46,XX testicular disorder of sex development

Mendelian MONDO:0100249 Pathograph 10 Disorder of sex development Gonadal development disorder Male infertility disorder

46,XX testicular disorder of sex development (also known as XX male syndrome or 46,XX male sex reversal) is a rare disorder of sex development in which individuals with a 46,XX karyotype develop testicular tissue and a male phenotype. The shared disease mechanism is inappropriate activation of the testis-determination pathway in a chromosomally female (46,XX) gonad. In approximately 80% of cases this is driven by translocation of the SRY gene onto the X chromosome (most often Xp) or, rarely, onto an autosome. SRY-negative cases (around 20%) involve gain-of-function lesions of pro-testis genes (notably SOX9 or SOX3 duplications) or loss-of-function variants in pro-ovarian genes (RSPO1, with biallelic NR5A1 dysregulation also contributing in some cases). Affected individuals typically present in adulthood with primary infertility, small testes, azoospermia, gynecomastia, and hypergonadotropic hypogonadism; SRY-negative cases more often present in childhood with ambiguous genitalia. This entry is mechanistically distinct from 46,XX gonadal dysgenesis (streak gonads, female phenotype, ovarian failure).

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1
Mappings
6
Pathophys.
10
Phenotypes
10
Pathograph
5
Genes
3
Treatments
2
Subtypes
3
Differentials
1
Deep Research
🔗

Mappings

MONDO
MONDO:0100249 46,XX testicular disorder of sex development
skos:exactMatch MONDO
Primary MONDO disease identifier for 46,XX testicular disorder of sex development.
◆

Subtypes

2
SRY-positive 46,XX testicular DSD
Most common form (approximately 80% of cases) caused by translocation of the SRY gene from the Y chromosome onto the X chromosome (typically Xp) or rarely onto an autosome. Patients usually have normal external male genitalia and present in adulthood with infertility, azoospermia, small testes, and gynecomastia.
SRY-negative 46,XX testicular DSD
Approximately 20% of cases. Testis differentiation occurs without SRY, typically driven by ectopic activation or duplication of pro-testis genes (SOX9, SOX3) or loss-of-function in pro-ovarian regulators (RSPO1). Patients more often present in childhood with ambiguous external genitalia, cryptorchidism, hypospadias, or ovotesticular tissue.
⚙

Pathophysiology

6
Inappropriate activation of testis determination in 46,XX gonad
The shared proximal disease mechanism is activation of the male testis-determination cascade in a chromosomally female (46,XX) gonad, diverting bipotential gonadal precursors toward testicular rather than ovarian differentiation. In SRY-positive cases this is driven by ectopic SRY transferred onto an X chromosome or autosome; in SRY-negative cases pro-testis genes (SOX9, SOX3) are inappropriately overexpressed or pro-ovarian genes (RSPO1) lose function.
Sertoli cell precursor link
sex determination link male gonad development link ↑ INCREASED
Downstream
Dysgenetic testis differentiation Activation of testis-determination programs in 46,XX gonadal tissue produces testicular but typically dysgenetic gonads with abnormal seminiferous tubule architecture and absent germ cells.
Show evidence (2 references)
PMID:31336995 SUPPORT Human Clinical
"The SRY gene is identified as the main gene regulating the testes determination cascade. The most important role of SRY is to regulate the SOX9 expression in Sertoli cell precursors. This pathway, in turn, activates testis-specific genes leading to testis determination"
This directly supports inappropriate activation of the SRY/SOX9 testis determination cascade in Sertoli cell precursors as the proximal mechanism in 46,XX testicular DSD.
PMID:36064700 SUPPORT Human Clinical
"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"
This explicitly supports overexpression of pro-testis genes (SOX9, SOX3) or loss of pro-ovarian genes as the mechanism in SRY-negative cases.
SRY translocation onto an X chromosome
The pathognomonic genetic lesion in SRY-positive 46,XX testicular DSD is a Y-to-X translocation during paternal meiosis, producing an X chromosome that carries SRY. The translocated SRY drives the testis determination cascade despite the otherwise female chromosomal complement.
SRY link
Downstream
Inappropriate activation of testis determination in 46,XX gonad Ectopic SRY translocated onto an X chromosome (or rarely an autosome) drives the testis-determination cascade in the otherwise 46,XX gonad, producing the inappropriate activation of male sex determination that is the proximal disease mechanism in SRY-positive cases.
Show evidence (2 references)
PMID:31336995 SUPPORT Human Clinical
"Various studies indicated that 80–90% of 46,XX males result from a Y to X translocation during meiosis"
This supports SRY translocation onto the X chromosome as the dominant causal lesion in SRY-positive 46,XX testicular DSD.
PMID:36341017 SUPPORT Human Clinical
"The presence of the SRY was identified in 130/154 (84.4%) patients: in 98.5% of cases, it was translocated on the Xp chromosome and in 1.5% on an autosome."
This quantifies the dominance of Xp-translocated SRY across a large review cohort.
SOX9 or SOX3 dysregulation in SRY-negative cases
In SRY-negative 46,XX testicular DSD, gain-of-function lesions in pro-testis genes substitute for SRY. Duplications of SOX9 (or its RevSex upstream regulatory element) and ectopic activation of SOX3 (an X-linked SRY paralog) drive testis determination in the absence of SRY.
SOX9 link SOX3 link
Downstream
Inappropriate activation of testis determination in 46,XX gonad Gain-of-function dysregulation of pro-testis genes (SOX9 duplication or its RevSex enhancer, ectopic SOX3) substitutes for SRY and triggers the testis-determination cascade in 46,XX gonadal precursors, producing the inappropriate male sex-determination program that defines the SRY-negative subtype.
Show evidence (3 references)
PMID:25077096 SUPPORT Human Clinical
"overexpression of SOX9 leads to the male development of 46,XX gonads in the absence of SRY"
This directly supports SOX9 overexpression as a sufficient driver of testis differentiation in SRY-negative 46,XX testicular DSD.
PMID:34050715 SUPPORT Human Clinical
"whole genome sequencing reported a pathogenic duplication in a non-coding region that contains the RevSex regulatory element, which modifies SOX9 expression and is associated with 46,XX OT-DSD and complete sex reversal"
This identifies cryptic non-coding duplications of the SOX9 RevSex enhancer as a mechanism in SRY-negative cases.
PMID:36064700 SUPPORT Human Clinical
"SOX3 duplication may cause sex reversal, and all 46,XX SRY-negative males should be screened for SOX3 mutations."
This supports SOX3 duplication as a recognized cause of SRY-negative 46,XX testicular DSD.
RSPO1-dependent canonical beta-catenin pro-ovarian signaling loss
In the rare autosomal recessive RSPO1-associated subset of SRY-negative 46,XX testicular DSD, biallelic RSPO1 loss of function reduces canonical beta-catenin signaling that normally promotes female gonadal differentiation. Loss of this pro-ovarian signal permits the 46,XX gonad to enter the testis-determination program.
RSPO1 link
canonical Wnt signaling pathway link ↓ DECREASED female gonad development link ↓ DECREASED
Downstream
Inappropriate activation of testis determination in 46,XX gonad Loss of RSPO1-dependent canonical beta-catenin pro-ovarian signaling removes a female-gonad-determining input, allowing testis differentiation in the 46,XX gonad.
Show evidence (1 reference)
PMID:29575617 SUPPORT Human Clinical
"RSPO1 acts by activating the canonical β-catenin pathway and is one of the most important genes controlling female gonadal differentiation."
This directly supports RSPO1 as an activator of canonical beta-catenin signaling required for female gonadal differentiation.
Dysgenetic testis differentiation
Although ectopic testis-determination signals successfully divert the 46,XX gonad toward testicular development, the absence of the full Y chromosome (and AZF spermatogenesis loci) leaves the resulting testis architecturally abnormal, with progressive loss of germ cells and Sertoli-cell-only seminiferous tubules in the adult.
Sertoli cell link germ cell link
spermatogenesis link ∅ ABSENT
Downstream
Hypergonadotropic hypogonadism and gynecomastia Dysgenetic testes produce inadequate testosterone and inhibin, leading to compensatory pituitary gonadotropin elevation and a relative imbalance that promotes gynecomastia at puberty.
Show evidence (1 reference)
PMID:36341017 SUPPORT Human Clinical
"All patients were azoospermic, due to the lack of AZF genetic regions."
This directly links absence of AZF spermatogenesis loci to azoospermia in 46,XX testicular DSD.
Hypergonadotropic hypogonadism and gynecomastia
Compromised testicular steroidogenesis lowers serum testosterone, removes feedback inhibition on the hypothalamic-pituitary axis, and elevates LH and FSH. The relative estrogen excess at puberty contributes to gynecomastia, while inadequate androgen drives small testes, sparse body hair, and reduced fertility.
Leydig cell link
steroid hormone biosynthetic process link ↓ DECREASED
Show evidence (1 reference)
PMID:36341017 SUPPORT Human Clinical
"All patients included in the review presented hypergonadotropic hypogonadism."
This directly supports hypergonadotropic hypogonadism as the universal endocrine pattern in 46,XX testicular DSD.
⬡

