46,XX Gonadal Dysgenesis

🔗

Mappings

MONDO

MONDO:0009299 46 XX gonadal dysgenesis

Primary MONDO disease identifier for 46,XX gonadal dysgenesis.

📘

Definitions

1

Clinical disease framing for 46,XX gonadal dysgenesis

46,XX gonadal dysgenesis is a disease-level ovarian developmental failure state defined by a normal 46,XX karyotype, phenotypically female external genitalia, underdeveloped or streak ovaries, absent spontaneous puberty, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism.

CASE_DEFINITION Disease anchor for isolated 46,XX gonadal dysgenesis rather than a generic 46,XX DSD phenotype bucket.

Show evidence (1 reference)

PMID:26485283 SUPPORT Human Clinical

"XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder that is characterized by underdeveloped, dysfunctional ovaries, with subsequent lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism."

This abstract provides a compact disease-level definition for isolated 46,XX gonadal dysgenesis.

👪

Inheritance

2

Autosomal recessive HP:0000007

Isolated FSHR-, NUP107-, and PSMC3IP-related forms are recessive, and Perrault-spectrum 46,XX ovarian dysfunction with hearing impairment is also recessive.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:26485283 SUPPORT Human Clinical

"Using homozygosity mapping and whole-exome sequencing, we identified a recessive missense mutation in nucleoporin-107 (NUP107, c.1339G>A, p.D447N)."

Establishes a recessive isolated subtype.

PMID:32423379 SUPPORT Other

"Perrault syndrome (MIM: 233400) is a rare recessive genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and ovarian dysfunction in females [1]."

Establishes recessive inheritance for the Perrault-spectrum branch.

Autosomal dominant with variable penetrance HP:0000006

NR5A1-related ovarian developmental failure can segregate dominantly with incomplete penetrance and variable expressivity, while rare recessive NR5A1 families have also been described.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:19246354 SUPPORT Human Clinical

"Families 1, 3, and 4 show a dominant mode of inheritance, whereas Family 2 shows a recessive mode."

Supports autosomal dominant inheritance for most NR5A1 families in this series and flags the documented recessive exception.

◆

Subtypes

5

gene

Ovarian dysgenesis 1 (FSHR-related) MONDO:0024463

FSHR link Autosomal recessive inheritance

Autosomal recessive FSHR-related ovarian dysgenesis caused by impaired follicle-stimulating hormone receptor binding and signal transduction in granulosa-cell pathways.

Show evidence (1 reference)

PMID:7553856 SUPPORT Human Clinical

"Hypergonadotropic ovarian dysgenesis (ODG) with normal karyotype is a heterogeneous condition that in some cases displays Mendelian recessive inheritance."

Establishes FSHR-related ovarian dysgenesis as a recessive subtype.

Ovarian dysgenesis 2 (NUP107-related) MONDO:0010349

NUP107 link Autosomal recessive inheritance

Autosomal recessive NUP107-related subtype linking nuclear pore dysfunction and defective oogenesis to isolated 46,XX gonadal dysgenesis.

Show evidence (1 reference)

PMID:26485283 SUPPORT Human Clinical

"Using homozygosity mapping and whole-exome sequencing, we identified a recessive missense mutation in nucleoporin-107 (NUP107, c.1339G>A, p.D447N)."

Defines the recessive NUP107-related subtype.

Ovarian dysgenesis 3 (PSMC3IP/HOP2-related) MONDO:0013689

PSMC3IP link Autosomal recessive inheritance

Autosomal recessive PSMC3IP-related subtype in which a homozygous HOP2 coactivator defect disrupts estrogen-driven transcription and follicular-pool maintenance.

Show evidence (1 reference)

PMID:21963259 SUPPORT Human Clinical

"Affected females were homozygous for a 3 bp deletion (NM_016556.2, c.600_602del) in the PSMC3IP gene, leading to deletion of a glutamic acid residue (p.Glu201del) in the highly conserved C-terminal acidic domain."

Defines the homozygous PSMC3IP-related subtype.

NR5A1-related 46,XX gonadal dysgenesis/ovarian insufficiency

NR5A1 link Autosomal dominant inheritance

NR5A1-related ovarian developmental failure overlaps 46,XX gonadal dysgenesis and primary ovarian insufficiency, most often through dominant familial variants with variable penetrance and expressivity.

Show evidence (1 reference)

PMID:19246354 SUPPORT Human Clinical

"Families 1, 3, and 4 show a dominant mode of inheritance, whereas Family 2 shows a recessive mode."

Supports dominant NR5A1 inheritance while preserving the reported variability in penetrance and inheritance mode.

syndromic

Perrault-spectrum 46,XX gonadal dysgenesis MONDO:0017312

HARS2 link HSD17B4 link CLPP link TWNK link LARS2 link Autosomal recessive inheritance

Autosomal recessive syndromic branch with ovarian dysgenesis or primary ovarian insufficiency in 46,XX individuals plus sensorineural hearing impairment.

Show evidence (1 reference)

PMID:32423379 SUPPORT Other

"Perrault syndrome (MIM: 233400) is a rare recessive genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and ovarian dysfunction in females [1]."

Supports the syndromic 46,XX gonadal-dysgenesis branch with hearing impairment.

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Pathophysiology

8

Genetic disruption of female gonad development

46,XX gonadal dysgenesis is genetically heterogeneous, but the shared proximal lesion is failure of gene programs required for ovarian development and maintenance.

female gonad development link ↓ DECREASED gonad development link ↓ DECREASED

Downstream

Impaired hormonal signaling and folliculogenesis Diverse causal lesions converge on disrupted ovarian signaling and follicle maturation.

Show evidence (2 references)

PMID:26485283 SUPPORT Human Clinical

"These results indicate a pivotal role for NUP107 in ovarian development and suggest that nucleoporin defects may play a role in milder and more common conditions such as premature ovarian failure."

This directly supports ovarian developmental failure as a proximal mechanism in 46,XX gonadal dysgenesis.

PMID:19246354 SUPPORT Human Clinical

"Mutations were associated with a range of ovarian anomalies, including 46,XX gonadal dysgenesis and 46,XX primary ovarian insufficiency."

This shows that multiple ovarian-development genes can anchor the same disease entity and its close overlap with ovarian insufficiency.

NUP107 nuclear-pore oogenesis defect

NUP107-related ovarian dysgenesis links a nuclear pore component to sex-specific defective oogenesis and ovarian development in 46,XX individuals.

oocyte link

NUP107 link

nuclear pore link

Downstream

Streak gonads and ovarian failure

Show evidence (2 references)

PMID:26485283 SUPPORT Model Organism

"NUP107 is a component of the nuclear pore complex, and the NUP107-associated protein SEH1 is required for oogenesis in Drosophila."

Supports the nuclear-pore and oogenesis mechanism for NUP107-related disease.

PMID:26485283 SUPPORT Model Organism

"In Drosophila, Nup107 knockdown in somatic gonadal cells resulted in female sterility, whereas males were fully fertile."

Supports a sex-specific ovarian requirement for NUP107 activity.

PSMC3IP estrogen-receptor coactivation failure

PSMC3IP/HOP2-related disease disrupts estrogen-driven nuclear-receptor coactivation, reducing fetal follicular-pool establishment and increasing vulnerability to follicular atresia during puberty.

oocyte link

PSMC3IP link

ovarian follicle development link ↓ DECREASED

Downstream

Impaired hormonal signaling and folliculogenesis

Show evidence (2 references)

PMID:21963259 SUPPORT In Vitro

"In cell lines, the p.Glu201del mutation abolished PSMC3IP activation of estrogen-driven transcription."

