46,XY complete gonadal dysgenesis

Mendelian MONDO:0010765 Pathograph 11 Disorder of sex development Gonadal development disorder Amenorrhea disorder

46,XY complete gonadal dysgenesis is a genetically heterogeneous disorder of sex development in which individuals with a 46,XY karyotype develop a female phenotype because testis determination fails. The shared disease mechanism is severe impairment of testis-determining and gonadal differentiation pathways, producing streak gonads, absent or markedly reduced sex-steroid production, delayed puberty, primary amenorrhea, hypergonadotropic hypogonadism, and a substantial risk of gonadoblastoma or dysgerminoma in dysgenetic gonads.

1
Mappings
0
Definitions
0
Inheritance
3
Pathophysiology
0
Histopathology
5
Phenotypes
11
Pathograph
3
Genes
1
Treatments
0
Subtypes
2
Differentials
0
Datasets
0
Trials
0
Models
🔗

Mappings

MONDO
MONDO:0010765 46,XY complete gonadal dysgenesis
skos:exactMatch MONDO
⚙

Pathophysiology

3
Failure of testis-determining signaling
46,XY complete gonadal dysgenesis arises when critical determinants of testis development such as SRY, NR5A1, or DHH are disrupted, preventing male gonadal differentiation in an XY embryo.
SRY link DHH link NR5A1 link
Show evidence (2 references)
PMID:33570214 SUPPORT Human Clinical
"The mutation affects down regulation of male sex differentiation pathway and is responsible for 46,XY sex reversal female with gonadal dysgenesis."
This directly supports failed male sex-determination signaling as a core proximal mechanism.
PMID:30298535 SUPPORT Human Clinical
"In humans, mutations of Desert Hedgehog gene (DHH) have been described in patients with 46,XY gonadal dysgenesis (GD), associated or not with polyneuropathy."
This shows that impaired DHH-mediated gonadal signaling is one disease-causing mechanistic route in 46,XY complete gonadal dysgenesis.
Streak gonads and gonadal failure
Dysgenetic streak gonads do not sustain normal pubertal hormone production and create the anatomic substrate for gonadal tumor risk.
steroid hormone biosynthetic process link ↓ DECREASED
Show evidence (1 reference)
PMID:35720238 SUPPORT Human Clinical
"Complete gonadal dysgenesis or Swyer syndrome is a rare genetic disorder characterized by 46,XY karyotype and female phenotype with undeveloped streak gonads and high malignancy risk."
This directly supports streak gonads as the defining structural lesion.
Hypergonadotropic pubertal failure
Loss of gonadal hormone production produces delayed puberty, primary amenorrhea, and a hypergonadotropic endocrine pattern.
steroid hormone mediated signaling pathway link ↓ DECREASED
Show evidence (1 reference)
PMID:35720238 SUPPORT Human Clinical
"Therefore, women with amenorrhea and lack of secondary sexual characteristics require careful investigation."
This supports the characteristic endocrine and pubertal failure state in affected individuals.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for 46,XY complete gonadal dysgenesis 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

5
Endocrine 2
Delayed puberty Delayed puberty (HP:0000823)
Show evidence (1 reference)
PMID:35720238 SUPPORT Human Clinical
"The condition usually manifests in teenage and young adults with delayed puberty and primary amenorrhea."
This directly supports delayed puberty as a core presenting feature.
Hypergonadotropic hypogonadism Hypergonadotropic hypogonadism (HP:0000815)
Show evidence (1 reference)
PMID:31809259 PARTIAL Human Clinical
"The initial laboratory investigation in our hospital revealed hypergonadotrophic hypogonadism (FSH 130 IU/L, LH 2 IU/L, serum estradiol <5 pg/mL) with confirmed 46, XX karyotype."
Although this is from the closely related 46,XX gonadal dysgenesis phenotype, it supports the expected endocrine signature of gonadal failure used in DSD workup.
Genitourinary 3
Gonadal dysgenesis Gonadal dysgenesis (HP:0000133)
Show evidence (1 reference)
PMID:35720238 SUPPORT Human Clinical
"Complete gonadal dysgenesis or Swyer syndrome is a rare genetic disorder characterized by 46,XY karyotype and female phenotype with undeveloped streak gonads and high malignancy risk."
This directly supports gonadal dysgenesis as the structural hallmark.
Primary amenorrhea Primary amenorrhea (HP:0000786)
Show evidence (1 reference)
PMID:35720238 SUPPORT Human Clinical
"The condition usually manifests in teenage and young adults with delayed puberty and primary amenorrhea."
This directly supports primary amenorrhea as a defining presentation.
Female phenotype with 46,XY karyotype Female external genitalia in individual with 46,XY karyotype (HP:0008730)
Show evidence (1 reference)
PMID:33570214 SUPPORT Human Clinical
"The cytogenetic analysis confirmed 46,XY sex reversal karyotype of a female."
This directly supports sex reversal as a defining clinical phenotype.
🧬

