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
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 5.0
  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.
  - target: Palmoplantar Keratoderma
    description: >-
      Biallelic RSPO1 loss produces the clinically distinctive SRY-negative
      46,XX DSD subtype with palmoplantar hyperkeratosis/keratoderma.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered RSPO1-dependent canonical beta-catenin signaling in skin
    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: >-
        The review identifies palmoplantar hyperkeratosis as part of the
        RSPO1-associated SRY-negative 46,XX DSD syndrome.
  - target: Squamous Cell Carcinoma of Skin Risk
    description: >-
      The RSPO1-associated palmoplantar hyperkeratosis/sex-reversal syndrome
      includes risk of cutaneous squamous cell carcinoma.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered RSPO1-dependent canonical beta-catenin signaling in skin
    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: >-
        The review directly includes skin squamous cell carcinoma in the
        RSPO1-associated SRY-negative syndrome.
- name: NR5A1 p.Arg92Trp gonadal fate dysregulation
  subtypes:
  - SRY-negative
  description: >-
    Recurrent heterozygous NR5A1 p.Arg92Trp variants can shift 46,XX fetal
    gonadal fate away from stable ovarian differentiation and toward
    SRY-independent testicular differentiation, probably by reducing
    female/anti-testis restraint of the male developmental pathway.
  genes:
  - preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  biological_processes:
  - preferred_term: female gonad development
    term:
      id: GO:0008585
      label: female gonad development
    modifier: DECREASED
  - preferred_term: male gonad development
    term:
      id: GO:0008584
      label: male gonad development
    modifier: INCREASED
  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: HUMAN_CLINICAL
    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: >-
      This directly supports the curated NR5A1 mechanism: a recurrent
      p.Arg92Trp variant reduces anti-testis/pro-ovarian restraint and shifts
      46,XX gonadal fate toward testicular differentiation.
  - 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: >-
      This independent human-family report supports NR5A1 p.Arg92Trp as a
      molecular switch that can produce testis development in 46,XX
      individuals.
  downstream:
  - target: Inappropriate activation of testis determination in 46,XX gonad
    description: >-
      Reduced NR5A1-dependent female/anti-testis restraint permits the male
      developmental pathway to dominate in 46,XX gonadal tissue, feeding into
      the shared inappropriate testis-determination program.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Downregulation of female antitestis genes reduces inhibition of 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: HUMAN_CLINICAL
      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: >-
        This supports the causal edge from NR5A1 p.Arg92Trp-mediated loss of
        anti-testis restraint to the shared 46,XX testis-determination
        mechanism.
- 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.
  - target: Azoospermia
    description: >-
      Dysgenetic 46,XX testes lack the Y-chromosomal AZF regions required for
      spermatogenesis, producing azoospermia.
    causal_link_type: DIRECT
    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: >-
        The review directly connects absence of AZF regions in 46,XX
        testicular DSD to azoospermia.
  - target: Decreased Testicular Size
    description: >-
      Dysgenetic testicular development produces small testes, the most common
      clinical finding in the adult presentation.
    causal_link_type: DIRECT
    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: >-
        The review identifies small testes as the most common clinical
        manifestation in 46,XX testicular DSD.
  - target: Male Infertility
    description: >-
      Azoospermia from dysgenetic testes and absent AZF regions causes the
      adult infertility presentation.
    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 adults with 46,XX and normal external genitalia generally discover
        their pathology in adulthood because of infertility.
      explanation: >-
        This supports infertility as the adult presentation downstream of the
        dysgenetic 46,XX testis phenotype.
  - target: Cryptorchidism
    description: >-
      Incompletely masculinized and dysgenetic testicular development can
      include undescended testes, especially in SRY-negative presentations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - incomplete fetal androgen and testicular descent signaling
    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: >-
        The systematic review documents cryptorchidism as a recognized
        urogenital phenotype in 46,XX testicular DSD.
  - target: Hypospadias
    description: >-
      Incomplete androgenization of the developing external genitalia can
      produce hypospadias in 46,XX testicular DSD, particularly SRY-negative
      cases.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - incomplete fetal androgen signaling during urethral development
    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: >-
        The systematic review documents anterior hypospadias as a recognized
        urogenital phenotype in 46,XX testicular DSD.
- 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.
  downstream:
  - target: Hypergonadotropic Hypogonadism
    description: >-
      Testicular failure lowers sex-steroid feedback and elevates
      gonadotropins, producing hypergonadotropic hypogonadism.
    causal_link_type: DIRECT
    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: >-
        The review identifies hypergonadotropic hypogonadism as the endocrine
        pattern in all reviewed patients.