Directly supports loss of estrogen-driven transcriptional coactivation.

PMID:21963259 SUPPORT Human Clinical

"Impaired estrogenic signaling can lead to ovarian dysgenesis both by affecting the size of the follicular pool created during fetal development and by failing to counteract follicular atresia during puberty."

Links PSMC3IP-driven estrogenic-signaling failure to the developmental and pubertal ovarian phenotype.

FSHR receptor signaling resistance

FSHR-related ovarian dysgenesis impairs follicle-stimulating hormone receptor signaling, producing follicular arrest with hypergonadotropic ovarian failure.

granulosa cell link

FSHR link

response to follicle-stimulating hormone link ↓ DECREASED

Downstream

Impaired hormonal signaling and folliculogenesis

Show evidence (1 reference)

PMID:7553856 SUPPORT In Vitro

"Expression of the gene in transfected cells demonstrated a dramatic reduction of binding capacity and signal transduction, but apparently normal ligand-binding affinity of the mutated receptor."

Directly supports receptor signaling resistance as the FSHR mechanism.

NR5A1 steroidogenic transcription dosage defect

NR5A1-related ovarian insufficiency reflects impaired transcriptional activation of steroidogenic and follicle-growth genes in ovarian cells, with variable penetrance and expressivity across families.

granulosa cell link

NR5A1 link

estrogen biosynthetic process link ↓ DECREASED

Downstream

Streak gonads and ovarian failure

Show evidence (1 reference)

PMID:19246354 SUPPORT In Vitro

"Our data show that mutated forms of NR5A1, detected in subjects with anomalies of ovarian development and function, show quantitative impairment in the transactivation of two of these factors (CYP11A1 and CYP19A1)."

Directly supports impaired NR5A1 transcriptional output as the molecular mechanism.

Impaired hormonal signaling and folliculogenesis

A major shared mechanistic branch is reduced ovarian hormone-response and follicular maintenance, including impaired FSH signaling and defective estrogen-responsive transcription.

granulosa cell link oocyte link

response to follicle-stimulating hormone link ↓ DECREASED ovarian follicle development link ↓ DECREASED

Downstream

Streak gonads and ovarian failure Chronic failure of follicle development and ovarian signaling produces streak or severely underdeveloped ovaries with loss of reproductive function.

Show evidence (2 references)

PMID:7553856 SUPPORT In Vitro

"Expression of the gene in transfected cells demonstrated a dramatic reduction of binding capacity and signal transduction, but apparently normal ligand-binding affinity of the mutated receptor."

This directly supports impaired FSH signaling as one disease-causing mechanistic branch in 46,XX gonadal dysgenesis.

PMID:21963259 SUPPORT Human Clinical

"Impaired estrogenic signaling can lead to ovarian dysgenesis both by affecting the size of the follicular pool created during fetal development and by failing to counteract follicular atresia during puberty."

This supports defective estrogen-responsive transcription and accelerated follicular loss as another shared mechanistic branch.

Streak gonads and ovarian failure

The convergent anatomical outcome is a streak or severely underdeveloped ovary with little or no effective steroidogenic or follicular function.

estrogen biosynthetic process link ↓ DECREASED

Downstream

Hypoestrogenic hypergonadotropic state Ovarian failure lowers estrogen output and disinhibits pituitary gonadotropin secretion.

Show evidence (2 references)

PMID:26485283 SUPPORT Human Clinical

"XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder that is characterized by underdeveloped, dysfunctional ovaries, with subsequent lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism."

This supports underdeveloped dysfunctional ovaries as the shared anatomic lesion of the disease.

PMID:21963259 SUPPORT Human Clinical

"XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads."

This explicitly identifies streak gonads as the proximate cause of the endocrine and reproductive phenotype.

Hypoestrogenic hypergonadotropic state

Loss of ovarian steroidogenic function results in estrogen deficiency and compensatory elevation of pituitary gonadotropins, driving pubertal failure and amenorrhea.

gonadotropin secretion link ↑ INCREASED

Show evidence (2 references)

PMID:26485283 SUPPORT Human Clinical

"XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder that is characterized by underdeveloped, dysfunctional ovaries, with subsequent lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism."

This supports the downstream hypoestrogenic hypergonadotropic endocrine state as a core mechanistic consequence.

PMID:8855829 SUPPORT Human Clinical

"Clinically, both groups of patients were characterized by primary or early secondary amenorrhea, variable development of secondary sex characteristics, and high serum levels of FSH and LH."

This links the endocrine state to amenorrhea and impaired pubertal development in a mechanistically defined XX-GD subset.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

7

Ear 1

Sensorineural hearing impairment Sensorineural hearing impairment (HP:0000407)

Show evidence (1 reference)

PMID:32423379 SUPPORT Human Clinical

"Perrault syndrome (MIM: 233400) is a rare recessive genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and ovarian dysfunction in females [1]."

Supports hearing impairment as the key syndromic feature of the Perrault-spectrum subtype.

Endocrine 2

Delayed Puberty Delayed puberty (HP:0000823)

Show evidence (1 reference)

PMID:26485283 SUPPORT Human Clinical

"XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder that is characterized by underdeveloped, dysfunctional ovaries, with subsequent lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism."

The abstract explicitly supports absent spontaneous pubertal development, which maps to delayed puberty at the phenotype level.

Hypergonadotropic Hypogonadism Hypergonadotropic hypogonadism (HP:0000815)

Show evidence (2 references)

PMID:26485283 SUPPORT Human Clinical

"XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder that is characterized by underdeveloped, dysfunctional ovaries, with subsequent lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism."

This explicitly identifies hypergonadotropic hypogonadism as part of the core XX-GD phenotype.

PMID:8855829 SUPPORT Human Clinical

"Clinically, both groups of patients were characterized by primary or early secondary amenorrhea, variable development of secondary sex characteristics, and high serum levels of FSH and LH."

This supports elevated gonadotropins as the endocrine signature of a mechanistically defined XX-GD subset.

Genitourinary 4

Gonadal Dysgenesis Gonadal dysgenesis (HP:0000133)

Show evidence (1 reference)

PMID:26485283 SUPPORT Human Clinical

"XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder that is characterized by underdeveloped, dysfunctional ovaries, with subsequent lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism."

This directly supports gonadal dysgenesis as the structural hallmark phenotype.

Primary Amenorrhea Primary amenorrhea (HP:0000786)

Show evidence (1 reference)

PMID:21963259 SUPPORT Human Clinical

"XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads."

This directly supports primary amenorrhea as a core diagnostic phenotype.

Uterine Hypoplasia Aplasia/hypoplasia of the uterus (HP:0008684)

Show evidence (1 reference)

PMID:26485283 SUPPORT Human Clinical

"XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder that is characterized by underdeveloped, dysfunctional ovaries, with subsequent lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism."

This directly supports uterine hypoplasia as part of the core disease phenotype.

Female Infertility Female infertility (HP:0008222)

Show evidence (1 reference)

PMID:21963259 SUPPORT Human Clinical

"XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads."

Streak gonads imply loss of functional ovarian tissue and support female infertility as a downstream reproductive consequence.

