3 pages 1-3)
Typical age / presentation About 80-90% have typical male external genitalia at birth and are often diagnosed after puberty or in adulthood during infertility workup, hypogonadism, or gynecomastia evaluation. A minority (~15%) present at birth/childhood with ambiguous genitalia, hypospadias, cryptorchidism, or micropenis. In the pediatric single-center cohort, median age at first presentation was 18 months (terribile201946xxtesticulardisorder pages 7-9, terribile201946xxtesticulardisorder pages 1-3, barseghyan2017identificationofgenetic pages 21-26, gong2025retrospectiveanalysisof pages 1-2, ferrari2024testiculardifferentiationin pages 1-2)
Typical phenotype Common findings include normal male phenotype or variable undervirilization, small testes/microorchidism, azoospermia/infertility, hypergonadotropic hypogonadism, gynecomastia, cryptorchidism, hypospadias, and occasionally residual Müllerian structures or prostatic utricle in SRY-negative cases (terribile201946xxtesticulardisorder pages 7-9, li201446xxtesticulardisorder pages 1-2, terribile201946xxtesticulardisorder pages 1-3, wei2022duplicationofsox3 pages 1-3)
Key management pearls Recommended evaluation includes careful genital exam, semen analysis, endocrine testing, karyotype, SRY testing by PCR/FISH, and abdominal ultrasound to assess Müllerian remnants; gonadal biopsy may help define gonadal tissue in selected SRY-negative cases. Genetic/endocrine consultation is recommended. TESE is generally not recommended; fertility options include donor-sperm IVF or adoption. Long-term follow-up should monitor pubertal progression, testicular failure/hypergonadotropic hypogonadism, tumor-risk markers, and individualized gender/psychosocial outcomes (terribile201946xxtesticulardisorder pages 9-11, terribile201946xxtesticulardisorder pages 1-3, wei2022duplicationofsox3 pages 1-3, gong2025retrospectiveanalysisof pages 1-2, audı2018geneticsinendocrinology pages 1-6)

Table: This table provides a compact evidence-based summary of names, epidemiology, SRY status distribution, presentation patterns, and practical management points for 46,XX testicular DSD. It is useful as a quick reference before the full narrative report.

Recent developments (prioritizing 2023–2024)

  1. 2024 synthesis of genetic causes: Ferrari et al. (Frontiers in Endocrinology, 2024-04, https://doi.org/10.3389/fendo.2024.1385901) consolidates known genetic mechanisms and emphasizes that many cases remain genetically unresolved; it also provides epidemiologic and presentation statistics (incidence ~1:20,000–1:25,000; ~2% of male infertility; typical male genitalia at birth with later diagnosis). (ferrari2024testiculardifferentiationin pages 1-2, ferrari2024testiculardifferentiationin pages 2-4)

  2. 2024 clinical perspective on non‑CAH 46,XX DSD: Abalı & Guran (Frontiers in Endocrinology, 2024-05, https://doi.org/10.3389/fendo.2024.1354759) provides an updated gene list spanning CNVs and sequence variants implicated in 46,XX testicular/ovotesticular DSD and highlights management uncertainty around gonadal function and gender outcomes. (abalı2024diagnosisandmanagement pages 1-2)

  3. 2023 focus on nuclear receptor genes and phenotypic variability: Hattori & Fukami (Biomolecules, 2023-04, https://doi.org/10.3390/biom13040691) situates NR5A1/NR0B1/NR2F2 as key nuclear receptor genes in atypical testicular development and explicitly notes NR5A1 variants in both 46,XY and 46,XX testicular/ovotesticular DSD, with possible oligogenic contributions. (hattori2023nuclearreceptorgene pages 1-3)

Limitations of this run

  • Formal mappings to OMIM/Orphanet/MONDO/ICD/MeSH identifiers could not be provided with tool-citable evidence.
  • Some additional potentially relevant papers were discovered by search but not fully retrieved/validated for citation in this run.