Genetic Associations

3
SRY (Causal pathogenic variant in a subset of cases)
Show evidence (1 reference)
PMID:33570214 SUPPORT Human Clinical
"The patient was confirmed with nucleotide substitution (c.226C>A; p.Arg76Ser) at in HMG box domain of SRY gene that causes 46,XY sex reversal female."
This directly links an SRY pathogenic variant to 46,XY complete gonadal dysgenesis.
DHH (Causal biallelic pathogenic variant in a subset of cases)
Show evidence (1 reference)
PMID:30298535 SUPPORT Human Clinical
"In humans, mutations of Desert Hedgehog gene (DHH) have been described in patients with 46,XY gonadal dysgenesis (GD), associated or not with polyneuropathy."
This directly supports DHH as a causal gene for a mechanistically defined subset of 46,XY gonadal dysgenesis.
NR5A1 (Causal pathogenic variant in a subset of cases)
Show evidence (1 reference)
PMID:19246354 PARTIAL Human Clinical
"Mutation of NR5A1 causes 46,XY disorders of sex development, with or without adrenal failure, but growing experimental evidence from studies in mice suggests a key role for this factor in ovarian development and function as well."
This supports NR5A1 as an established DSD gene that also contributes to 46,XY gonadal dysgenesis phenotypes.
💊

Treatments

1
Prophylactic gonadectomy
Action: gonadectomy MAXO:0001055
Early gonadectomy is used to reduce the substantial gonadal malignancy risk associated with dysgenetic streak gonads.
Show evidence (1 reference)
PMID:35720238 SUPPORT Human Clinical
"Gonadectomy was performed in 12 cases (80%)."
This directly supports gonadectomy as a standard management step in many affected patients.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from 46,XY complete gonadal dysgenesis:

Complete androgen insensitivity syndrome Not Yet Curated MONDO:0021023
Overlapping Features Complete androgen insensitivity syndrome can also present as a phenotypic female with a 46,XY karyotype, but differs by the presence of testes rather than streak gonads.
Mayer-Rokitansky-Kuster-Hauser syndrome Not Yet Curated MONDO:0017771
Overlapping Features MRKH syndrome enters the differential diagnosis of primary amenorrhea in a phenotypically female patient, but normal ovarian function and 46,XX karyotype distinguish it from 46,XY complete gonadal dysgenesis.
{ }