  - target: Gynecomastia
    description: >-
      Testicular failure and relative estrogen-androgen imbalance can produce
      gynecomastia.
    causal_link_type: DIRECT
    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: >-
        The review reports gynecomastia as a recurrent endocrine/secondary-sex
        phenotype in 46,XX testicular DSD.
  - target: Micropenis
    description: >-
      Inadequate androgen action in the developing or pubertal phenotype can
      produce small penis size.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - incomplete androgen-driven phallic growth
    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 review reports small penis in nearly one-third of affected
        individuals, supporting micropenis as a downstream androgenization
        phenotype.
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: HP:0006739
      label: Squamous cell carcinoma of the skin
  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.
histopathology:
- name: Pediatric Gonadal Biopsy Findings
  description: >-
    Childhood 46,XX testicular/ovotesticular DSD cohorts can show seminiferous
    tubule tissue on biopsy, with no overt tumors in the reported cohort but
    occasional OCT3/4 immunopositivity as a tumor-risk marker.
  evidence:
  - reference: PMID:40487758
    reference_title: >-
      Retrospective analysis of children with 46,XX testicular/ovotesticular
      DSD: a 10-year single-center experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 47 children underwent gonadal biopsy and showed no evidence of
      tumors. However, immunohistochemical analysis revealed that 2 of 16
      children were OCT3/4 positive. The most frequent type of gonadal pathology
      (17/47) was bilateral seminiferous tubules.
    explanation: >-
      This pediatric cohort directly documents the gonadal biopsy pattern and
      modest tumor-risk-marker positivity in childhood 46,XX
      testicular/ovotesticular DSD.
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: CAUSATIVE
  features: >-
    Rare heterozygous NR5A1 p.Arg92Trp variants cause SRY-negative 46,XX
    testicular/ovotesticular DSD by shifting the fetal gonadal regulatory
    balance away from stable ovarian differentiation and toward testicular
    differentiation, with incomplete penetrance and variable expressivity.
  subtype: SRY-negative
  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: HUMAN_CLINICAL
    snippet: >-
      We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary
      ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD.
    explanation: >-
      This primary human genetics study directly establishes NR5A1 as a disease
      gene for 46,XX testicular/ovotesticular DSD.
  - 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: >-
      This independently supports recurrent NR5A1 p.Arg92Trp as a molecular
      switch that can cause testicular differentiation in 46,XX individuals.
  - reference: PMID:37189438
    reference_title: >-
      Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex
      Development through Abnormal Testicular Development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NR5A1 variants are associated with 46,XY DSD and 46,XX
      testicular/ovotesticular DSD.
    explanation: >-
      This recent review supports NR5A1 as a recognized gene in the 46,XX
      testicular/ovotesticular DSD spectrum.
  - 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: NCIT:C15240
      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.
- name: Abdominal ultrasound for Müllerian remnants
  description: >-
    Abdominal ultrasound can be used in the diagnostic workup to evaluate for
    residual Müllerian structures, which may be present in some 46,XX
    testicular DSD presentations.
  diagnosis_term:
    preferred_term: abdominal ultrasound
    term:
      id: NCIT:C19337
      label: Diagnostic Ultrasound
  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: >-
      An abdominal ultrasound is useful in order to exclude residual Müllerian
      structures.
    explanation: >-
      This supports abdominal ultrasound as a diagnostic procedure for checking
      residual Müllerian structures in 46,XX testicular DSD workup.
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 was expanded with Falcon deep research on 2026-05-30.
  Falcon findings were treated as leads and only incorporated when independently
  verified against fetched reference caches.
references:
- reference: DOI:10.1038/gim.2016.118
  title: NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings:
  - statement: NR5A1 is a disease gene for 46,XX testicular/ovotesticular DSD.
    supporting_text: >-
      We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary
      ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD.
    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: HUMAN_CLINICAL
      snippet: >-
        We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary
        ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD.
      explanation: Deep research cited this publication as relevant literature for 46 XX Testicular DSD.
- reference: DOI:10.1093/hmg/ddw186
  title: A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings:
  - statement: Recurrent NR5A1 p.Arg92Trp can switch 46,XX gonadal fate toward testis development.
    supporting_text: >-
      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.
    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: Deep research cited this publication as relevant literature for 46 XX Testicular DSD.