🧬

Genetic Associations

4

NUP107 (CAUSATIVE)

Autosomal recessive

Show evidence (1 reference)

PMID:26485283 SUPPORT Human Clinical

"Using homozygosity mapping and whole-exome sequencing, we identified a recessive missense mutation in nucleoporin-107 (NUP107, c.1339G>A, p.D447N)."

This identifies NUP107 as a causal recessive gene for familial 46,XX gonadal dysgenesis.

PSMC3IP (CAUSATIVE)

Autosomal recessive

Show evidence (1 reference)

PMID:21963259 SUPPORT Human Clinical

"Affected females were homozygous for a 3 bp deletion (NM_016556.2, c.600_602del) in the PSMC3IP gene, leading to deletion of a glutamic acid residue (p.Glu201del) in the highly conserved C-terminal acidic domain."

This establishes PSMC3IP as a causal gene in a familial 46,XX gonadal dysgenesis pedigree.

FSHR (CAUSATIVE)

Autosomal recessive

Show evidence (1 reference)

PMID:7553856 SUPPORT Human Clinical

"We conclude that the mutation causes ODG in these families."

This provides direct causal evidence for FSHR-mediated ovarian dysgenesis.

NR5A1 (CAUSATIVE)

Autosomal dominant with variable penetrance

Show evidence (1 reference)

PMID:19246354 SUPPORT Human Clinical

"Mutations were associated with a range of ovarian anomalies, including 46,XX gonadal dysgenesis and 46,XX primary ovarian insufficiency."

This shows that NR5A1 can anchor both 46,XX gonadal dysgenesis and the adjacent ovarian-insufficiency phenotype space.

💊

Treatments

6

Pubertal induction and long-term hormone replacement

Action: sex hormone modifying agent therapy MAXO:0000282

Estrogen-based pubertal induction followed by estrogen-progestogen maintenance is used to initiate and sustain puberty, support secondary sexual characteristics, and reduce long-term consequences of hypoestrogenism.

Target Phenotypes: Delayed puberty ↗ Hypergonadotropic hypogonadism ↗

Show evidence (2 references)

PMID:36300209 SUPPORT Other

"Girls with hypogonadism require hormone replacement therapy to initiate and sustain puberty."

Supports pubertal induction and maintenance hormone replacement for hypogonadal adolescents.

PMID:35142292 SUPPORT Human Clinical

"Hormone replacement therapy remains the only therapeutic option for the development of secondary sexual characteristics and the prevention of osteoporosis."

This directly supports hormone replacement therapy as core conservative management for 46,XX gonadal dysgenesis.

Cyclic estrogen-progestogen maintenance when uterus is present

Action: sex hormone modifying agent therapy MAXO:0000282

Once estrogenized uterine tissue is present, cyclic progestogen is used with estrogen to oppose endometrial effects during long-term replacement.

Target Phenotypes: Hypergonadotropic hypogonadism ↗

Show evidence (1 reference)

PMID:31809259 SUPPORT Human Clinical

"Treatment with estrogen and progesterone are required for reducing the risk of endometrial hyperplasia and carcinoma, which will increase due to long-term application of estrogen without opposition."

Supports cyclic progestogen addition to estrogen replacement when uterine tissue is present.

Bone-health monitoring and calcium-vitamin D support

Action: Dual-energy X-ray absorptiometry procedure MAXO:0020004

Delayed diagnosis and prolonged hypoestrogenism can cause osteopenia or osteoporosis, so bone-density monitoring plus calcium and vitamin D support should accompany hormone replacement.

Show evidence (2 references)

PMID:31809259 SUPPORT Human Clinical

"Early initiation of estrogen therapy is essential to minimize bone loss. Moreover, lifelong oral calcium and vitamin D supplement should be given to maintain bone health."

Supports bone-focused management in hypoestrogenic 46,XX gonadal dysgenesis.

PMID:24945456 SUPPORT Other

"The goals of hormonal therapy extend beyond simply symptom relief to levels that support bone, cardiovascular, and sexual health."

General adolescent POI guidance supports bone-health goals for hormone therapy.

Fertility and reproductive counseling

Action: behavioral counseling MAXO:0000077

Counseling should cover infertility expectations, reproductive endocrinology referral, donor-oocyte or gestational-surrogacy pathways when relevant, and recurrence-risk implications for inherited subtypes.

Target Phenotypes: Female infertility ↗

Show evidence (2 references)

PMID:24945456 SUPPORT Other

"Patients and their families should be counseled on the effect of the patient's condition on future fertility, on the risk of comorbidities associated with primary ovarian insufficiency, and on the condition's potential for genetic inheritance."

Supports fertility and inheritance counseling in adolescent ovarian insufficiency.

PMID:31809259 PARTIAL Human Clinical

"She has been informed about future options for having children by adoption or gestational surrogacy."

Case-level evidence supports reproductive-option counseling, though it is not a comparative intervention study.

Psychologic support and longitudinal follow-up

Action: behavioral counseling MAXO:0000077

Diagnosis can affect self-esteem, emotional health, fertility expectations, and identity; longitudinal care should include psychologic counseling and at least annual follow-up for ovarian-insufficiency consequences.

Show evidence (2 references)

PMID:24945456 SUPPORT Other

"Psychologic counseling also should be offered because impaired self-esteem and emotional distress have been reported after diagnosis of primary ovarian insufficiency."

Supports psychologic counseling after diagnosis.

PMID:24945456 SUPPORT Other

"Once primary ovarian insufficiency is diagnosed, patients should be evaluated at least annually."

Supports longitudinal follow-up.

Audiology and hearing-support management for Perrault-spectrum cases

Action: audiologist evaluation MAXO:0000734

Perrault-spectrum patients need multidisciplinary hearing assessment and intervention planning in parallel with endocrine surveillance.

Target Phenotypes: Sensorineural hearing impairment ↗

Show evidence (1 reference)

PMID:32423379 SUPPORT Other

"Hearing loss should be assessed and treated by a multidisciplinary team including an audiologist and otolaryngologist."

Supports audiology-led hearing management for the Perrault-spectrum subtype.