Source YAML

click to show 
name: 46,XY complete gonadal dysgenesis
creation_date: '2026-04-14T12:00:00Z'
updated_date: '2026-04-15T01:00:00Z'
category: Mendelian
description: >-
  46,XY complete gonadal dysgenesis is a genetically heterogeneous disorder of
  sex development in which individuals with a 46,XY karyotype develop a female
  phenotype because testis determination fails. The shared disease mechanism is
  severe impairment of testis-determining and gonadal differentiation pathways,
  producing streak gonads, absent or markedly reduced sex-steroid production,
  delayed puberty, primary amenorrhea, hypergonadotropic hypogonadism, and a
  substantial risk of gonadoblastoma or dysgerminoma in dysgenetic gonads.
disease_term:
  preferred_term: 46,XY complete gonadal dysgenesis
  term:
    id: MONDO:0010765
    label: 46,XY complete gonadal dysgenesis
synonyms:
- Swyer syndrome
- 46,XY pure gonadal dysgenesis
- 46,XY sex reversal
parents:
- Disorder of sex development
- Gonadal development disorder
- Amenorrhea disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010765
      label: 46,XY complete gonadal dysgenesis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
pathophysiology:
- name: Failure of testis-determining signaling
  description: >-
    46,XY complete gonadal dysgenesis arises when critical determinants of
    testis development such as SRY, NR5A1, or DHH are disrupted, preventing
    male gonadal differentiation in an XY embryo.
  genes:
  - preferred_term: SRY
    term:
      id: hgnc:11311
      label: SRY
  - preferred_term: DHH
    term:
      id: hgnc:3719
      label: DHH
  - preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  evidence:
  - reference: PMID:33570214
    reference_title: >-
      A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function
      in 46,XY sex reversal female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation affects down regulation of male sex differentiation pathway
      and is responsible for 46,XY sex reversal female with gonadal
      dysgenesis.
    explanation: >-
      This directly supports failed male sex-determination signaling as a core
      proximal mechanism.
  - reference: PMID:30298535
    reference_title: >-
      In vitro functional characterization of the novel DHH mutations
      p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In humans, mutations of Desert Hedgehog gene (DHH) have been described in
      patients with 46,XY gonadal dysgenesis (GD), associated or not with
      polyneuropathy.
    explanation: >-
      This shows that impaired DHH-mediated gonadal signaling is one
      disease-causing mechanistic route in 46,XY complete gonadal dysgenesis.
  downstream:
  - target: Streak gonads and gonadal failure
    description: >-
      Absent testicular differentiation leaves dysgenetic streak gonads with
      little functional steroidogenic tissue.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35720238
      reference_title: >-
        Complete gonadal dysgenesis analysis in the population of Latvia:
        malignant outcomes and a review of literature.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Complete gonadal dysgenesis or Swyer syndrome is a rare genetic
        disorder characterized by 46,XY karyotype and female phenotype with
        undeveloped streak gonads and high malignancy risk.
      explanation: >-
        This directly links failed gonadal differentiation to undeveloped
        streak gonads in the disease.
  - target: Female phenotype with 46,XY karyotype
    description: Failed testis determination leads to female external development despite an XY karyotype.
    causal_link_type: DIRECT
- name: Streak gonads and gonadal failure
  description: >-
    Dysgenetic streak gonads do not sustain normal pubertal hormone production
    and create the anatomic substrate for gonadal tumor risk.
  biological_processes:
  - preferred_term: steroid hormone biosynthetic process
    term:
      id: GO:0006694
      label: steroid biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:35720238
    reference_title: >-
      Complete gonadal dysgenesis analysis in the population of Latvia:
      malignant outcomes and a review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete gonadal dysgenesis or Swyer syndrome is a rare genetic disorder
      characterized by 46,XY karyotype and female phenotype with undeveloped
      streak gonads and high malignancy risk.
    explanation: >-
      This directly supports streak gonads as the defining structural lesion.
  downstream:
  - target: Gonadal dysgenesis
    description: The structural consequence of failed gonadal differentiation is gonadal dysgenesis.
    causal_link_type: DIRECT
  - target: Hypergonadotropic pubertal failure
    description: >-
      Gonadal failure causes absent spontaneous pubertal progression, primary
      amenorrhea, and hypergonadotropic hypogonadism.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35720238
      reference_title: >-
        Complete gonadal dysgenesis analysis in the population of Latvia:
        malignant outcomes and a review of literature.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The condition usually manifests in teenage and young adults with delayed
        puberty and primary amenorrhea.
      explanation: >-
        This directly supports pubertal failure as a downstream clinical outcome
        of gonadal failure.
- name: Hypergonadotropic pubertal failure
  description: >-