References

  1. (terribile201946xxtesticulardisorder pages 1-3): Marco Terribile, Marco Stizzo, Celeste Manfredi, Carmelo Quattrone, Francesco Bottone, Dario Ranieri Giordano, Giuseppe Bellastella, Davide Arcaniolo, and Marco De Sio. 46,xx testicular disorder of sex development (dsd): a case report and systematic review. Medicina, 55:371, Jul 2019. URL: https://doi.org/10.3390/medicina55070371, doi:10.3390/medicina55070371. This article has 81 citations.

  2. (ferrari2024testiculardifferentiationin pages 1-2): Maria Tereza Martins Ferrari, Elinaelma Suelane do Nascimento Silva, Mirian Yumie Nishi, Rafael Loch Batista, Berenice Bilharinho Mendonca, and Sorahia Domenice. Testicular differentiation in 46,xx dsd: an overview of genetic causes. Frontiers in Endocrinology, Apr 2024. URL: https://doi.org/10.3389/fendo.2024.1385901, doi:10.3389/fendo.2024.1385901. This article has 20 citations.

  3. (li201446xxtesticulardisorder pages 1-2): Tian-Fu Li, Qiu-Yue Wu, Cui Zhang, Wei-Wei Li, Qing Zhou, Wei-Jun Jiang, Ying-Xia Cui, Xin-Yi Xia, and Yi-Chao Shi. 46,xx testicular disorder of sexual development with sry-negative caused by some unidentified mechanisms: a case report and review of the literature. BMC Urology, Dec 2014. URL: https://doi.org/10.1186/1471-2490-14-104, doi:10.1186/1471-2490-14-104. This article has 46 citations and is from a peer-reviewed journal.

  4. (gong2025retrospectiveanalysisof pages 1-2): Yan Gong, Xiaoqin Yin, Jing Xu, Yan Li, Qingxu Liu, Shasha Zhou, Fei Wang, Yiqing Lyu, Sheng Guo, Wenyan Huang, and Pin Li. Retrospective analysis of children with 46,xx testicular/ovotesticular dsd: a 10-year single-center experience. Frontiers in Endocrinology, May 2025. URL: https://doi.org/10.3389/fendo.2025.1571467, doi:10.3389/fendo.2025.1571467. This article has 2 citations.

  5. (ferrari2024testiculardifferentiationin pages 2-4): Maria Tereza Martins Ferrari, Elinaelma Suelane do Nascimento Silva, Mirian Yumie Nishi, Rafael Loch Batista, Berenice Bilharinho Mendonca, and Sorahia Domenice. Testicular differentiation in 46,xx dsd: an overview of genetic causes. Frontiers in Endocrinology, Apr 2024. URL: https://doi.org/10.3389/fendo.2024.1385901, doi:10.3389/fendo.2024.1385901. This article has 20 citations.

  6. (abalı2024diagnosisandmanagement pages 1-2): Zehra Yavas Abalı and Tulay Guran. Diagnosis and management of non-cah 46,xx disorders/differences in sex development. Frontiers in Endocrinology, May 2024. URL: https://doi.org/10.3389/fendo.2024.1354759, doi:10.3389/fendo.2024.1354759. This article has 11 citations.

  7. (terribile201946xxtesticulardisorder pages 7-9): Marco Terribile, Marco Stizzo, Celeste Manfredi, Carmelo Quattrone, Francesco Bottone, Dario Ranieri Giordano, Giuseppe Bellastella, Davide Arcaniolo, and Marco De Sio. 46,xx testicular disorder of sex development (dsd): a case report and systematic review. Medicina, 55:371, Jul 2019. URL: https://doi.org/10.3390/medicina55070371, doi:10.3390/medicina55070371. This article has 81 citations.

  8. (wei2022duplicationofsox3 pages 1-3): Jiansheng Wei, Changrong Liu, Minyan Zhang, Shen Liu, Junjie Fu, and Peng Lin. Duplication of sox3 in an sry-negative 46,xx male with prostatic utricle: case report and literature review. BMC Medical Genomics, Sep 2022. URL: https://doi.org/10.1186/s12920-022-01347-0, doi:10.1186/s12920-022-01347-0. This article has 19 citations and is from a peer-reviewed journal.

