46,XX Disorders/Differences of Sex Development

name: 46,XX Disorder of Sex Development
display_name: 46,XX Disorders/Differences of Sex Development
creation_date: "2026-08-28T00:00:00Z"
description: >-
  Congenital conditions in which the karyotype is 46,XX but gonadal or anatomical
  sex development is atypical. What holds these conditions together is the
  karyotype and the clinical presentation it frames — a newborn or adolescent
  with a 46,XX karyotype and atypical genital, gonadal, or reproductive-tract
  anatomy — not a shared mechanism. Three mechanistically independent routes
  reach that presentation. In the androgen-excess route the gonad is a normal
  ovary and the lesion is steroidogenic: an enzyme block in the fetal adrenal,
  placenta, or ovary raises androgen delivery to the genital tubercle and
  urogenital sinus during the critical window of external genital
  differentiation. In the gonadal route the steroidogenic pathway is intact and
  the lesion is in gonadal determination itself: ectopic or de-repressed
  testis-determining activity commits an XX gonad to testis, or the
  ovary-determining program fails and the gonad is dysgenetic. A third route is
  structural, affecting Müllerian duct and urogenital-sinus development with a
  normally determined ovary and normal androgen exposure. This entry uses the
  Chicago consensus nomenclature: these are disorders/differences of sex
  development, described by karyotype and mechanism rather than by the older
  intersex and hermaphroditism terms the consensus retired.
grouping_basis:
- SHARED_PHENOTYPE
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped on a shared karyotype plus the shared clinical presentation that
  karyotype frames, and on the clinical convention — the 2006 Chicago consensus
  nomenclature and every classification descended from it — that partitions DSD
  first by karyotype and evaluates 46,XX presentations along one diagnostic
  pathway with one multidisciplinary team.

  Modeled as a Grouping rather than as a single Disease with `has_subtypes`
  because the members do not share a pathograph. The androgen-excess arm and the
  gonadal arm are not two branches of one causal chain; they are two chains that
  never touch. In congenital adrenal hyperplasia the gonad is an ovary and the
  lesion is a steroidogenic enzyme block upstream of cortisol, with virilization
  as a downstream consequence of ACTH-driven precursor shunting — a mechanism
  that is fully present in 46,XY individuals too, where it causes no DSD at all.
  In 46,XX testicular DSD steroidogenesis is unremarkable and the lesion is in
  the sex-determination switch, with androgen exposure a consequence of the
  testis that was built rather than its cause. In 46,XX gonadal dysgenesis
  neither applies: the gonad fails to develop, external genital anatomy is
  typically female, and the presentation is hypergonadotropic ovarian failure.
  A single Disease entry over these would need a pathophysiology section whose
  nodes are false for most of the entity, which is the blending a Grouping
  exists to avoid. Each member is already a curated Disease entry with its own
  MONDO term, so a union over them reconciles existing content rather than
  duplicating it.

  This grouping is deliberately orthogonal to the two mechanism-axis groupings
  dismech already carries. `Gonadal_Dysgenesis` unites gonadal-determination
  defects across karyotypes (it holds 46,XY complete gonadal dysgenesis
  alongside two members listed here); `Androgen_Synthesis_and_Action_Disorders`
  unites the 46,XY androgen pathway. Neither can express the 46,XX clinical
  category, because that category cuts across both mechanisms and is defined by
  karyotype. Membership overlap with `Gonadal_Dysgenesis` is expected and is not
  a duplication: the two groupings assert different things about the same
  diseases.