    Loss of gonadal hormone production produces delayed puberty, primary
    amenorrhea, and a hypergonadotropic endocrine pattern.
  biological_processes:
  - preferred_term: steroid hormone mediated signaling pathway
    term:
      id: GO:0043401
      label: steroid hormone receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:35720238
    reference_title: >-
      Complete gonadal dysgenesis analysis in the population of Latvia:
      malignant outcomes and a review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, women with amenorrhea and lack of secondary sexual
      characteristics require careful investigation.
    explanation: >-
      This supports the characteristic endocrine and pubertal failure state in
      affected individuals.
  downstream:
  - target: Delayed puberty
    description: Loss of gonadal steroid output causes delayed puberty.
    causal_link_type: DIRECT
  - target: Primary amenorrhea
    description: Absent pubertal gonadal hormone production causes primary amenorrhea.
    causal_link_type: DIRECT
  - target: Hypergonadotropic hypogonadism
    description: Gonadal failure produces the characteristic hypergonadotropic hypogonadism phenotype.
    causal_link_type: DIRECT
phenotypes:
- name: Gonadal dysgenesis
  category: Reproductive
  diagnostic: true
  description: >-
    Undeveloped streak gonads are the defining structural abnormality in the
    disease.
  phenotype_term:
    preferred_term: gonadal dysgenesis
    term:
      id: HP:0000133
      label: Gonadal dysgenesis
  evidence:
  - reference: PMID:35720238
    reference_title: >-
      Complete gonadal dysgenesis analysis in the population of Latvia:
      malignant outcomes and a review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete gonadal dysgenesis or Swyer syndrome is a rare genetic disorder
      characterized by 46,XY karyotype and female phenotype with undeveloped
      streak gonads and high malignancy risk.
    explanation: >-
      This directly supports gonadal dysgenesis as the structural hallmark.
- name: Delayed puberty
  category: Reproductive
  diagnostic: true
  description: >-
    Pubertal progression is delayed or absent because dysgenetic gonads do not
    provide normal sex-steroid production.
  phenotype_term:
    preferred_term: delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  evidence:
  - reference: PMID:35720238
    reference_title: >-
      Complete gonadal dysgenesis analysis in the population of Latvia:
      malignant outcomes and a review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The condition usually manifests in teenage and young adults with delayed
      puberty and primary amenorrhea.
    explanation: >-
      This directly supports delayed puberty as a core presenting feature.
- name: Primary amenorrhea
  category: Reproductive
  diagnostic: true
  description: >-
    Menarche fails to occur because complete gonadal failure prevents normal
    pubertal maturation.
  phenotype_term:
    preferred_term: primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  evidence:
  - reference: PMID:35720238
    reference_title: >-
      Complete gonadal dysgenesis analysis in the population of Latvia:
      malignant outcomes and a review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The condition usually manifests in teenage and young adults with delayed
      puberty and primary amenorrhea.
    explanation: >-
      This directly supports primary amenorrhea as a defining presentation.
- name: Hypergonadotropic hypogonadism
  category: Endocrine
  diagnostic: true
  description: >-
    Gonadal failure produces low sex-steroid output with compensatory
    gonadotropin elevation.
  phenotype_term:
    preferred_term: hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  evidence:
  - reference: PMID:31809259
    reference_title: >-
      Misdiagnosis of Mullerian agenesis in a patient with 46, XX gonadal
      dysgenesis: a missed opportunity for prevention of osteoporosis.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The initial laboratory investigation in our hospital revealed
      hypergonadotrophic hypogonadism (FSH 130 IU/L, LH 2 IU/L, serum estradiol
      <5 pg/mL) with confirmed 46, XX karyotype.
    explanation: >-
      Although this is from the closely related 46,XX gonadal dysgenesis
      phenotype, it supports the expected endocrine signature of gonadal
      failure used in DSD workup.
- name: Female phenotype with 46,XY karyotype
  category: Reproductive
  diagnostic: true
  description: >-
    Affected individuals have a female phenotype despite a 46,XY karyotype.
  phenotype_term:
    preferred_term: Female external genitalia in individual with 46,XY karyotype
    term:
      id: HP:0008730
      label: Female external genitalia in individual with 46,XY karyotype
  evidence:
  - reference: PMID:33570214
    reference_title: >-
      A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function
      in 46,XY sex reversal female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cytogenetic analysis confirmed 46,XY sex reversal karyotype of a
      female.
    explanation: >-
      This directly supports sex reversal as a defining clinical phenotype.
biochemical: []
genetic:
- name: SRY
  gene_term:
    preferred_term: SRY
    term:
      id: hgnc:11311
      label: SRY
  association: Causal pathogenic variant in a subset of cases
  evidence:
  - reference: PMID:33570214
    reference_title: >-
      A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function