{ }

Source YAML

click to show

name: 46,XX Gonadal Dysgenesis
creation_date: "2026-04-14T05:40:11Z"
updated_date: "2026-05-31T10:35:00Z"
category: Mendelian
description: >-
  46,XX gonadal dysgenesis is a rare, genetically heterogeneous ovarian
  developmental disorder in phenotypically female individuals with a normal
  46,XX karyotype. The shared disease mechanism is failure of ovarian
  development and folliculogenesis, producing streak or severely
  underdeveloped ovaries, estrogen deficiency, hypergonadotropic hypogonadism,
  absent spontaneous pubertal development, primary amenorrhea, uterine
  hypoplasia, and infertility. The entry includes isolated gene-defined forms
  and a Perrault-spectrum syndromic branch with sensorineural hearing
  impairment, but anchors ovarian developmental failure rather than broader
  46,XX disorder-of-sex-development phenotype mentions caused by other
  mechanisms such as prenatal androgen excess.
disease_term:
  preferred_term: 46,XX gonadal dysgenesis
  term:
    id: MONDO:0009299
    label: 46 XX gonadal dysgenesis
synonyms:
- 46 XX gonadal dysgenesis
- XX female gonadal dysgenesis
- 46,XX ovarian dysgenesis
- 46,XX pure gonadal dysgenesis
parents:
- Disorder of sex development
- Primary ovarian insufficiency
- Gonadal development disorder
definitions:
- name: Clinical disease framing for 46,XX gonadal dysgenesis
  definition_type: CASE_DEFINITION
  description: >-
    46,XX gonadal dysgenesis is a disease-level ovarian developmental failure
    state defined by a normal 46,XX karyotype, phenotypically female external
    genitalia, underdeveloped or streak ovaries, absent spontaneous puberty,
    primary amenorrhea, uterine hypoplasia, and hypergonadotropic
    hypogonadism.
  scope: >-
    Disease anchor for isolated 46,XX gonadal dysgenesis rather than a generic
    46,XX DSD phenotype bucket.
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous
      disorder that is characterized by underdeveloped, dysfunctional ovaries,
      with subsequent lack of spontaneous pubertal development, primary
      amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism.
    explanation: >-
      This abstract provides a compact disease-level definition for isolated
      46,XX gonadal dysgenesis.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0009299
      label: 46 XX gonadal dysgenesis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for 46,XX gonadal dysgenesis.
has_subtypes:
- name: ODG1-FSHR
  display_name: Ovarian dysgenesis 1 (FSHR-related)
  classification: gene
  description: >-
    Autosomal recessive FSHR-related ovarian dysgenesis caused by impaired
    follicle-stimulating hormone receptor binding and signal transduction in
    granulosa-cell pathways.
  subtype_term:
    preferred_term: ovarian dysgenesis 1
    term:
      id: MONDO:0024463
      label: ovarian dysgenesis 1
  genes:
  - preferred_term: FSHR
    term:
      id: hgnc:3969
      label: FSHR
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:7553856
    reference_title: >-
      Mutation in the follicle-stimulating hormone receptor gene causes
      hereditary hypergonadotropic ovarian failure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypergonadotropic ovarian dysgenesis (ODG) with normal karyotype is a
      heterogeneous condition that in some cases displays Mendelian recessive
      inheritance.
    explanation: >-
      Establishes FSHR-related ovarian dysgenesis as a recessive subtype.
- name: ODG2-NUP107
  display_name: Ovarian dysgenesis 2 (NUP107-related)
  classification: gene
  description: >-
    Autosomal recessive NUP107-related subtype linking nuclear pore dysfunction
    and defective oogenesis to isolated 46,XX gonadal dysgenesis.
  subtype_term:
    preferred_term: ovarian dysgenesis 2
    term:
      id: MONDO:0010349
      label: ovarian dysgenesis 2
  genes:
  - preferred_term: NUP107
    term:
      id: hgnc:29914
      label: NUP107
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using homozygosity mapping and whole-exome sequencing, we identified a
      recessive missense mutation in nucleoporin-107 (NUP107, c.1339G>A,
      p.D447N).
    explanation: >-
      Defines the recessive NUP107-related subtype.
- name: ODG3-PSMC3IP
  display_name: Ovarian dysgenesis 3 (PSMC3IP/HOP2-related)
  classification: gene
  description: >-
    Autosomal recessive PSMC3IP-related subtype in which a homozygous HOP2
    coactivator defect disrupts estrogen-driven transcription and follicular-pool
    maintenance.
  subtype_term:
    preferred_term: ovarian dysgenesis 3
    term:
      id: MONDO:0013689
      label: ovarian dysgenesis 3
  genes:
  - preferred_term: PSMC3IP
    term:
      id: hgnc:17928
      label: PSMC3IP
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:21963259
    reference_title: >-
      XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes
      coactivation of estrogen-driven transcription.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected females were homozygous for a 3 bp deletion (NM_016556.2,
      c.600_602del) in the PSMC3IP gene, leading to deletion of a glutamic acid
      residue (p.Glu201del) in the highly conserved C-terminal acidic domain.
    explanation: >-
      Defines the homozygous PSMC3IP-related subtype.
- name: ODG4-NR5A1
  display_name: NR5A1-related 46,XX gonadal dysgenesis/ovarian insufficiency
  classification: gene
  description: >-
    NR5A1-related ovarian developmental failure overlaps 46,XX gonadal
    dysgenesis and primary ovarian insufficiency, most often through dominant
    familial variants with variable penetrance and expressivity.
  genes:
  - preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  inheritance:
  - name: Autosomal dominant with variable penetrance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:19246354
    reference_title: Mutations in NR5A1 associated with ovarian insufficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Families 1, 3, and 4 show a dominant mode of inheritance, whereas Family 2
      shows a recessive mode.
    explanation: >-
      Supports dominant NR5A1 inheritance while preserving the reported
      variability in penetrance and inheritance mode.
- name: Perrault-spectrum
  display_name: Perrault-spectrum 46,XX gonadal dysgenesis
  classification: syndromic
  description: >-
    Autosomal recessive syndromic branch with ovarian dysgenesis or primary
    ovarian insufficiency in 46,XX individuals plus sensorineural hearing
    impairment.
  subtype_term:
    preferred_term: Perrault syndrome
    term:
      id: MONDO:0017312
      label: Perrault syndrome
  genes:
  - preferred_term: HARS2
    term:
      id: hgnc:4817
      label: HARS2
  - preferred_term: HSD17B4
    term:
      id: hgnc:5213
      label: HSD17B4
  - preferred_term: CLPP
    term:
      id: hgnc:2084
      label: CLPP
  - preferred_term: TWNK
    term:
      id: hgnc:1160
      label: TWNK
  - preferred_term: LARS2
    term:
      id: hgnc:17095
      label: LARS2
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:32423379
    reference_title: "LARS2-Perrault syndrome: a new case report and literature review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Perrault syndrome (MIM: 233400) is a rare recessive genetically
      heterogeneous disorder characterized by sensorineural hearing loss in males
      and females and ovarian dysfunction in females [1].
    explanation: >-
      Supports the syndromic 46,XX gonadal-dysgenesis branch with hearing
      impairment.
prevalence:
- population: Reported 46,XX gonadal dysgenesis cases
  percentage: Rare
  evidence:
  - reference: PMID:23087880
    reference_title: "A rare cause for primary amenorrhea: Sporadic perrault syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gonadal (ovarian) dysgenesis with normal chromosomes (46, XX), XX female
      gonadal dysgenesis (XX-GD) is a rare genetically heterogeneous disorder.
    explanation: >-
      This report explicitly describes 46,XX gonadal dysgenesis as a rare
      genetically heterogeneous disorder.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Isolated FSHR-, NUP107-, and PSMC3IP-related forms are recessive, and
    Perrault-spectrum 46,XX ovarian dysfunction with hearing impairment is also
    recessive.
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using homozygosity mapping and whole-exome sequencing, we identified a
      recessive missense mutation in nucleoporin-107 (NUP107, c.1339G>A,
      p.D447N).
    explanation: >-
      Establishes a recessive isolated subtype.
  - reference: PMID:32423379
    reference_title: "LARS2-Perrault syndrome: a new case report and literature review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Perrault syndrome (MIM: 233400) is a rare recessive genetically
      heterogeneous disorder characterized by sensorineural hearing loss in males
      and females and ovarian dysfunction in females [1].
    explanation: >-
      Establishes recessive inheritance for the Perrault-spectrum branch.