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

10
Breast 1
Gynecomastia Gynecomastia (HP:0000771)
Show evidence (1 reference)
PMID:36341017 SUPPORT Human Clinical
"Small testes were the most common clinical characteristic present in 90.2% of the patients, followed by small penis (31.8%), gynecomastia (26.8%) and poor hair distribution (15.4%)."
This documents gynecomastia as a recognized clinical feature, present in roughly a quarter of patients.
Endocrine 1
Hypergonadotropic Hypogonadism Hypergonadotropic hypogonadism (HP:0000815)
Show evidence (1 reference)
PMID:36341017 SUPPORT Human Clinical
"All patients included in the review presented hypergonadotropic hypogonadism."
This directly supports universal hypergonadotropic hypogonadism as a defining endocrine feature.
Genitourinary 6
Azoospermia Azoospermia (HP:0000027)
Show evidence (1 reference)
PMID:36341017 SUPPORT Human Clinical
"All patients were azoospermic, due to the lack of AZF genetic regions."
This directly supports azoospermia as a uniform finding in 46,XX testicular DSD.
Decreased Testicular Size Decreased testicular size (HP:0008734)
Show evidence (1 reference)
PMID:36341017 SUPPORT Human Clinical
"Small testes were the most common clinical characteristic present in 90.2% of the patients"
This directly supports small testes as the most common physical exam finding in 46,XX testicular DSD.
Male Infertility Male infertility (HP:0003251)
Show evidence (1 reference)
PMID:31336995 SUPPORT Human Clinical
"Male adults with 46,XX and normal external genitalia generally discover their pathology in adulthood because of infertility."
This supports infertility as the most common presenting feature in adults with 46,XX testicular DSD.
Cryptorchidism Cryptorchidism (HP:0000028)
Show evidence (1 reference)
PMID:31336995 SUPPORT Human Clinical
"Cryptorchidism is present in 15% and anterior hypospadias in around 10%."
This documents cryptorchidism as a recognized phenotype in 46,XX testicular DSD.
Hypospadias Hypospadias (HP:0000047)
Show evidence (1 reference)
PMID:31336995 SUPPORT Human Clinical
"Cryptorchidism is present in 15% and anterior hypospadias in around 10%."
This supports hypospadias as a recognized urogenital phenotype in 46,XX testicular DSD.
Micropenis Micropenis (HP:0000054)
Show evidence (1 reference)
PMID:36341017 SUPPORT Human Clinical
"small penis (31.8%)"
The systematic review reports small penis in 31.8% of patients with 46,XX testicular DSD, supporting micropenis as a recognized genitourinary feature of this disorder.
Integument 1
Palmoplantar Keratoderma Palmoplantar keratoderma (HP:0000982)
Show evidence (1 reference)
PMID:29575617 SUPPORT Human Clinical
"Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal (MIM # 610644) is a clinically distinctive form of SRY-negative 46,XX disorder of sex development."
This directly supports palmoplantar hyperkeratosis as the clinically-distinguishing extra-gonadal feature of the RSPO1-associated SRY-negative subtype.
Other 1
Squamous Cell Carcinoma of Skin Risk skin squamous cell carcinoma (MONDO:0002529)
Show evidence (1 reference)
PMID:29575617 SUPPORT Human Clinical
"Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal (MIM # 610644) is a clinically distinctive form of SRY-negative 46,XX disorder of sex development."
This directly identifies skin squamous cell carcinoma as part of the RSPO1-associated SRY-negative clinical syndrome.
🧬