  This is a deliberate departure from the `CURATE_ROOT_WITH_SUBTYPES` hint
  carried on MONDO:0017576 by the curation dashboard and repeated in issue
  #9607. Per issue #8727 that hint is a prioritization signal, not a
  lump-versus-split ruling; the split is recorded here so the decision is
  auditable rather than implicit.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0017576
      label: 46,XX disorder of sex development
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      closeMatch, not exactMatch, because the extensions differ in both
      directions. This grouping under-covers MONDO:0017576: the Müllerian and
      structural arm (Mayer-Rokitansky-Kuster-Hauser syndrome, cloacal exstrophy,
      vaginal atresia), 46,XX ovotesticular DSD, and the virilizing adrenal and
      ovarian tumour causes have no dismech Disease entry yet. In the other
      direction, two listed members are broader than the MONDO class: congenital
      adrenal hyperplasia (MONDO:0018479) and aromatase deficiency
      (MONDO:0013301) are curated as karyotype-agnostic disease entities whose
      46,XY manifestations are not 46,XX DSD, so the grouping is not a subset of
      MONDO:0017576 either. Because the predicate is closeMatch, MONDO:0017576 is
      deliberately NOT retired from the curation queue by this entry.
    consistency:
    - reference: MONDO
      consistent: UNKNOWN
      notes: >-
        46,XX testicular disorder of sex development (MONDO:0100249) and 46,XX
        gonadal dysgenesis (MONDO:0009299) sit in the 46,XX DSD region of MONDO.
        Congenital adrenal hyperplasia (MONDO:0018479) and aromatase deficiency
        (MONDO:0013301) are classified by MONDO as adrenal and steroidogenesis
        disorders, not as descendants of MONDO:0017576, even though they are the
        commonest causes of the clinical category. The grouping is therefore not
        an is-a subtree of the mapped class.
membership_criteria:
- description: >-
    A member is a congenital condition that produces atypical gonadal or
    anatomical sex development in individuals with a 46,XX karyotype.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: OTHER
    description: >-
      Atypical gonadal or anatomical sex development in a 46,XX karyotype.
      Expressed as an OTHER leaf because the criteria vocabulary has no
      karyotype predicate; the claim is checked by a curator against each
      member's disease_term, description, and genetic section rather than
      automatically.
- description: >-
    A member's lesion sits either in gonadal determination and differentiation or
    in steroid biosynthesis — the two independent routes to the shared 46,XX
    presentation.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    description: >-
      Perturbs gonadal development, sex determination, or steroid biosynthesis.
    operands:
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: The gonadal route - involves gonad development.
      biological_processes:
      - preferred_term: gonad development
        term:
          id: GO:0008406
          label: gonad development
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: The gonadal route - involves sex determination.
      biological_processes:
      - preferred_term: sex determination
        term:
          id: GO:0007530
          label: sex determination
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: >-
        The steroidogenic route - involves steroid biosynthesis, whether the
        androgen excess is generated in the fetal adrenal, the placenta, or the
        gonad.
      biological_processes:
      - preferred_term: steroid biosynthetic process
        term:
          id: GO:0006694
          label: steroid biosynthetic process
members:
- member: Congenital Adrenal Hyperplasia
  member_type: DISEASE
  disease_term:
    preferred_term: congenital adrenal hyperplasia
    term:
      id: MONDO:0018479
      label: congenital adrenal hyperplasia
  differentiating_mechanisms:
  - description: >-
      The commonest cause of the group and the only member in which the DSD is a
      side effect of a cortisol-synthesis defect rather than of a
      sex-development defect. A 21-hydroxylase block impairs cortisol synthesis,
      releasing ACTH from negative feedback; the accumulating
      17-hydroxyprogesterone is shunted into the androgen pathway, and the
      resulting fetal
      androgen excess virilizes the external genitalia of a 46,XX fetus whose
      ovaries and Mullerian structures are entirely normal. It is the only
      member that also carries a life-threatening non-DSD phenotype - salt-wasting
      adrenal crisis - and correspondingly the only one whose acute management is
      glucocorticoid and mineralocorticoid replacement rather than anything
      addressed to sex development. 21-hydroxylase deficiency is about 90% of
      CAH and is described here as the representative route, but the member
      entity MONDO:0018479 is wider: 11-beta-hydroxylase (CYP11B1),
      3-beta-hydroxysteroid dehydrogenase type 2 (HSD3B2), and P450
      oxidoreductase (POR) deficiency each reach the same 46,XX presentation
      through a different block in the same steroidogenic pathway, and POR
      deficiency additionally impairs placental aromatization, which is the
      aromatase-deficiency route. It is also the member whose disease entity is
      widest of the group: the same enzyme block in a 46,XY fetus produces adrenal
      insufficiency with no genital atypia at all.