- name: Autosomal dominant with variable penetrance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    NR5A1-related ovarian developmental failure can segregate dominantly with
    incomplete penetrance and variable expressivity, while rare recessive NR5A1
    families have also been described.
  evidence:
  - reference: PMID:19246354
    reference_title: Mutations in NR5A1 associated with ovarian insufficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Families 1, 3, and 4 show a dominant mode of inheritance, whereas Family 2
      shows a recessive mode.
    explanation: >-
      Supports autosomal dominant inheritance for most NR5A1 families in this
      series and flags the documented recessive exception.
progression:
- phase: Fetal ovarian developmental phase
  age_range: fetal development
  notes: >-
    Causal lesions impair female gonad development, follicle-pool
    establishment, or early oogenesis before the disorder is clinically
    recognized.
  evidence:
  - reference: PMID:21963259
    reference_title: >-
      XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that
      abolishes coactivation of estrogen-driven transcription.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Impaired estrogenic signaling can lead to ovarian dysgenesis both by
      affecting the size of the follicular pool created during fetal
      development and by failing to counteract follicular atresia during
      puberty.
    explanation: >-
      This supports an early developmental phase in which abnormal ovarian
      signaling reduces the follicular pool before puberty.
- phase: Pubertal failure recognition phase
  age_range: adolescence
  notes: >-
    The disorder commonly becomes clinically apparent when spontaneous puberty
    fails and primary amenorrhea with hypergonadotropic ovarian failure is
    recognized.
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous
      disorder that is characterized by underdeveloped, dysfunctional ovaries,
      with subsequent lack of spontaneous pubertal development, primary
      amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism.
    explanation: >-
      This abstract ties the clinical recognition phase to absent puberty and
      primary amenorrhea in adolescence.
pathophysiology:
- name: Genetic disruption of female gonad development
  description: >-
    46,XX gonadal dysgenesis is genetically heterogeneous, but the shared
    proximal lesion is failure of gene programs required for ovarian
    development and maintenance.
  biological_processes:
  - preferred_term: female gonad development
    term:
      id: GO:0008585
      label: female gonad development
    modifier: DECREASED
  - preferred_term: gonad development
    term:
      id: GO:0008406
      label: gonad development
    modifier: DECREASED
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results indicate a pivotal role for NUP107 in ovarian development
      and suggest that nucleoporin defects may play a role in milder and more
      common conditions such as premature ovarian failure.
    explanation: >-
      This directly supports ovarian developmental failure as a proximal
      mechanism in 46,XX gonadal dysgenesis.
  - reference: PMID:19246354
    reference_title: Mutations in NR5A1 associated with ovarian insufficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations were associated with a range of ovarian anomalies, including
      46,XX gonadal dysgenesis and 46,XX primary ovarian insufficiency.
    explanation: >-
      This shows that multiple ovarian-development genes can anchor the same
      disease entity and its close overlap with ovarian insufficiency.
  downstream:
  - target: Impaired hormonal signaling and folliculogenesis
    description: >-
      Diverse causal lesions converge on disrupted ovarian signaling and
      follicle maturation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - defective ovarian transcriptional regulation
    - impaired gonadotropin responsiveness
    evidence:
    - reference: PMID:21963259
      reference_title: >-
        XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that
        abolishes coactivation of estrogen-driven transcription.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        PSMC3IP joins previous genes known to be mutated in XX-GD, the FSH
        receptor, and BMP15, highlighting the importance of hormonal signaling
        in ovarian development and maintenance and suggesting a common pathway
        perturbed in isolated XX-GD.
      explanation: >-
        This directly supports convergence on shared ovarian hormonal-signaling
        mechanisms across multiple XX-GD genes.
- name: NUP107 nuclear-pore oogenesis defect
  description: >-
    NUP107-related ovarian dysgenesis links a nuclear pore component to
    sex-specific defective oogenesis and ovarian development in 46,XX
    individuals.
  genes:
  - preferred_term: NUP107
    term:
      id: hgnc:29914
      label: NUP107
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  cellular_components:
  - preferred_term: nuclear pore
    term:
      id: GO:0005643
      label: nuclear pore
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      NUP107 is a component of the nuclear pore complex, and the
      NUP107-associated protein SEH1 is required for oogenesis in Drosophila.
    explanation: >-
      Supports the nuclear-pore and oogenesis mechanism for NUP107-related
      disease.
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In Drosophila, Nup107 knockdown in somatic gonadal cells resulted in female
      sterility, whereas males were fully fertile.
    explanation: >-
      Supports a sex-specific ovarian requirement for NUP107 activity.
  downstream:
  - target: Streak gonads and ovarian failure
- name: PSMC3IP estrogen-receptor coactivation failure
  description: >-
    PSMC3IP/HOP2-related disease disrupts estrogen-driven nuclear-receptor
    coactivation, reducing fetal follicular-pool establishment and increasing
    vulnerability to follicular atresia during puberty.
  genes:
  - preferred_term: PSMC3IP
    term:
      id: hgnc:17928
      label: PSMC3IP
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  biological_processes:
  - preferred_term: ovarian follicle development
    term:
      id: GO:0001541
      label: ovarian follicle development
    modifier: DECREASED
  evidence:
  - reference: PMID:21963259
    reference_title: >-
      XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes
      coactivation of estrogen-driven transcription.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In cell lines, the p.Glu201del mutation abolished PSMC3IP activation of
      estrogen-driven transcription.
    explanation: >-
      Directly supports loss of estrogen-driven transcriptional coactivation.
  - reference: PMID:21963259
    reference_title: >-
      XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes
      coactivation of estrogen-driven transcription.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Impaired estrogenic signaling can lead to ovarian dysgenesis both by
      affecting the size of the follicular pool created during fetal development
      and by failing to counteract follicular atresia during puberty.
    explanation: >-
      Links PSMC3IP-driven estrogenic-signaling failure to the developmental and
      pubertal ovarian phenotype.
  downstream:
  - target: Impaired hormonal signaling and folliculogenesis
- name: FSHR receptor signaling resistance
  description: >-
    FSHR-related ovarian dysgenesis impairs follicle-stimulating hormone receptor
    signaling, producing follicular arrest with hypergonadotropic ovarian failure.
  genes:
  - preferred_term: FSHR
    term:
      id: hgnc:3969
      label: FSHR
  cell_types:
  - preferred_term: granulosa cell
    term:
      id: CL:0000501
      label: granulosa cell
  biological_processes:
  - preferred_term: response to follicle-stimulating hormone
    term:
      id: GO:0032354
      label: response to follicle-stimulating hormone
    modifier: DECREASED
  evidence:
  - reference: PMID:7553856
    reference_title: >-
      Mutation in the follicle-stimulating hormone receptor gene causes
      hereditary hypergonadotropic ovarian failure.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Expression of the gene in transfected cells demonstrated a dramatic
      reduction of binding capacity and signal transduction, but apparently
      normal ligand-binding affinity of the mutated receptor.
    explanation: >-
      Directly supports receptor signaling resistance as the FSHR mechanism.
  downstream:
  - target: Impaired hormonal signaling and folliculogenesis
- name: NR5A1 steroidogenic transcription dosage defect
  description: >-
    NR5A1-related ovarian insufficiency reflects impaired transcriptional
    activation of steroidogenic and follicle-growth genes in ovarian cells, with
    variable penetrance and expressivity across families.
  genes:
  - preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  cell_types:
  - preferred_term: granulosa cell
    term:
      id: CL:0000501
      label: granulosa cell
  biological_processes:
  - preferred_term: estrogen biosynthetic process
    term:
      id: GO:0006703
      label: estrogen biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:19246354
    reference_title: Mutations in NR5A1 associated with ovarian insufficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our data show that mutated forms of NR5A1, detected in subjects with
      anomalies of ovarian development and function, show quantitative
      impairment in the transactivation of two of these factors (CYP11A1 and
      CYP19A1).
    explanation: >-
      Directly supports impaired NR5A1 transcriptional output as the molecular
      mechanism.
  downstream:
  - target: Streak gonads and ovarian failure
- name: Impaired hormonal signaling and folliculogenesis
  description: >-
    A major shared mechanistic branch is reduced ovarian hormone-response and
    follicular maintenance, including impaired FSH signaling and defective
    estrogen-responsive transcription.
  cell_types:
  - preferred_term: granulosa cell
    term:
      id: CL:0000501
      label: granulosa cell
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  biological_processes:
  - preferred_term: response to follicle-stimulating hormone
    term:
      id: GO:0032354
      label: response to follicle-stimulating hormone
    modifier: DECREASED
  - preferred_term: ovarian follicle development
    term:
      id: GO:0001541
      label: ovarian follicle development
    modifier: DECREASED
  evidence:
  - reference: PMID:7553856
    reference_title: >-
      Mutation in the follicle-stimulating hormone receptor gene causes
      hereditary hypergonadotropic ovarian failure.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Expression of the gene in transfected cells demonstrated a dramatic
      reduction of binding capacity and signal transduction, but apparently
      normal ligand-binding affinity of the mutated receptor.
    explanation: >-
      This directly supports impaired FSH signaling as one disease-causing
      mechanistic branch in 46,XX gonadal dysgenesis.
  - reference: PMID:21963259
    reference_title: >-
      XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that
      abolishes coactivation of estrogen-driven transcription.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Impaired estrogenic signaling can lead to ovarian dysgenesis both by
      affecting the size of the follicular pool created during fetal
      development and by failing to counteract follicular atresia during
      puberty.
    explanation: >-
      This supports defective estrogen-responsive transcription and accelerated
      follicular loss as another shared mechanistic branch.
  downstream:
  - target: Streak gonads and ovarian failure
    description: >-
      Chronic failure of follicle development and ovarian signaling produces
      streak or severely underdeveloped ovaries with loss of reproductive
      function.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21963259
      reference_title: >-
        XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that
        abolishes coactivation of estrogen-driven transcription.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        XX female gonadal dysgenesis (XX-GD) is a rare, genetically
        heterogeneous disorder characterized by lack of spontaneous pubertal
        development, primary amenorrhea, uterine hypoplasia, and
        hypergonadotropic hypogonadism as a result of streak gonads.
      explanation: >-
        This directly links impaired ovarian signaling to streak gonads and
        ovarian failure.
- name: Streak gonads and ovarian failure
  description: >-
    The convergent anatomical outcome is a streak or severely underdeveloped
    ovary with little or no effective steroidogenic or follicular function.
  biological_processes:
  - preferred_term: estrogen biosynthetic process
    term:
      id: GO:0006703
      label: estrogen biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous
      disorder that is characterized by underdeveloped, dysfunctional ovaries,
      with subsequent lack of spontaneous pubertal development, primary
      amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism.
    explanation: >-
      This supports underdeveloped dysfunctional ovaries as the shared anatomic
      lesion of the disease.
  - reference: PMID:21963259
    reference_title: >-
      XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that
      abolishes coactivation of estrogen-driven transcription.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XX female gonadal dysgenesis (XX-GD) is a rare, genetically
      heterogeneous disorder characterized by lack of spontaneous pubertal
      development, primary amenorrhea, uterine hypoplasia, and
      hypergonadotropic hypogonadism as a result of streak gonads.
    explanation: >-
      This explicitly identifies streak gonads as the proximate cause of the
      endocrine and reproductive phenotype.
  downstream:
  - target: Hypoestrogenic hypergonadotropic state
    description: >-
      Ovarian failure lowers estrogen output and disinhibits pituitary
      gonadotropin secretion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:8855829
      reference_title: >-
        Clinical features of primary ovarian failure caused by a point mutation
        in the follicle-stimulating hormone receptor gene.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinically, both groups of patients were characterized by primary or
        early secondary amenorrhea, variable development of secondary sex
        characteristics, and high serum levels of FSH and LH.
      explanation: >-
        This directly supports the endocrine consequence of ovarian failure as
        amenorrhea with elevated gonadotropins.
- name: Hypoestrogenic hypergonadotropic state
  description: >-
    Loss of ovarian steroidogenic function results in estrogen deficiency and
    compensatory elevation of pituitary gonadotropins, driving pubertal failure
    and amenorrhea.
  biological_processes:
  - preferred_term: gonadotropin secretion
    term:
      id: GO:0032274
      label: gonadotropin secretion
    modifier: INCREASED
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous
      disorder that is characterized by underdeveloped, dysfunctional ovaries,
      with subsequent lack of spontaneous pubertal development, primary
      amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism.
    explanation: >-
      This supports the downstream hypoestrogenic hypergonadotropic endocrine
      state as a core mechanistic consequence.
  - reference: PMID:8855829
    reference_title: >-
      Clinical features of primary ovarian failure caused by a point mutation
      in the follicle-stimulating hormone receptor gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinically, both groups of patients were characterized by primary or
      early secondary amenorrhea, variable development of secondary sex
      characteristics, and high serum levels of FSH and LH.
    explanation: >-
      This links the endocrine state to amenorrhea and impaired pubertal
      development in a mechanistically defined XX-GD subset.
genetic:
- name: NUP107
  gene_term:
    preferred_term: NUP107
    term:
      id: hgnc:29914
      label: NUP107
  association: CAUSATIVE
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:26485283
      reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Using homozygosity mapping and whole-exome sequencing, we identified a
        recessive missense mutation in nucleoporin-107 (NUP107, c.1339G>A,
        p.D447N).
      explanation: >-
        NUP107-related 46,XX gonadal dysgenesis segregates recessively in the
        reported family.
  features: >-
    Recessive NUP107 missense variants cause isolated 46,XX gonadal
    dysgenesis with defective oogenesis and ovarian developmental failure.
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using homozygosity mapping and whole-exome sequencing, we identified a
      recessive missense mutation in nucleoporin-107 (NUP107, c.1339G>A,
      p.D447N).
    explanation: >-
      This identifies NUP107 as a causal recessive gene for familial 46,XX
      gonadal dysgenesis.
- name: PSMC3IP
  gene_term:
    preferred_term: PSMC3IP
    term:
      id: hgnc:17928
      label: PSMC3IP
  association: CAUSATIVE
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:21963259
      reference_title: >-
        XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that
        abolishes coactivation of estrogen-driven transcription.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most cases are unexplained but thought to be autosomal recessive.
      explanation: >-
        The PSMC3IP family is part of the recessive isolated XX-GD pattern and
        had homozygous affected females.
  features: >-
    Homozygous PSMC3IP/HOP2 variants abolish coactivation of
    estrogen-driven transcription and cause isolated XX gonadal dysgenesis.
  evidence:
  - reference: PMID:21963259
    reference_title: >-
      XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that