- reference: DOI:10.1159/000445088
  title: 'Disorders of Sex Development with Testicular Differentiation in SRY-Negative 46,XX Individuals: Clinical and Genetic Aspects'
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings: []
- reference: DOI:10.1186/1471-2490-14-104
  title: '46,XX testicular disorder of sexual development with SRY-negative caused by some unidentified mechanisms: a case report and review of the literature'
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings: []
- reference: DOI:10.1186/s12920-022-01347-0
  title: 'Duplication of SOX3 in an SRY-negative 46,XX male with prostatic utricle: case report and literature review'
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings: []
- reference: DOI:10.1371/journal.pone.0186331
  title: XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris)
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings: []
- reference: DOI:10.1530/eje-18-0256
  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'
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings: []
- reference: DOI:10.23736/s2724-5276.21.06512-5
  title: 'Differences of sex development in the newborn: from clinical scenario to molecular diagnosis'
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings: []
- reference: DOI:10.3389/fendo.2024.1354759
  title: Diagnosis and management of non-CAH 46,XX disorders/differences in sex development
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings:
  - statement: Non-CAH 46,XX testicular/ovotesticular DSD has a broad sex-determination gene list.
    supporting_text: >-
      Many genes are involved in the mechanisms of gonadal development, and
      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.
    evidence:
    - reference: PMID:38812815
      reference_title: Diagnosis and management of non-CAH 46,XX disorders/differences in sex development.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Many genes are involved in the mechanisms of gonadal development, and
        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.
      explanation: Deep research cited this publication as relevant literature for 46 XX Testicular DSD.
- reference: DOI:10.3389/fendo.2024.1385901
  title: 'Testicular differentiation in 46,XX DSD: an overview of genetic causes'
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings:
  - statement: Many 46,XX testicular/ovotesticular DSD cases remain genetically unresolved.
    supporting_text: >-
      However, it is important to note that a significant number of patients
      with these DSD conditions have not yet recognized a genetic diagnosis.
    evidence:
    - reference: PMID:38721146
      reference_title: 'Testicular differentiation in 46,XX DSD: an overview of genetic causes.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      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: Deep research cited this publication as relevant literature for 46 XX Testicular DSD.
- reference: DOI:10.3389/fendo.2025.1571467
  title: 'Retrospective analysis of children with 46,XX testicular/ovotesticular DSD: a 10-year single-center experience'
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings:
  - statement: Pediatric 46,XX testicular/ovotesticular DSD can show biopsy seminiferous tubules and modest OCT3/4 tumor-risk-marker positivity.
    supporting_text: >-
      A total of 47 children underwent gonadal biopsy and showed no evidence of
      tumors. However, immunohistochemical analysis revealed that 2 of 16
      children were OCT3/4 positive. The most frequent type of gonadal pathology
      (17/47) was bilateral seminiferous tubules.
    evidence:
    - reference: PMID:40487758
      reference_title: >-
        Retrospective analysis of children with 46,XX testicular/ovotesticular
        DSD: a 10-year single-center experience.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A total of 47 children underwent gonadal biopsy and showed no evidence
        of tumors. However, immunohistochemical analysis revealed that 2 of 16
        children were OCT3/4 positive. The most frequent type of gonadal
        pathology (17/47) was bilateral seminiferous tubules.
      explanation: Deep research cited this publication as relevant literature for 46 XX Testicular DSD.
- reference: DOI:10.3389/fendo.2026.1829751
  title: 'Rare SRY-negative 46,XX disorder of sex development with male phenotype and ectopic gonads: a case report'
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings: []
- reference: DOI:10.3390/biom13040691
  title: Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings:
  - statement: NR5A1, NR0B1, and NR2F2 nuclear-receptor variants are part of atypical testicular-development DSD mechanisms.
    supporting_text: >-
      To date, pathogenic variants of three nuclear receptor genes (NR5A1,
      NR0B1, and NR2F2) have been reported to cause DSD via atypical testicular
      development.
    evidence:
    - reference: PMID:37189438
      reference_title: >-
        Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex
        Development through Abnormal Testicular Development.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        To date, pathogenic variants of three nuclear receptor genes (NR5A1,
        NR0B1, and NR2F2) have been reported to cause DSD via atypical
        testicular development.
      explanation: Deep research cited this publication as relevant literature for 46 XX Testicular DSD.
- reference: DOI:10.3390/medicina55070371
  title: '46,XX Testicular Disorder of Sex Development (DSD): A Case Report and Systematic Review'
  found_in:
  - 46_XX_Testicular_DSD-deep-research-falcon.md
  findings: []