  9. (baetens2017nr5a1isa pages 1-2): Dorien Baetens, Hans Stoop, Frank Peelman, Anne-Laure Todeschini, Toon Rosseel, Frauke Coppieters, Reiner A. Veitia, Leendert H.J. Looijenga, Elfride De Baere, and Martine Cools. Nr5a1 is a novel disease gene for 46,xx testicular and ovotesticular disorders of sex development. Genetics in Medicine, 19:367-376, Apr 2017. URL: https://doi.org/10.1038/gim.2016.118, doi:10.1038/gim.2016.118. This article has 152 citations and is from a highest quality peer-reviewed journal.

  10. (bashamboo2016arecurrentp.arg92trp pages 1-3): Anu Bashamboo, Patricia A. Donohoue, Eric Vilain, Sandra Rojo, Pierre Calvel, Sumudu N. Seneviratne, Federica Buonocore, Hayk Barseghyan, Nathan Bingham, Jill A. Rosenfeld, Surya Narayan Mulukutla, Mahim Jain, Lindsay Burrage, Shweta Dhar, Ashok Balasubramanyam, Brendan Lee, Marie-Charlotte Dumargne, Caroline Eozenou, Jenifer P. Suntharalingham, KSH de Silva, Lin Lin, Joelle Bignon-Topalovic, Francis Poulat, Carlos F. Lagos, Ken McElreavey, and John C. Achermann. A recurrent p.arg92trp variant in steroidogenic factor-1 (nr5a1) can act as a molecular switch in human sex development. Human Molecular Genetics, 25:3446-3453, Jul 2016. URL: https://doi.org/10.1093/hmg/ddw186, doi:10.1093/hmg/ddw186. This article has 152 citations and is from a domain leading peer-reviewed journal.

  11. (terribile201946xxtesticulardisorder pages 9-11): Marco Terribile, Marco Stizzo, Celeste Manfredi, Carmelo Quattrone, Francesco Bottone, Dario Ranieri Giordano, Giuseppe Bellastella, Davide Arcaniolo, and Marco De Sio. 46,xx testicular disorder of sex development (dsd): a case report and systematic review. Medicina, 55:371, Jul 2019. URL: https://doi.org/10.3390/medicina55070371, doi:10.3390/medicina55070371. This article has 81 citations.

  12. (hattori2023nuclearreceptorgene pages 1-3): Atsushi Hattori and Maki Fukami. Nuclear receptor gene variants underlying disorders/differences of sex development through abnormal testicular development. Biomolecules, 13:691, Apr 2023. URL: https://doi.org/10.3390/biom13040691, doi:10.3390/biom13040691. This article has 11 citations.

  13. (luo2026raresrynegative46xx pages 4-5): Jianxu Luo, Fuxin Huang, Jianlin Li, Enhao Mo, Hu Wang, Jianyong Zhang, Caifeng Pang, Dezheng Lei, and Jiabo Chen. Rare sry-negative 46,xx disorder of sex development with male phenotype and ectopic gonads: a case report. Frontiers in Endocrinology, Apr 2026. URL: https://doi.org/10.3389/fendo.2026.1829751, doi:10.3389/fendo.2026.1829751. This article has 0 citations.

  14. (abalı2024diagnosisandmanagement pages 14-14): Zehra Yavas Abalı and Tulay Guran. Diagnosis and management of non-cah 46,xx disorders/differences in sex development. Frontiers in Endocrinology, May 2024. URL: https://doi.org/10.3389/fendo.2024.1354759, doi:10.3389/fendo.2024.1354759. This article has 11 citations.

  15. (audı2018geneticsinendocrinology pages 1-6): L. Audı́, S. Ahmed, N. Krone, M. Cools, K. McElreavey, P. Holterhus, A. Greenfield, A. Bashamboo, O. Hiort, S. Wudy, and R. McGowan. Genetics in endocrinology: approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (dsd): position paper of eu cost action bm 1303 ‘dsdnet’. European Journal of Endocrinology, 179:R197-R206, Oct 2018. URL: https://doi.org/10.1530/eje-18-0256, doi:10.1530/eje-18-0256. This article has 140 citations and is from a highest quality peer-reviewed journal.