      abolishes coactivation of estrogen-driven transcription.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected females were homozygous for a 3 bp deletion (NM_016556.2,
      c.600_602del) in the PSMC3IP gene, leading to deletion of a glutamic acid
      residue (p.Glu201del) in the highly conserved C-terminal acidic domain.
    explanation: >-
      This establishes PSMC3IP as a causal gene in a familial 46,XX gonadal
      dysgenesis pedigree.
- name: FSHR
  gene_term:
    preferred_term: FSHR
    term:
      id: hgnc:3969
      label: FSHR
  association: CAUSATIVE
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:7553856
      reference_title: >-
        Mutation in the follicle-stimulating hormone receptor gene causes
        hereditary hypergonadotropic ovarian failure.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hypergonadotropic ovarian dysgenesis (ODG) with normal karyotype is a
        heterogeneous condition that in some cases displays Mendelian recessive
        inheritance.
      explanation: >-
        Supports recessive inheritance for FSHR-related ovarian dysgenesis.
  features: >-
    Recessive FSHR variants define an FSH-resistant ovarian dysgenesis subset
    with impaired receptor signaling and elevated gonadotropins.
  evidence:
  - reference: PMID:7553856
    reference_title: >-
      Mutation in the follicle-stimulating hormone receptor gene causes
      hereditary hypergonadotropic ovarian failure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that the mutation causes ODG in these families.
    explanation: >-
      This provides direct causal evidence for FSHR-mediated ovarian
      dysgenesis.
- name: NR5A1
  gene_term:
    preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  association: CAUSATIVE
  inheritance:
  - name: Autosomal dominant with variable penetrance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:19246354
      reference_title: Mutations in NR5A1 associated with ovarian insufficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Families 1, 3, and 4 show a dominant mode of inheritance, whereas Family
        2 shows a recessive mode.
      explanation: >-
        Supports dominant NR5A1 inheritance with documented variability.
  features: >-
    NR5A1 variants span 46,XX gonadal dysgenesis to primary ovarian
    insufficiency, illustrating disease overlap within ovarian developmental
    failure.
  evidence:
  - reference: PMID:19246354
    reference_title: Mutations in NR5A1 associated with ovarian insufficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations were associated with a range of ovarian anomalies, including
      46,XX gonadal dysgenesis and 46,XX primary ovarian insufficiency.
    explanation: >-
      This shows that NR5A1 can anchor both 46,XX gonadal dysgenesis and the
      adjacent ovarian-insufficiency phenotype space.
phenotypes:
- category: Reproductive
  name: Gonadal Dysgenesis
  description: >-
    Streak or severely underdeveloped ovaries are the defining structural
    lesion of the disease.
  diagnostic: true
  phenotype_term:
    preferred_term: gonadal dysgenesis
    term:
      id: HP:0000133
      label: Gonadal dysgenesis
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous
      disorder that is characterized by underdeveloped, dysfunctional ovaries,
      with subsequent lack of spontaneous pubertal development, primary
      amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism.
    explanation: >-
      This directly supports gonadal dysgenesis as the structural hallmark
      phenotype.
- category: Reproductive
  name: Delayed Puberty
  description: >-
    Spontaneous pubertal development fails because ovarian estrogen production
    is inadequate.
  diagnostic: true
  phenotype_term:
    preferred_term: delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous
      disorder that is characterized by underdeveloped, dysfunctional ovaries,
      with subsequent lack of spontaneous pubertal development, primary
      amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism.
    explanation: >-
      The abstract explicitly supports absent spontaneous pubertal development,
      which maps to delayed puberty at the phenotype level.
- category: Reproductive
  name: Primary Amenorrhea
  description: >-
    Menarche does not occur because ovarian failure prevents normal pubertal
    maturation.
  diagnostic: true
  phenotype_term:
    preferred_term: primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  evidence:
  - reference: PMID:21963259
    reference_title: >-
      XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that
      abolishes coactivation of estrogen-driven transcription.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XX female gonadal dysgenesis (XX-GD) is a rare, genetically
      heterogeneous disorder characterized by lack of spontaneous pubertal
      development, primary amenorrhea, uterine hypoplasia, and
      hypergonadotropic hypogonadism as a result of streak gonads.
    explanation: >-
      This directly supports primary amenorrhea as a core diagnostic phenotype.
- category: Endocrine
  name: Hypergonadotropic Hypogonadism
  description: >-
    Ovarian failure lowers sex-steroid output and drives compensatory
    gonadotropin elevation.
  diagnostic: true
  phenotype_term:
    preferred_term: hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous
      disorder that is characterized by underdeveloped, dysfunctional ovaries,
      with subsequent lack of spontaneous pubertal development, primary
      amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism.
    explanation: >-
      This explicitly identifies hypergonadotropic hypogonadism as part of the
      core XX-GD phenotype.
  - reference: PMID:8855829
    reference_title: >-
      Clinical features of primary ovarian failure caused by a point mutation
      in the follicle-stimulating hormone receptor gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinically, both groups of patients were characterized by primary or
      early secondary amenorrhea, variable development of secondary sex
      characteristics, and high serum levels of FSH and LH.
    explanation: >-
      This supports elevated gonadotropins as the endocrine signature of a
      mechanistically defined XX-GD subset.
- category: Reproductive
  name: Uterine Hypoplasia
  description: >-
    Uterine growth remains poor when ovarian estrogen production is absent or
    severely reduced.
  diagnostic: true
  phenotype_term:
    preferred_term: uterine hypoplasia
    term:
      id: HP:0008684
      label: Aplasia/hypoplasia of the uterus
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous
      disorder that is characterized by underdeveloped, dysfunctional ovaries,
      with subsequent lack of spontaneous pubertal development, primary
      amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism.
    explanation: >-
      This directly supports uterine hypoplasia as part of the core disease
      phenotype.
- category: Reproductive
  name: Female Infertility
  description: >-
    Streak gonads and ovarian failure prevent normal ovulation and reproductive
    capacity.
  phenotype_term:
    preferred_term: female infertility
    term:
      id: HP:0008222
      label: Female infertility
  evidence:
  - reference: PMID:21963259
    reference_title: >-
      XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that
      abolishes coactivation of estrogen-driven transcription.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XX female gonadal dysgenesis (XX-GD) is a rare, genetically
      heterogeneous disorder characterized by lack of spontaneous pubertal
      development, primary amenorrhea, uterine hypoplasia, and
      hypergonadotropic hypogonadism as a result of streak gonads.
    explanation: >-
      Streak gonads imply loss of functional ovarian tissue and support female
      infertility as a downstream reproductive consequence.
- category: Hearing
  name: Sensorineural hearing impairment
  subtype: Perrault-spectrum
  description: >-
    Sensorineural hearing impairment distinguishes Perrault-spectrum disease from
    isolated 46,XX gonadal dysgenesis and should prompt audiology and syndromic
    genetic evaluation.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:32423379
    reference_title: "LARS2-Perrault syndrome: a new case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Perrault syndrome (MIM: 233400) is a rare recessive genetically
      heterogeneous disorder characterized by sensorineural hearing loss in males
      and females and ovarian dysfunction in females [1].
    explanation: >-
      Supports hearing impairment as the key syndromic feature of the
      Perrault-spectrum subtype.
diagnosis:
- name: 46,XX karyotype confirmation
  presence: Normal 46,XX complement without Turner mosaicism or Y-chromosome material.
  description: >-
    Karyotyping confirms the 46,XX disease boundary, excludes Turner-spectrum
    causes of gonadal dysgenesis, and helps prevent applying 46,XY tumor-risk