    gene:
      preferred_term: CYP21A2
      term:
        id: hgnc:2600
        label: CYP21A2
    biological_processes:
    - preferred_term: C21-steroid hormone biosynthetic process
      term:
        id: GO:0006700
        label: C21-steroid hormone biosynthetic process
      modifier: DECREASED
  evidence:
  - reference: PMID:31533357
    reference_title: "46,XX DSD due to Androgen Excess in Monogenic Disorders of Steroidogenesis: Genetic, Biochemical, and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The most common condition that presents a normal 46,XX karyotype and DSD is
      congenital adrenal hyperplasia (CAH) due to severe or complete
      21-hydroxylase deficiency
    explanation: >-
      Establishes CAH as the numerically dominant member of this grouping and
      places it in the androgen-excess arm.
- member: Aromatase Deficiency
  member_type: DISEASE
  disease_term:
    preferred_term: aromatase deficiency
    term:
      id: MONDO:0013301
      label: aromatase deficiency
  differentiating_mechanisms:
  - description: >-
      The androgen-excess member in which the excess is placental and gonadal
      rather than adrenal, and in which the primary lesion is a failure to remove
      androgen rather than a failure to make cortisol. Biallelic CYP19A1
      loss-of-function blocks the aromatization of androgen precursors to
      estrogens, so precursors crossing the placenta from the fetal adrenal are
      not cleared; the fetus is virilized and, distinctively for this group, so
      is the mother during the pregnancy. It is the only member whose postnatal
      course is dominated by estrogen deficiency - unfused epiphyses, tall stature,
      osteopenia, and a polycystic ovarian picture at puberty - which makes
      estrogen replacement rather than androgen suppression the treatment axis.
    gene:
      preferred_term: CYP19A1
      term:
        id: hgnc:2594
        label: CYP19A1
    biological_processes:
    - preferred_term: estrogen biosynthetic process
      term:
        id: GO:0006703
        label: estrogen biosynthetic process
      modifier: DECREASED
  evidence:
  - reference: PMID:31533357
    reference_title: "46,XX DSD due to Androgen Excess in Monogenic Disorders of Steroidogenesis: Genetic, Biochemical, and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      in contrast, aromatase deficiency mainly involves the steroidogenetic
      activity of the gonads
    explanation: >-
      Distinguishes the tissue of origin of the androgen excess in aromatase
      deficiency from the adrenal origin in the CAH members of this grouping.
  - reference: PMID:31533357
    reference_title: "46,XX DSD due to Androgen Excess in Monogenic Disorders of Steroidogenesis: Genetic, Biochemical, and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Fetuses that lack aromatase activity are not able to convert the DHEA-S
      that is produced by the fetal adrenal gland into estrogens in the placenta;
      DHEA-S is, therefore, converted to testosterone, resulting in the
      virilization of both the fetus and the mother.
    explanation: >-
      States the placental origin of the fetal androgen excess and the maternal
      virilization, which are the two features that separate this member from
      the adrenal androgen-excess route.
- member: 46,XX testicular disorder of sex development
  member_type: DISEASE
  disease_term:
    preferred_term: 46,XX testicular disorder of sex development
    term:
      id: MONDO:0100249
      label: 46,XX testicular disorder of sex development
  differentiating_mechanisms:
  - description: >-
      The sex-reversal member: the lesion is in gonadal determination, not in
      steroidogenesis, and the direction of the defect is the opposite of every
      other member - a gonad is built as a testis rather than failing to be built
      as an ovary. Around 90% of cases carry ectopic SRY translocated onto an X
      chromosome or an autosome; SRY-negative cases arise from regulatory
      copy-number variants that overexpress the pro-testis factors SOX9 or SOX3,
      or from loss of the pro-ovarian, anti-testis factors RSPO1 and WNT4. It is
      the only member in which Mullerian structures are ordinarily absent, and
      the only one whose typical adult presentation is azoospermic infertility
      rather than atypical genitalia in the newborn.