Genetic Associations

5
SRY (CAUSATIVE)
Show evidence (1 reference)
PMID:36341017 SUPPORT Human Clinical
"Genetic analyses showed translocation of the SRY on Xp chromosome and complete absence of all Azoospermia factor (AZF) genetic regions."
This directly identifies SRY-on-Xp translocation as the causal molecular lesion in SRY-positive cases.
SOX9 (CAUSATIVE)
Show evidence (2 references)
PMID:25077096 SUPPORT Human Clinical
"SOX9 duplication has been found to be a rare cause of 46,XX testicular DSD in humans."
This directly establishes SOX9 duplication as a recognized causal mechanism in SRY-negative 46,XX testicular DSD.
PMID:34050715 SUPPORT Human Clinical
"whole genome sequencing reported a pathogenic duplication in a non-coding region that contains the RevSex regulatory element, which modifies SOX9 expression and is associated with 46,XX OT-DSD and complete sex reversal"
This supports cryptic non-coding SOX9 regulatory duplications (RevSex) as a clinically relevant SOX9-pathway mechanism.
SOX3 (CAUSATIVE)
Show evidence (1 reference)
PMID:36064700 SUPPORT Human Clinical
"We report the first case of an SRY-negative 46 XX male with prostatic utricle caused by SOX3 duplication."
This directly establishes SOX3 duplication as a causal lesion for SRY-negative 46,XX testicular DSD.
RSPO1 (CAUSATIVE)
Show evidence (1 reference)
PMID:29575617 SUPPORT Human Clinical
"It is a rare autosomal recessive disorder caused due to biallelic loss of function mutations in RSPO1 gene."
This directly identifies biallelic RSPO1 loss-of-function variants as causal in this rare SRY-negative subset.
NR5A1 (CONTRIBUTING)
Show evidence (1 reference)
PMID:31336995 PARTIAL Human Clinical
"we suggest searching for mutations of other genes involved in the sex determination cascade such as SOX9, SOX3, DAX1, WT1, FGF9, and SF1."
This supports SF1 (NR5A1) as a recognized contributory gene in the sex determination cascade screened in SRY-negative 46,XX testicular DSD.
💊

Treatments

3
Testosterone Replacement Therapy
Action: testosterone replacement therapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: testosterone ↗
Long-term androgen replacement is used to treat hypergonadotropic hypogonadism, support secondary sexual characteristics, and protect bone health in adults with 46,XX testicular DSD.
Show evidence (1 reference)
PMID:31336995 PARTIAL Human Clinical
"the patient may not be able to avoid drug-dependence for maintaining the secondary sex characteristics."
The systematic review describes long-term hormonal management as necessary to maintain secondary sex characteristics in affected patients.
Genetic counseling
Action: genetic counseling MAXO:0000079
Genetic counseling is recommended to discuss the rare recurrence risk, fertility limitations, and the need for cytogenetic and targeted molecular testing in family members.
Show evidence (1 reference)
PMID:25077096 SUPPORT Human Clinical
"an effort to make an accurate diagnosis is important for the provision of proper genetic counseling and for guiding patients in their long-term management."
This directly supports genetic counseling as a core management element after molecular diagnosis.
Donor sperm assisted reproduction
Action: in vitro fertilization with donor sperm Ontology label: In Vitro Fertilization NCIT:C16580
Because affected individuals are uniformly azoospermic and testicular sperm extraction is not recommended, in vitro fertilization with donor sperm or adoption are the principal fertility options.
Show evidence (1 reference)
PMID:31336995 SUPPORT Human Clinical
"Testicular sperm extraction is not recommended, and adoption or in vitro fertilization with a sperm donor are fertility options."
This directly supports donor-sperm assisted reproduction as the standard fertility recommendation.
🔀

Differential Diagnoses

3

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

Klinefelter syndrome MONDO:0006823
Overlapping Features Klinefelter syndrome (47,XXY) shares small testes, gynecomastia, and hypergonadotropic hypogonadism with 46,XX testicular DSD; the difference is detected by karyotyping (47,XXY versus 46,XX).
46,XX gonadal dysgenesis MONDO:0009299
Overlapping Features 46,XX gonadal dysgenesis also has a 46,XX karyotype but presents with a female phenotype, streak gonads, primary amenorrhea, and uterine hypoplasia rather than testicular tissue and a male phenotype.
Congenital adrenal hyperplasia MONDO:0018479
Overlapping Features Congenital adrenal hyperplasia in 46,XX individuals can produce virilization of the external genitalia from prenatal androgen excess but preserves ovarian tissue and is excluded by adrenal hormone testing.
{ }