  16. (audı2018geneticsinendocrinology pages 6-9): L. Audı́, S. Ahmed, N. Krone, M. Cools, K. McElreavey, P. Holterhus, A. Greenfield, A. Bashamboo, O. Hiort, S. Wudy, and R. McGowan. Genetics in endocrinology: approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (dsd): position paper of eu cost action bm 1303 ‘dsdnet’. European Journal of Endocrinology, 179:R197-R206, Oct 2018. URL: https://doi.org/10.1530/eje-18-0256, doi:10.1530/eje-18-0256. This article has 140 citations and is from a highest quality peer-reviewed journal.

  17. (ibba2022differencesofsex pages 18-21): Anastasia IBBA, Marta DEL PISTOIA, Antonio BALSAMO, Federico BARONIO, Donatella CAPALBO, Gianni RUSSO, Luisa DE SANCTIS, and Carla BIZZARRI. Differences of sex development in the newborn: from clinical scenario to molecular diagnosis. Jan 2022. URL: https://doi.org/10.23736/s2724-5276.21.06512-5, doi:10.23736/s2724-5276.21.06512-5. This article has 8 citations.

  18. (grinspon2016disordersofsex pages 1-2): Romina P. Grinspon and Rodolfo A. Rey. Disorders of sex development with testicular differentiation in sry-negative 46,xx individuals: clinical and genetic aspects. Sexual Development, 10:1-11, Apr 2016. URL: https://doi.org/10.1159/000445088, doi:10.1159/000445088. This article has 110 citations and is from a peer-reviewed journal.

  19. (barseghyan2017identificationofgenetic pages 21-26): H Barseghyan. Identification of genetic etiology in disorders of sex development. Unknown journal, 2017.

Artifacts

46,XX Testicular DSD Deep Research Fallback ▸

46,XX Testicular DSD Deep Research Fallback

Provider Attempts

  • 2026-05-08T15:00Z: just research-disorder asta 46_XX_Testicular_DSD failed: ERROR - No research providers available. Please set API keys (no ASTA_API_KEY configured in this environment).
  • 2026-05-08T15:00Z: just research-disorder openai 46_XX_Testicular_DSD failed with the same provider-unavailable error (no OPENAI_API_KEY).
  • 2026-05-08T15:00Z: just research-disorder perplexity 46_XX_Testicular_DSD failed with the same provider-unavailable error (no PERPLEXITY_API_KEY).
  • 2026-05-08T15:00Z: just research-disorder falcon 46_XX_Testicular_DSD failed with the same provider-unavailable error (no provider keys at all, including Edison/Falcon).

just research-providers confirmed no providers are configured in this worktree. No provider-generated research artifact was available to integrate. Curation therefore proceeded from the PubMed-cached abstracts already referenced in kb/disorders/46_XX_Testicular_DSD.yaml, without hand-editing any references_cache/*.md files.