    gene:
      preferred_term: SRY
      term:
        id: hgnc:11311
        label: SRY
    biological_processes:
    - preferred_term: sex determination
      term:
        id: GO:0007530
        label: sex determination
  evidence:
  - reference: PMID:38721146
    reference_title: "Testicular differentiation in 46,XX DSD: an overview of genetic causes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This includes translocation of SRY to the X chromosome or an autosome. In
      the absence of SRY, other genes associated with testis development may be
      overexpressed or there may be a reduction in the activity of
      pro-ovarian/antitesticular factors.
    explanation: >-
      States the gonadal-determination mechanism that separates this member from
      the steroidogenic members of the grouping.
- member: 46,XX Gonadal Dysgenesis
  member_type: DISEASE
  disease_term:
    preferred_term: 46,XX gonadal dysgenesis
    term:
      id: MONDO:0009299
      label: 46 XX gonadal dysgenesis
  differentiating_mechanisms:
  - description: >-
      The member with no androgen excess and no ectopic testis: the ovary itself
      fails, through failure of ovarian development, germ-cell or follicle-pool
      depletion, follicular arrest, or gonadotropin resistance. It is
      consequently the only member that ordinarily presents with typical female
      external genitalia, and it is recognized not in the newborn but at
      adolescence, as absent puberty and primary amenorrhea with
      hypergonadotropic hypoestrogenism. Its inclusion is what makes this
      grouping a category rather than a mechanism: it shares the karyotype and
      the diagnostic pathway with the virilized members while sharing neither
      their steroidogenic lesion nor their presentation.
    biological_processes:
    - preferred_term: female gonad development
      term:
        id: GO:0008585
        label: female gonad development
      modifier: DECREASED
    - preferred_term: ovarian follicle development
      term:
        id: GO:0001541
        label: ovarian follicle development
      modifier: DECREASED
  evidence:
  - reference: PMID:26846580
    reference_title: "Molecular mechanisms associated with 46,XX disorders of sex development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We discuss how disruption to these molecular pathways can lead to 46,XX
      disorders of ovarian development.
    explanation: >-
      Places disorders of ovarian development inside the 46,XX DSD category,
      which is the basis for listing gonadal dysgenesis as a member.
references:
- reference: PMID:34441313
  title: "46,XX DSD: Developmental, Clinical and Genetic Aspects."
  findings:
  - statement: >-
      The classification this grouping follows, and the reason it is a category
      rather than a mechanism. DSD are partitioned first by karyotype, and the
      46,XX category is then subdivided into gonadal-differentiation disorders,
      androgen-excess disorders, and structural/Mullerian disorders - three
      independent mechanistic arms under one karyotype heading.
    supporting_text: >-
      The 46,XX DSD are classified as follows: 1. disorders of gonadal
      differentiation (testicular DSD—SRY positive, SOX9 duplication;
      ovotesticular DSD; primary ovarian insufficiency due to genes involved in
      gonadal development—FSH receptor mutation, NR5A1, WT1; syndromic forms); 2.
      disorders with excessive amounts of androgens, such as fetal
      cause—congenital adrenal hyperplasia—21 hydroxylase deficiency, 11 beta
      hydroxylase deficiency, 3 beta hydroxysteroid dehydrogenase deficiency;
      virilizing ovarian tumors; virilizing adrenal tumors; glucocorticoid
      receptor gene mutation, POR; placental cause—aromatase deficiency, POR;
      maternal cause—luteoma, exogenous
  - statement: >-
      Karyotype, not mechanism, is the first partition in the DSD classification
      the clinic uses - which is exactly the axis this grouping records and the
      axis the existing mechanism-based DSD groupings cannot express.