Source YAML

click to show 
name: 46,XX testicular disorder of sex development
creation_date: "2026-05-08T12:00:00Z"
updated_date: "2026-05-08T15:40:44Z"
category: Mendelian
description: >-
  46,XX testicular disorder of sex development (also known as XX male syndrome
  or 46,XX male sex reversal) is a rare disorder of sex development in which
  individuals with a 46,XX karyotype develop testicular tissue and a male
  phenotype. The shared disease mechanism is inappropriate activation of the
  testis-determination pathway in a chromosomally female (46,XX) gonad. In
  approximately 80% of cases this is driven by translocation of the SRY gene
  onto the X chromosome (most often Xp) or, rarely, onto an autosome.
  SRY-negative cases (around 20%) involve gain-of-function lesions of
  pro-testis genes (notably SOX9 or SOX3 duplications) or loss-of-function
  variants in pro-ovarian genes (RSPO1, with biallelic NR5A1 dysregulation also
  contributing in some cases). Affected individuals typically present in
  adulthood with primary infertility, small testes, azoospermia, gynecomastia,
  and hypergonadotropic hypogonadism; SRY-negative cases more often present in
  childhood with ambiguous genitalia. This entry is mechanistically distinct
  from 46,XX gonadal dysgenesis (streak gonads, female phenotype, ovarian
  failure).
disease_term:
  preferred_term: 46,XX testicular disorder of sex development
  term:
    id: MONDO:0100249
    label: 46,XX testicular disorder of sex development
synonyms:
- XX male syndrome
- 46,XX male sex reversal
- 46,XX testicular DSD
- de la Chapelle syndrome
parents:
- Disorder of sex development
- Gonadal development disorder
- Male infertility disorder
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 disease identifier for 46,XX testicular disorder of sex development.
has_subtypes:
- name: SRY-positive
  display_name: SRY-positive 46,XX testicular DSD
  description: >-
    Most common form (approximately 80% of cases) caused by translocation of
    the SRY gene from the Y chromosome onto the X chromosome (typically Xp) or
    rarely onto an autosome. Patients usually have normal external male
    genitalia and present in adulthood with infertility, azoospermia, small
    testes, and gynecomastia.
- name: SRY-negative
  display_name: SRY-negative 46,XX testicular DSD
  description: >-
    Approximately 20% of cases. Testis differentiation occurs without SRY,
    typically driven by ectopic activation or duplication of pro-testis genes
    (SOX9, SOX3) or loss-of-function in pro-ovarian regulators (RSPO1).
    Patients more often present in childhood with ambiguous external genitalia,
    cryptorchidism, hypospadias, or ovotesticular tissue.
prevalence:
- population: General male population
  percentage: "~1:20,000"
  evidence:
  - reference: PMID:31336995
    reference_title: >-
      46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
      Systematic Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is a rare disease occurring in about 1:20,000 males
    explanation: >-
      This systematic review provides the standard prevalence estimate for
      46,XX testicular DSD.
pathophysiology:
- name: Inappropriate activation of testis determination in 46,XX gonad
  description: >-
    The shared proximal disease mechanism is activation of the male
    testis-determination cascade in a chromosomally female (46,XX) gonad,
    diverting bipotential gonadal precursors toward testicular rather than
    ovarian differentiation. In SRY-positive cases this is driven by ectopic
    SRY transferred onto an X chromosome or autosome; in SRY-negative cases
    pro-testis genes (SOX9, SOX3) are inappropriately overexpressed or
    pro-ovarian genes (RSPO1) lose function.
  cell_types:
  - preferred_term: Sertoli cell precursor
    term:
      id: CL:0000216
      label: Sertoli cell
  biological_processes:
  - preferred_term: sex determination
    term:
      id: GO:0007530
      label: sex determination
  - preferred_term: male gonad development
    term:
      id: GO:0008584
      label: male gonad development
    modifier: INCREASED
  evidence:
  - reference: PMID:31336995
    reference_title: >-
      46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
      Systematic Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The SRY gene is identified as the main gene regulating the testes
      determination cascade. The most important role of SRY is to regulate the
      SOX9 expression in Sertoli cell precursors. This pathway, in turn,
      activates testis-specific genes leading to testis determination
    explanation: >-
      This directly supports inappropriate activation of the SRY/SOX9 testis
      determination cascade in Sertoli cell precursors as the proximal
      mechanism in 46,XX testicular DSD.
  - reference: PMID:36064700
    reference_title: >-
      Duplication of SOX3 in an SRY-negative 46,XX male with prostatic utricle:
      case report and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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
    explanation: >-
      This explicitly supports overexpression of pro-testis genes (SOX9, SOX3)
      or loss of pro-ovarian genes as the mechanism in SRY-negative cases.
  downstream:
  - target: Dysgenetic testis differentiation
    description: >-
      Activation of testis-determination programs in 46,XX gonadal tissue
      produces testicular but typically dysgenetic gonads with abnormal
      seminiferous tubule architecture and absent germ cells.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36064700
      reference_title: >-
        Duplication of SOX3 in an SRY-negative 46,XX male with prostatic
        utricle: case report and literature review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        almost all testicles exhibit dysgenesis
      explanation: >-
        This directly links inappropriate testis-determination signals in 46,XX
        gonads to dysgenetic testicular tissue.
- name: SRY translocation onto an X chromosome
  subtypes:
  - SRY-positive
  description: >-
    The pathognomonic genetic lesion in SRY-positive 46,XX testicular DSD is a
    Y-to-X translocation during paternal meiosis, producing an X chromosome
    that carries SRY. The translocated SRY drives the testis determination
    cascade despite the otherwise female chromosomal complement.
  genes:
  - preferred_term: SRY
    term:
      id: hgnc:11311
      label: SRY
  evidence:
  - reference: PMID:31336995
    reference_title: >-
      46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
      Systematic Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Various studies indicated that 80–90% of 46,XX males result from a Y to
      X translocation during meiosis
    explanation: >-
      This supports SRY translocation onto the X chromosome as the dominant
      causal lesion in SRY-positive 46,XX testicular DSD.
  - reference: PMID:36341017
    reference_title: >-
      A 46,XX Karyotype in Men with Infertility: Two New Cases and Review of
      the Literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of the SRY was identified in 130/154 (84.4%) patients: in
      98.5% of cases, it was translocated on the Xp chromosome and in 1.5% on
      an autosome.
    explanation: >-
      This quantifies the dominance of Xp-translocated SRY across a large
      review cohort.
  downstream:
  - target: Inappropriate activation of testis determination in 46,XX gonad
    description: >-
      Ectopic SRY translocated onto an X chromosome (or rarely an autosome)
      drives the testis-determination cascade in the otherwise 46,XX gonad,
      producing the inappropriate activation of male sex determination that is
      the proximal disease mechanism in SRY-positive cases.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31336995
      reference_title: >-
        46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
        Systematic Review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        male sex differentiation is mostly dependent on the presence of the
        SRY gene, which drives the primitive gonads into testes formation
        during early human embryonic development
      explanation: >-
        This supports translocated SRY as the proximate driver of testis
        formation in the 46,XX gonad, instantiating the inappropriate
        testis-determination program.
- name: SOX9 or SOX3 dysregulation in SRY-negative cases
  subtypes:
  - SRY-negative
  description: >-
    In SRY-negative 46,XX testicular DSD, gain-of-function lesions in
    pro-testis genes substitute for SRY. Duplications of SOX9 (or its RevSex
    upstream regulatory element) and ectopic activation of SOX3 (an X-linked
    SRY paralog) drive testis determination in the absence of SRY.
  genes:
  - preferred_term: SOX9
    term:
      id: hgnc:11204
      label: SOX9
  - preferred_term: SOX3
    term:
      id: hgnc:11199
      label: SOX3
  evidence:
  - reference: PMID:25077096
    reference_title: >-
      A Korean boy with 46,XX testicular disorder of sex development caused by
      SOX9 duplication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      overexpression of SOX9 leads to the male development of 46,XX gonads in
      the absence of SRY
    explanation: >-
      This directly supports SOX9 overexpression as a sufficient driver of
      testis differentiation in SRY-negative 46,XX testicular DSD.
  - reference: PMID:34050715
    reference_title: >-
      Whole genome sequencing identifies a cryptic SOX9 regulatory element
      duplication underlying a case of 46,XX ovotesticular difference of sexual
      development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whole genome sequencing reported a pathogenic duplication in a
      non-coding region that contains the RevSex regulatory element, which
      modifies SOX9 expression and is associated with 46,XX OT-DSD and complete
      sex reversal
    explanation: >-
      This identifies cryptic non-coding duplications of the SOX9 RevSex
      enhancer as a mechanism in SRY-negative cases.
  - reference: PMID:36064700
    reference_title: >-
      Duplication of SOX3 in an SRY-negative 46,XX male with prostatic utricle:
      case report and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SOX3 duplication may cause sex reversal, and all 46,XX SRY-negative
      males should be screened for SOX3 mutations.
    explanation: >-
      This supports SOX3 duplication as a recognized cause of SRY-negative
      46,XX testicular DSD.
  downstream:
  - target: Inappropriate activation of testis determination in 46,XX gonad
    description: >-
      Gain-of-function dysregulation of pro-testis genes (SOX9 duplication or
      its RevSex enhancer, ectopic SOX3) substitutes for SRY and triggers the
      testis-determination cascade in 46,XX gonadal precursors, producing the
      inappropriate male sex-determination program that defines the
      SRY-negative subtype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25077096
      reference_title: >-
        A Korean boy with 46,XX testicular disorder of sex development caused
        by SOX9 duplication.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        overexpression of SOX9 leads to the male development of 46,XX gonads
        in the absence of SRY
      explanation: >-
        This explicitly supports SOX9 overexpression as a sufficient driver of
        the inappropriate testis-determination program in SRY-negative cases.
- name: RSPO1-dependent canonical beta-catenin pro-ovarian signaling loss
  subtypes:
  - SRY-negative
  description: >-
    In the rare autosomal recessive RSPO1-associated subset of SRY-negative
    46,XX testicular DSD, biallelic RSPO1 loss of function reduces canonical
    beta-catenin signaling that normally promotes female gonadal
    differentiation. Loss of this pro-ovarian signal permits the 46,XX gonad
    to enter the testis-determination program.
  genes:
  - preferred_term: RSPO1
    term:
      id: hgnc:21679
      label: RSPO1
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  - preferred_term: female gonad development
    term:
      id: GO:0008585
      label: female gonad development
    modifier: DECREASED
  evidence:
  - reference: PMID:29575617
    reference_title: >-
      Novel RSPO1 mutation causing 46,XX testicular disorder of sex development
      with palmoplantar keratoderma: A review of literature and expansion of
      clinical phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RSPO1 acts by activating the canonical β-catenin pathway and is one of
      the most important genes controlling female gonadal differentiation.
    explanation: >-
      This directly supports RSPO1 as an activator of canonical beta-catenin
      signaling required for female gonadal differentiation.
  downstream:
  - target: Inappropriate activation of testis determination in 46,XX gonad
    description: >-
      Loss of RSPO1-dependent canonical beta-catenin pro-ovarian signaling
      removes a female-gonad-determining input, allowing testis differentiation
      in the 46,XX gonad.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced canonical beta-catenin signaling impairs female gonadal differentiation.
    evidence:
    - reference: PMID:29575617
      reference_title: >-
        Novel RSPO1 mutation causing 46,XX testicular disorder of sex
        development with palmoplantar keratoderma: A review of literature and
        expansion of clinical phenotype.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        RSPO1 acts by activating the canonical β-catenin pathway and is one of
        the most important genes controlling female gonadal differentiation.
      explanation: >-
        The snippet supports the intermediate step linking RSPO1 loss to
        impaired pro-ovarian signaling in SRY-negative disease.
- name: Dysgenetic testis differentiation
  description: >-
    Although ectopic testis-determination signals successfully divert the 46,XX
    gonad toward testicular development, the absence of the full Y chromosome
    (and AZF spermatogenesis loci) leaves the resulting testis architecturally
    abnormal, with progressive loss of germ cells and Sertoli-cell-only
    seminiferous tubules in the adult.
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  - preferred_term: germ cell
    term:
      id: CL:0000586
      label: germ cell
  biological_processes:
  - preferred_term: spermatogenesis
    term:
      id: GO:0007283
      label: spermatogenesis
    modifier: ABSENT
  evidence:
  - reference: PMID:36341017
    reference_title: >-
      A 46,XX Karyotype in Men with Infertility: Two New Cases and Review of