      in 46,XY sex reversal female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was confirmed with nucleotide substitution (c.226C>A;
      p.Arg76Ser) at in HMG box domain of SRY gene that causes 46,XY sex
      reversal female.
    explanation: >-
      This directly links an SRY pathogenic variant to 46,XY complete gonadal
      dysgenesis.
- name: DHH
  gene_term:
    preferred_term: DHH
    term:
      id: hgnc:3719
      label: DHH
  association: Causal biallelic pathogenic variant in a subset of cases
  evidence:
  - reference: PMID:30298535
    reference_title: >-
      In vitro functional characterization of the novel DHH mutations
      p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In humans, mutations of Desert Hedgehog gene (DHH) have been described
      in patients with 46,XY gonadal dysgenesis (GD), associated or not with
      polyneuropathy.
    explanation: >-
      This directly supports DHH as a causal gene for a mechanistically defined
      subset of 46,XY gonadal dysgenesis.
- name: NR5A1
  gene_term:
    preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  association: Causal pathogenic variant in a subset of cases
  evidence:
  - reference: PMID:19246354
    reference_title: Mutations in NR5A1 associated with ovarian insufficiency.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation of NR5A1 causes 46,XY disorders of sex development, with or
      without adrenal failure, but growing experimental evidence from studies
      in mice suggests a key role for this factor in ovarian development and
      function as well.
    explanation: >-
      This supports NR5A1 as an established DSD gene that also contributes to
      46,XY gonadal dysgenesis phenotypes.
environmental: []
treatments:
- name: Prophylactic gonadectomy
  description: >-
    Early gonadectomy is used to reduce the substantial gonadal malignancy risk
    associated with dysgenetic streak gonads.
  treatment_term:
    preferred_term: gonadectomy
    term:
      id: MAXO:0001055
      label: gonadectomy
  evidence:
  - reference: PMID:35720238
    reference_title: >-
      Complete gonadal dysgenesis analysis in the population of Latvia:
      malignant outcomes and a review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gonadectomy was performed in 12 cases (80%).
    explanation: >-
      This directly supports gonadectomy as a standard management step in many
      affected patients.
diagnosis:
- name: Karyotype analysis
  description: >-
    Cytogenetic testing is used to confirm the defining 46,XY chromosomal
    complement in a phenotypically female patient.
  diagnosis_term:
    preferred_term: karyotyping
    term:
      id: MAXO:0001611
      label: karyotyping
  evidence:
  - reference: PMID:33570214
    reference_title: >-
      A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function
      in 46,XY sex reversal female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cytogenetic analysis confirmed 46,XY sex reversal karyotype of a
      female.
    explanation: >-
      This directly supports karyotype analysis as a diagnostic procedure.
- name: Gonadal histopathology
  description: >-
    Histopathologic examination of resected gonads is used to detect
    gonadoblastoma or dysgerminoma in dysgenetic gonadal tissue.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  evidence:
  - reference: PMID:35720238
    reference_title: >-
      Complete gonadal dysgenesis analysis in the population of Latvia:
      malignant outcomes and a review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The histopathology results from the gonadal biopsy showed malignancy in 7
      cases (58.3%).
    explanation: >-
      This directly supports gonadal histopathology as an important diagnostic
      and risk-stratifying procedure.
- name: Targeted molecular testing
  description: >-
    Molecular testing of established DSD genes helps identify the causal lesion
    in genetically heterogeneous cases.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:33570214
    reference_title: >-
      A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function
      in 46,XY sex reversal female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using molecular approach, we screened open reading frame of the SRY gene
      by PCR and targeted DNA Sanger sequencing.
    explanation: >-
      This directly supports gene-level molecular testing in the diagnostic
      workup.
differential_diagnoses:
- name: Complete androgen insensitivity syndrome
  description: >-
    Complete androgen insensitivity syndrome can also present as a phenotypic
    female with a 46,XY karyotype, but differs by the presence of testes rather
    than streak gonads.
  disease_term:
    preferred_term: complete androgen insensitivity syndrome
    term:
      id: MONDO:0021023
      label: complete androgen insensitivity syndrome
- name: Mayer-Rokitansky-Kuster-Hauser syndrome
  description: >-
    MRKH syndrome enters the differential diagnosis of primary amenorrhea in a
    phenotypically female patient, but normal ovarian function and 46,XX
    karyotype distinguish it from 46,XY complete gonadal dysgenesis.
  disease_term:
    preferred_term: Mayer-Rokitansky-Kuster-Hauser syndrome
    term:
      id: MONDO:0017771
      label: Mayer-Rokitansky-Kuster-Hauser syndrome
clinical_trials: []
datasets: []
notes: >-
  Asta research was completed for this disorder. Final curation prioritized
  direct human clinical and mechanistic references from the local cache and
  disorder-specific PubMed literature.