    supporting_text: >-
      DSD are classified, depending on karyotype, into the following three
      categories: 46,XX DSD, 46,XY DSD, and sex chromosomes abnormalities DSD
- reference: PMID:26820577
  title: "Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care."
  findings:
  - statement: >-
      The nomenclature and care framework this entry is written in, updating the
      2006 Chicago consensus. Supports describing these conditions by karyotype
      and mechanism, and framing care around quality of life and disclosure
      rather than around the retired intersex terminology.
    supporting_text: >-
      The goal of this update regarding the diagnosis and care of persons with
      disorders of sex development (DSDs) is to address changes in the clinical
      approach since the 2005 Consensus Conference
- reference: PMID:20688619
  title: "Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals."
  findings:
  - statement: >-
      An independent statement of the same three-category partition of 46,XX DSD
      that this grouping's membership follows, and the source for the
      nomenclature choice recorded in the description - "disorders of sex
      development" replacing "intersex disorders", and testicular DSD replacing
      "XX males".
    supporting_text: >-
      The term "disorders of sex development" (DSD) is proposed to substitute
      the previous term "intersex disorders". Three main categories have been
      used to describe DSD in the 46,XX individual: 1) disorders of gonadal
      (ovarian) development: ovotesticular
      DSD, previously named true hermaphroditism, testicular DSD, previously
      named XX males, and gonadal dysgenesis; 2) disorders related to androgen
      excess (congenital adrenal hyperplasia, aromatase deficiency and P450
      oxidoreductase deficiency); and 3) other rare disorders.
- reference: PMID:20541149
  title: "46,XX DSD: the masculinised female."
  findings:
  - statement: >-
      Illustrates why the karyotype category needs an explicit membership
      boundary. This review treats 46,XX DSD as coextensive with the
      androgen-excess arm, asserting a single final common pathway through fetal
      androgen exposure. That is accurate for the CAH and aromatase-deficiency
      members and false for the gonadal members, where the androgen exposure is a
      consequence of a determined testis or is absent altogether - so the
      "final common pathway" claim is scoped to one arm, not to the group.
    supporting_text: >-
      The final common pathway of all 46,XX DSDs is excess dihydrotestosterone
      (DHT) or potent foreign androgen in the genital tissue during the critical
      period of sexual differentiation.
notes: >-
  Coverage is incomplete by design rather than by oversight. The third arm of the
  classification - the structural and Mullerian disorders - has no dismech Disease
  entry, so it contributes no member here. Mayer-Rokitansky-Kuster-Hauser syndrome
  is an open stub (stubs/Mayer-Rokitansky-Kuster-Hauser_Syndrome.yaml); 46,XX
  ovotesticular DSD, cloacal exstrophy, vaginal atresia, and the virilizing
  adrenal and ovarian tumour causes are not yet curated. Each would add a further
  mechanistically independent arm and would strengthen, not weaken, the split
  rationale above.

  NR5A1-related sex development disorder is deliberately not listed. It is a
  curated dismech entry and NR5A1 variants do cause 46,XX testicular and
  ovotesticular DSD, but the entry is written across both karyotypes and its
  dominant presentation is 46,XY DSD; listing it would make the 46,XX karyotype
  criterion untrue of a member. Its 46,XX arm is already represented here through
  46,XX testicular DSD, which names NR5A1 among its causes.

  Congenital adrenal hyperplasia and aromatase deficiency are listed even though
  their disease entities are not karyotype-restricted, because they are the
  commonest causes of the clinical category and omitting them would make the
  grouping unrecognizable as 46,XX DSD. The consequence is recorded in the MONDO
  mapping justification: the grouping is not a subset of MONDO:0017576, which is
  part of why the mapping predicate is closeMatch.

  The listed members are audited against NECESSARY criteria only. There are no
  SUFFICIENT criteria, so `just check-groupings` will not propose candidate
  members from elsewhere in the knowledge base - deliberately, because the
  defining property is a karyotype the criteria vocabulary cannot express, and a
  process-only rule would match every steroidogenic and gonadal disorder in the
  knowledge base regardless of karyotype.