      the Literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients were azoospermic, due to the lack of AZF genetic regions.
    explanation: >-
      This directly links absence of AZF spermatogenesis loci to azoospermia
      in 46,XX testicular DSD.
  downstream:
  - target: Hypergonadotropic hypogonadism and gynecomastia
    description: >-
      Dysgenetic testes produce inadequate testosterone and inhibin, leading to
      compensatory pituitary gonadotropin elevation and a relative imbalance
      that promotes gynecomastia at puberty.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31336995
      reference_title: >-
        46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
        Systematic Review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Endocrine testing normally reveals hypergonadotropic hypogonadism
        secondary to testicular failure
      explanation: >-
        This directly supports hypergonadotropic hypogonadism as the
        downstream endocrine consequence of dysgenetic testis function.
- name: Hypergonadotropic hypogonadism and gynecomastia
  description: >-
    Compromised testicular steroidogenesis lowers serum testosterone, removes
    feedback inhibition on the hypothalamic-pituitary axis, and elevates LH
    and FSH. The relative estrogen excess at puberty contributes to
    gynecomastia, while inadequate androgen drives small testes, sparse body
    hair, and reduced fertility.
  cell_types:
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
  biological_processes:
  - preferred_term: steroid hormone biosynthetic process
    term:
      id: GO:0006694
      label: steroid biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:36341017
    reference_title: >-
      A 46,XX Karyotype in Men with Infertility: Two New Cases and Review of
      the Literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients included in the review presented hypergonadotropic
      hypogonadism.
    explanation: >-
      This directly supports hypergonadotropic hypogonadism as the universal
      endocrine pattern in 46,XX testicular DSD.
phenotypes:
- category: Reproductive
  name: Azoospermia
  description: >-
    Affected individuals are uniformly azoospermic because the 46,XX karyotype
    lacks the AZF spermatogenesis loci required for sperm production.
  diagnostic: true
  phenotype_term:
    preferred_term: azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  evidence:
  - reference: PMID:36341017
    reference_title: >-
      A 46,XX Karyotype in Men with Infertility: Two New Cases and Review of
      the Literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients were azoospermic, due to the lack of AZF genetic regions.
    explanation: >-
      This directly supports azoospermia as a uniform finding in 46,XX
      testicular DSD.
- category: Reproductive
  name: Decreased Testicular Size
  description: >-
    Small testes are the most common physical finding, reflecting the
    dysgenetic testicular tissue and impaired spermatogenesis.
  diagnostic: true
  phenotype_term:
    preferred_term: decreased testicular size
    term:
      id: HP:0008734
      label: Decreased testicular size
  evidence:
  - reference: PMID:36341017
    reference_title: >-
      A 46,XX Karyotype in Men with Infertility: Two New Cases and Review of
      the Literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Small testes were the most common clinical characteristic present in
      90.2% of the patients
    explanation: >-
      This directly supports small testes as the most common physical exam
      finding in 46,XX testicular DSD.
- category: Endocrine
  name: Hypergonadotropic Hypogonadism
  description: >-
    Reduced testosterone production and elevated FSH and LH define the
    endocrine pattern, reflecting failure of the dysgenetic testes to maintain
    normal steroidogenesis.
  diagnostic: true
  phenotype_term:
    preferred_term: hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  evidence:
  - reference: PMID:36341017
    reference_title: >-
      A 46,XX Karyotype in Men with Infertility: Two New Cases and Review of
      the Literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients included in the review presented hypergonadotropic
      hypogonadism.
    explanation: >-
      This directly supports universal hypergonadotropic hypogonadism as a
      defining endocrine feature.
- category: Reproductive
  name: Gynecomastia
  description: >-
    Pubertal breast development occurs in a subset of patients, attributed to
    a relatively elevated estrogen:androgen ratio in the setting of testicular
    failure.
  phenotype_term:
    preferred_term: gynecomastia
    term:
      id: HP:0000771
      label: Gynecomastia
  evidence:
  - reference: PMID:36341017
    reference_title: >-
      A 46,XX Karyotype in Men with Infertility: Two New Cases and Review of
      the Literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Small testes were the most common clinical characteristic present in
      90.2% of the patients, followed by small penis (31.8%), gynecomastia
      (26.8%) and poor hair distribution (15.4%).
    explanation: >-
      This documents gynecomastia as a recognized clinical feature, present in
      roughly a quarter of patients.
- category: Reproductive
  name: Male Infertility
  description: >-
    Affected individuals are infertile because of azoospermia from the
    dysgenetic testes; testicular sperm extraction is generally not
    successful.
  diagnostic: true
  phenotype_term:
    preferred_term: male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:31336995
    reference_title: >-
      46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
      Systematic Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Male adults with 46,XX and normal external genitalia generally discover
      their pathology in adulthood because of infertility.
    explanation: >-
      This supports infertility as the most common presenting feature in
      adults with 46,XX testicular DSD.
- category: Reproductive
  name: Cryptorchidism
  description: >-
    Cryptorchidism is more common in SRY-negative cases and reflects
    incomplete androgen-driven testicular descent during fetal development.
  subtype: SRY-negative
  phenotype_term:
    preferred_term: cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:31336995
    reference_title: >-
      46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
      Systematic Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cryptorchidism is present in 15% and anterior hypospadias in around 10%.
    explanation: >-
      This documents cryptorchidism as a recognized phenotype in 46,XX
      testicular DSD.
- category: Reproductive
  name: Hypospadias
  description: >-
    Hypospadias is more frequent in SRY-negative cases due to incomplete
    androgenization of the developing genital tubercle.
  subtype: SRY-negative
  phenotype_term:
    preferred_term: hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:31336995
    reference_title: >-
      46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
      Systematic Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cryptorchidism is present in 15% and anterior hypospadias in around 10%.
    explanation: >-
      This supports hypospadias as a recognized urogenital phenotype in 46,XX
      testicular DSD.
- category: Genitourinary
  name: Micropenis
  description: >-