Evidence Scope Used For Curation

  • PMID:31336995 (Terribile et al. 2019, Medicina) — case report + systematic review of 46,XX testicular DSD. Used as the canonical clinical-presentation reference: SRY-positive vs SRY-negative classification, adult presentation with infertility, hypergonadotropic hypogonadism, gynecomastia, small testes, cryptorchidism (~15%) and anterior hypospadias (~10%), and the rationale for long-term testosterone replacement.
  • PMID:36341017 (Kouvidi et al. 2022) — two new cases plus literature review cohort. Used for SRY-translocation epidemiology (84.4% SRY-positive, 98.5% Xp), absence of AZF regions, and quantitative phenotype frequencies in the cohort: small testes (90.2%), small penis (31.8%), gynecomastia (26.8%), poor hair distribution (15.4%). The "small penis (31.8%)" figure is the source for the new Micropenis (HP:0000054) phenotype entry.
  • PMID:25077096 (Lee et al. 2014, Ann Pediatr Endocrinol Metab) — Korean boy with 46,XX testicular DSD caused by SOX9 duplication. Supports the SRY-negative SOX9 gain-of-function mechanism in which duplications upstream of SOX9 drive ectopic testis determination in 46,XX gonads.
  • PMID:34050715 (Qian et al. 2021) — whole-genome sequencing of an SRY-negative 46,XX ovotesticular DSD case identifying a cryptic SOX9 regulatory-element duplication. Reinforces the SOX9 enhancer-duplication mechanism and shows how cryptic non-coding variants can be missed by standard cytogenetics.
  • PMID:36064700 (Wei et al. 2022) — SRY-negative 46,XX male with SOX3 duplication and prostatic utricle. Supports SOX3 duplication as an alternative SRY-independent driver of testis determination, expanding the set of SRY-negative genetic etiologies beyond SOX9.
  • PMID:29575617 (Tallapaka et al. 2018, Am J Med Genet A) — novel RSPO1 mutation causing SRY-negative 46,XX testicular DSD with palmoplantar keratoderma. Defines the RSPO1-associated subtype and establishes palmoplantar hyperkeratosis as the pathognomonic extra-gonadal feature that clinically distinguishes RSPO1 cases from other SRY-negative etiologies.

Curation Conclusions

46,XX testicular disorder of sex development is a sex-reversal phenotype in which 46,XX gonads commit to the testis pathway despite the absence of a typical Y chromosome. Two broad mechanistic classes account for nearly all cases. In SRY-positive 46,XX testicular DSD (~85% of patients), aberrant paternal-meiosis recombination translocates SRY onto the X chromosome (most commonly Xp22), with rare autosomal landings; the translocated SRY drives Sertoli-cell specification and the canonical SOX9-mediated testis cascade, producing essentially complete masculinization at birth and an adult presentation dominated by hypergonadotropic hypogonadism, azoospermia, and infertility. In SRY-negative 46,XX testicular DSD, testis determination is driven by genetic perturbations that bypass SRY: gain-of-function copy-number gains around SOX9 (including cryptic enhancer duplications detectable only by whole-genome sequencing), SOX3 duplications that act as ectopic SRY-like inducers, and biallelic loss of RSPO1 that disrupts the WNT/RSPO1/CTNNB1 ovarian-determining program and permits default testis differentiation. The RSPO1 subtype is uniquely identifiable by palmoplantar keratoderma — the clinically distinguishing extra-gonadal feature.

Regardless of upstream genetic mechanism, the downstream gonadal pathology converges on dysgenetic testes lacking germ-cell development. Loss of the AZF regions on Yq and absence of normal seminiferous tubule architecture result in azoospermia in essentially all affected individuals; testicular sperm extraction is generally unsuccessful. Sertoli-cell and Leydig-cell function is partially preserved in childhood (giving rise to externally masculine genitalia and pubertal initiation), but post-pubertal Leydig-cell insufficiency manifests as low testosterone with elevated LH/FSH — hypergonadotropic hypogonadism — driving the adult clinical phenotype: small testes (~90% of patients), small penis (~32%), gynecomastia (~27%), sparse body hair (~15%), reduced bone mineral density, and infertility. SRY-negative cases more commonly show ambiguous or undermasculinized external genitalia at birth (hypospadias, cryptorchidism), reflecting attenuated fetal androgen production, and may present in childhood rather than adulthood.

Treatment is supportive and lifelong. Long-term testosterone replacement (captured here as MAXO:0000058 pharmacotherapy with CHEBI:17347 testosterone as the therapeutic agent) addresses hypogonadism, supports secondary sexual characteristics, and protects bone health. Genetic counseling addresses the rare familial recurrence risk (notably for RSPO1 biallelic families and inherited SOX3/SOX9 CNVs) and the reproductive limitations. Assisted-reproduction options are restricted to donor sperm with intrauterine insemination or IVF, since affected individuals are azoospermic. Surgical correction is appropriate for hypospadias and cryptorchidism in SRY-negative presentations.