    Small penis size is a recognized clinical feature of 46,XX testicular DSD,
    reflecting incomplete androgen-driven phallic development; cohort data
    report it in approximately one-third of affected individuals.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  evidence:
  - reference: PMID:36341017
    reference_title: >-
      A 46,XX Karyotype in Men with Infertility: Two New Cases and Review of
      the Literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "small penis (31.8%)"
    explanation: >-
      The systematic review reports small penis in 31.8% of patients with
      46,XX testicular DSD, supporting micropenis as a recognized
      genitourinary feature of this disorder.
- category: Dermatological
  name: Palmoplantar Keratoderma
  description: >-
    Biallelic loss-of-function mutations in RSPO1 cause palmoplantar
    hyperkeratosis as a pathognomonic extra-gonadal feature of the
    RSPO1-associated form of SRY-negative 46,XX testicular DSD. Skin
    involvement is the cardinal differentiating finding from other SRY-negative
    causes and is diagnostically informative for the RSPO1 subtype.
  subtype: SRY-negative
  phenotype_term:
    preferred_term: palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:29575617
    reference_title: >-
      Novel RSPO1 mutation causing 46,XX testicular disorder of sex development
      with palmoplantar keratoderma: A review of literature and expansion of
      clinical phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal (MIM # 610644) is a clinically distinctive form of SRY-negative 46,XX disorder of sex development."
    explanation: >-
      This directly supports palmoplantar hyperkeratosis as the
      clinically-distinguishing extra-gonadal feature of the RSPO1-associated
      SRY-negative subtype.
- category: Dermatological
  name: Squamous Cell Carcinoma of Skin Risk
  description: >-
    RSPO1-associated SRY-negative 46,XX testicular DSD is described as a
    palmoplantar hyperkeratosis syndrome with squamous cell carcinoma of skin,
    making cutaneous carcinoma risk a clinically significant feature of this
    molecular subtype.
  subtype: SRY-negative
  phenotype_term:
    preferred_term: skin squamous cell carcinoma
    term:
      id: MONDO:0002529
      label: skin squamous cell carcinoma
  evidence:
  - reference: PMID:29575617
    reference_title: >-
      Novel RSPO1 mutation causing 46,XX testicular disorder of sex development
      with palmoplantar keratoderma: A review of literature and expansion of
      clinical phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal (MIM # 610644) is a clinically distinctive form of SRY-negative 46,XX disorder of sex development."
    explanation: >-
      This directly identifies skin squamous cell carcinoma as part of the
      RSPO1-associated SRY-negative clinical syndrome.
genetic:
- name: SRY
  gene_term:
    preferred_term: SRY
    term:
      id: hgnc:11311
      label: SRY
  association: CAUSATIVE
  features: >-
    Translocation of SRY from the Y chromosome onto Xp (most commonly) or
    rarely onto an autosome accounts for approximately 80% of cases of 46,XX
    testicular DSD. The translocated SRY initiates the testis-determination
    cascade and drives a male phenotype despite the 46,XX karyotype.
  subtype: SRY-positive
  evidence:
  - reference: PMID:36341017
    reference_title: >-
      A 46,XX Karyotype in Men with Infertility: Two New Cases and Review of
      the Literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic analyses showed translocation of the SRY on Xp chromosome and
      complete absence of all Azoospermia factor (AZF) genetic regions.
    explanation: >-
      This directly identifies SRY-on-Xp translocation as the causal molecular
      lesion in SRY-positive cases.
- name: SOX9
  gene_term:
    preferred_term: SOX9
    term:
      id: hgnc:11204
      label: SOX9
  association: CAUSATIVE
  features: >-
    SOX9 duplications (including duplications of upstream regulatory elements
    such as RevSex) cause SRY-negative 46,XX testicular and ovotesticular DSD
    by ectopically driving SOX9 expression in 46,XX gonads.
  subtype: SRY-negative
  evidence:
  - reference: PMID:25077096
    reference_title: >-
      A Korean boy with 46,XX testicular disorder of sex development caused by
      SOX9 duplication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SOX9 duplication has been found to be a rare cause of 46,XX testicular
      DSD in humans.
    explanation: >-
      This directly establishes SOX9 duplication as a recognized causal
      mechanism in SRY-negative 46,XX testicular DSD.
  - reference: PMID:34050715
    reference_title: >-
      Whole genome sequencing identifies a cryptic SOX9 regulatory element
      duplication underlying a case of 46,XX ovotesticular difference of sexual
      development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whole genome sequencing reported a pathogenic duplication in a
      non-coding region that contains the RevSex regulatory element, which
      modifies SOX9 expression and is associated with 46,XX OT-DSD and complete
      sex reversal
    explanation: >-
      This supports cryptic non-coding SOX9 regulatory duplications (RevSex)
      as a clinically relevant SOX9-pathway mechanism.
- name: SOX3
  gene_term:
    preferred_term: SOX3
    term:
      id: hgnc:11199
      label: SOX3
  association: CAUSATIVE
  features: >-
    Duplications spanning the X-linked SOX3 locus cause SRY-negative 46,XX
    testicular DSD through ectopic SOX3 expression that mimics SRY-driven
    testis determination.
  subtype: SRY-negative
  evidence:
  - reference: PMID:36064700
    reference_title: >-
      Duplication of SOX3 in an SRY-negative 46,XX male with prostatic utricle:
      case report and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the first case of an SRY-negative 46 XX male with prostatic
      utricle caused by SOX3 duplication.
    explanation: >-
      This directly establishes SOX3 duplication as a causal lesion for
      SRY-negative 46,XX testicular DSD.
- name: RSPO1
  gene_term:
    preferred_term: RSPO1
    term:
      id: hgnc:21679
      label: RSPO1
  association: CAUSATIVE
  features: >-
    Biallelic loss-of-function variants in RSPO1 cause an autosomal recessive
    SRY-negative 46,XX testicular/ovotesticular DSD with palmoplantar
    keratoderma. RSPO1 normally activates canonical WNT/β-catenin signaling
    that promotes ovarian determination; its loss permits ectopic testis
    development.
  subtype: SRY-negative
  evidence:
  - reference: PMID:29575617
    reference_title: >-
      Novel RSPO1 mutation causing 46,XX testicular disorder of sex development
      with palmoplantar keratoderma: A review of literature and expansion of
      clinical phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is a rare autosomal recessive disorder caused due to biallelic loss
      of function mutations in RSPO1 gene.
    explanation: >-
      This directly identifies biallelic RSPO1 loss-of-function variants as
      causal in this rare SRY-negative subset.
- name: NR5A1
  gene_term:
    preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  association: CONTRIBUTING
  features: >-
    NR5A1 (SF1) variants more commonly cause 46,XY DSD or 46,XX primary
    ovarian insufficiency, but rare gain-of-function or regulatory
    perturbations have been associated with 46,XX testicular/ovotesticular DSD
    via dysregulation of pro-testis transcriptional programs.
  subtype: SRY-negative
  evidence:
  - reference: PMID:31336995
    reference_title: >-
      46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
      Systematic Review.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we suggest searching for mutations of other genes involved in the sex
      determination cascade such as SOX9, SOX3, DAX1, WT1, FGF9, and SF1.
    explanation: >-
      This supports SF1 (NR5A1) as a recognized contributory gene in the sex
      determination cascade screened in SRY-negative 46,XX testicular DSD.
treatments:
- name: Testosterone Replacement Therapy
  description: >-
    Long-term androgen replacement is used to treat hypergonadotropic
    hypogonadism, support secondary sexual characteristics, and protect bone
    health in adults with 46,XX testicular DSD.
  treatment_term:
    preferred_term: testosterone replacement therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: testosterone
      term:
        id: CHEBI:17347
        label: testosterone
  evidence:
  - reference: PMID:31336995
    reference_title: >-
      46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
      Systematic Review.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the patient may not be able to avoid drug-dependence for maintaining the
      secondary sex characteristics.
    explanation: >-
      The systematic review describes long-term hormonal management as
      necessary to maintain secondary sex characteristics in affected
      patients.
- name: Genetic counseling
  description: >-
    Genetic counseling is recommended to discuss the rare recurrence risk,
    fertility limitations, and the need for cytogenetic and targeted molecular
    testing in family members.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:25077096
    reference_title: >-
      A Korean boy with 46,XX testicular disorder of sex development caused by
      SOX9 duplication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an effort to make an accurate diagnosis is important for the provision
      of proper genetic counseling and for guiding patients in their long-term
      management.
    explanation: >-
      This directly supports genetic counseling as a core management element
      after molecular diagnosis.
- name: Donor sperm assisted reproduction
  description: >-
    Because affected individuals are uniformly azoospermic and testicular
    sperm extraction is not recommended, in vitro fertilization with donor
    sperm or adoption are the principal fertility options.
  treatment_term:
    preferred_term: in vitro fertilization with donor sperm
    term:
      id: NCIT:C16580
      label: In Vitro Fertilization
  evidence:
  - reference: PMID:31336995
    reference_title: >-
      46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
      Systematic Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Testicular sperm extraction is not recommended, and adoption or in vitro
      fertilization with a sperm donor are fertility options.
    explanation: >-
      This directly supports donor-sperm assisted reproduction as the standard
      fertility recommendation.
diagnosis:
- name: Karyotype analysis
  description: >-
    Cytogenetic testing on peripheral blood lymphocytes establishes the 46,XX
    karyotype in a phenotypically male patient and is the cornerstone of
    diagnosis.
  diagnosis_term:
    preferred_term: karyotyping
    term:
      id: MAXO:0001611
      label: karyotyping
  evidence:
  - reference: PMID:31336995
    reference_title: >-
      46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
      Systematic Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Semen analysis is mandatory and so is the karyotype test.
    explanation: >-
      This supports karyotyping as a mandatory step in diagnosing 46,XX
      testicular DSD.
- name: SRY molecular detection (FISH or PCR)
  description: >-
    Detection and localization of the SRY gene by fluorescence in situ
    hybridization or PCR distinguishes SRY-positive from SRY-negative cases
    and guides further molecular workup.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:31336995
    reference_title: >-
      46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
      Systematic Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The investigation is usually based on fluorescence in situ hybridization
      (FISH) or polymerase chain reaction (PCR) amplification of the SRY gene.
    explanation: >-
      This directly supports FISH or PCR for SRY as the standard molecular
      test in 46,XX testicular DSD diagnosis.
- name: Targeted molecular testing for SRY-negative cases
  description: >-
    In SRY-negative patients, targeted screening for duplications and
    pathogenic variants in pro-testis genes (SOX9, SOX3) and pro-ovarian genes
    (RSPO1, with NR5A1 also assessed) is recommended; whole genome sequencing
    can detect cryptic non-coding regulatory duplications such as RevSex.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:31336995
    reference_title: >-
      46,XX Testicular Disorder of Sex Development (DSD): A Case Report and
      Systematic Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In SRY-negative patients, no further instrumental or blood tests are
      necessary, however, we suggest searching for mutations of other genes
      involved in the sex determination cascade such as SOX9, SOX3, DAX1, WT1,
      FGF9, and SF1.
    explanation: >-
      This directly recommends gene-panel testing for SOX9, SOX3, and other
      sex-determination pathway genes in SRY-negative cases.
differential_diagnoses:
- name: Klinefelter syndrome
  description: >-
    Klinefelter syndrome (47,XXY) shares small testes, gynecomastia, and
    hypergonadotropic hypogonadism with 46,XX testicular DSD; the difference
    is detected by karyotyping (47,XXY versus 46,XX).
  disease_term:
    preferred_term: Klinefelter syndrome
    term:
      id: MONDO:0006823
      label: Klinefelter syndrome
- name: 46,XX gonadal dysgenesis
  description: >-
    46,XX gonadal dysgenesis also has a 46,XX karyotype but presents with a
    female phenotype, streak gonads, primary amenorrhea, and uterine
    hypoplasia rather than testicular tissue and a male phenotype.
  disease_term:
    preferred_term: 46,XX gonadal dysgenesis
    term:
      id: MONDO:0009299
      label: 46 XX gonadal dysgenesis
- name: Congenital adrenal hyperplasia
  description: >-
    Congenital adrenal hyperplasia in 46,XX individuals can produce
    virilization of the external genitalia from prenatal androgen excess but
    preserves ovarian tissue and is excluded by adrenal hormone testing.
  disease_term:
    preferred_term: congenital adrenal hyperplasia
    term:
      id: MONDO:0018479
      label: congenital adrenal hyperplasia
clinical_trials: []
datasets: []
notes: >-
  PubMed-driven curation. No deep-research provider was available
  (ASTA/OpenAI/Perplexity/OpenScientist API keys not configured); evidence
  PMIDs were sourced via PubMed E-utilities searches and validated against
  cached abstracts. All snippets are exact quotes from PubMed-cached content.
📚

References & Deep Research

Deep Research

1
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.