    assumptions to isolated 46,XX disease.
  diagnosis_term:
    preferred_term: karyotyping
    term:
      id: MAXO:0001611
      label: karyotyping
  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: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The chromosome study confirmed normal 46, XX karyotype.
    explanation: >-
      Supports early DSD diagnostic workup, including karyotype confirmation.
  - reference: PMID:28216916
    reference_title: "A rare case of 46,XX gonadal dysgenesis and Mayer-Rokitansky-Kuster-Hauser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 46,XX karyotype complement
    explanation: >-
      Confirms that the case definition relies on a 46,XX karyotype.
- name: Gonadotropin and ovarian hormone profile
  presence: Elevated FSH/LH with low estradiol and low ovarian reserve markers where measured.
  description: >-
    Hormone evaluation distinguishes hypoestrogenic hypergonadotropic gonadal
    dysgenesis from MRKH and other causes of primary amenorrhea with normal
    ovarian function.
  diagnosis_term:
    preferred_term: circulating hormone measurement
    term:
      id: MAXO:0035005
      label: circulating hormone measurement
  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: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hormone profiles and karyotype should be investigated in all cases of the
      presumptive diagnosis of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome or
      Mullerian agenesis.
    explanation: >-
      Directly supports hormone-profile testing in the primary-amenorrhea
      differential.
  - 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: SUPPORT
    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: >-
      Provides the expected endocrine pattern in a 46,XX gonadal dysgenesis
      diagnostic workup.
- name: Pubertal staging and estrogenization assessment
  presence: Absent or incomplete breast development and other delayed secondary sex characteristics.
  description: >-
    Tanner staging and focused physical examination document pubertal failure
    and provide a quick clinical clue to severe estrogen deficiency.
  diagnosis_term:
    preferred_term: physical examination
    term:
      id: MAXO:0000527
      label: physical examination
  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: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Determining the presence or absence of secondary sexual characteristics
      especially breast development is a simple first step to ensure the presence
      of circulating estrogen level (3).
    explanation: >-
      Supports pubertal and secondary-sex-characteristic assessment as part of
      diagnosis.
- name: Pelvic ultrasound and MRI
  presence: Streak or nonvisualized ovaries, uterine hypoplasia, or apparent uterine nonvisualization under estrogen deficiency.
  description: >-
    Pelvic imaging evaluates uterus, ovaries, streak gonads, and possible
    Mullerian-anomaly overlap. MRI can clarify ultrasound findings, and repeat
    imaging after estrogen replacement may prevent misclassification as MRKH.
  diagnosis_term:
    preferred_term: pelvis MRI
    term:
      id: MAXO:0035034
      label: pelvis MRI
  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: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Internal genitalia (ovaries, uterus, and upper two third of vagina) and
      streak gonad could not be identified on the pelvic magnetic resonance
      imaging (MRI).
    explanation: >-
      Supports pelvic MRI for internal reproductive-structure evaluation.
  - 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: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subsequent identification of the uterus needs to be re-evaluated after at
      least 6–12 months of estrogen replacement.
    explanation: >-
      Supports repeat imaging after estrogen replacement when severe
      hypoestrogenism obscures uterine structures.
- name: Baseline bone-density assessment
  presence: Osteopenia, osteoporosis, or prolonged untreated estrogen deficiency.
  description: >-
    Baseline and follow-up DXA are relevant because delayed diagnosis and
    untreated hypoestrogenism can cause early bone loss.
  diagnosis_term:
    preferred_term: Dual-energy X-ray absorptiometry procedure
    term:
      id: MAXO:0020004
      label: Dual-energy X-ray absorptiometry procedure
  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: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone density scan (DEXA scan) revealed osteoporosis at the lumbar spine (T
      score −2.7) and osteopenia at the hip (T score −1.5).
    explanation: >-
      Documents clinically relevant bone-density loss after delayed diagnosis.
- name: Molecular testing for hereditary forms
  presence: Pathogenic variants in FSHR, NUP107, PSMC3IP, NR5A1, or Perrault-spectrum genes.
  description: >-
    Gene panel or exome testing should cover isolated 46,XX ovarian dysgenesis
    genes and syndromic Perrault genes when hearing loss or family history
    suggests that branch.
  diagnosis_term:
    preferred_term: gene panel testing
    term:
      id: MAXO:0001615
      label: gene panel testing
  evidence:
  - reference: PMID:26485283
    reference_title: A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using homozygosity mapping and whole-exome sequencing, we identified a
      recessive missense mutation in nucleoporin-107 (NUP107, c.1339G>A,
      p.D447N).
    explanation: >-
      Demonstrates molecular diagnosis for a hereditary isolated subtype.
  - reference: PMID:32423379
    reference_title: "LARS2-Perrault syndrome: a new case report and literature review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Systematic genetic screening of children with hearing loss allows the
      early identification of a Perrault syndrome in order to ensure specific
      endocrinological surveillance and management to prevent secondary
      complications.
    explanation: >-
      Supports molecular testing when the syndromic hearing-loss branch is
      suspected.
- name: Audiology assessment for Perrault-spectrum disease
  presence: Sensorineural hearing loss or pathogenic variants in Perrault-spectrum genes.
  description: >-
    Audiology evaluation distinguishes Perrault-spectrum disease from isolated
    46,XX gonadal dysgenesis and guides hearing support.
  diagnosis_term:
    preferred_term: audiologist evaluation
    term:
      id: MAXO:0000734
      label: audiologist evaluation
  evidence:
  - reference: PMID:32423379
    reference_title: "LARS2-Perrault syndrome: a new case report and literature review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hearing loss should be assessed and treated by a multidisciplinary team
      including an audiologist and otolaryngologist.
    explanation: >-
      Supports audiology assessment and hearing-care referral for the
      Perrault-spectrum subtype.
treatments:
- name: Pubertal induction and long-term hormone replacement
  description: >-
    Estrogen-based pubertal induction followed by estrogen-progestogen
    maintenance is used to initiate and sustain puberty, support secondary
    sexual characteristics, and reduce long-term consequences of
    hypoestrogenism.
  treatment_term:
    preferred_term: sex hormone modifying agent therapy
    term:
      id: MAXO:0000282
      label: sex hormone modifying agent therapy
  target_phenotypes:
  - preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  - preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  evidence:
  - reference: PMID:36300209
    reference_title: "Hypogonadism in adolescent girls: treatment and long-term effects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Girls with hypogonadism require hormone replacement therapy to initiate and
      sustain puberty.
    explanation: >-
      Supports pubertal induction and maintenance hormone replacement for
      hypogonadal adolescents.
  - reference: PMID:35142292
    reference_title: >-
      A rare case of 46,XX gonadal dysgenesis, Mayer-Rokitansky-Kuster-Hauser
      syndrome, pituitary and thyroid hypoplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hormone replacement therapy remains the only therapeutic option for the
      development of secondary sexual characteristics and the prevention of
      osteoporosis.
    explanation: >-
      This directly supports hormone replacement therapy as core conservative
      management for 46,XX gonadal dysgenesis.
- name: Cyclic estrogen-progestogen maintenance when uterus is present
  description: >-
    Once estrogenized uterine tissue is present, cyclic progestogen is used with
    estrogen to oppose endometrial effects during long-term replacement.
  treatment_term:
    preferred_term: sex hormone modifying agent therapy
    term:
      id: MAXO:0000282
      label: sex hormone modifying agent therapy
  target_phenotypes:
  - 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: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with estrogen and progesterone are required for reducing the risk
      of endometrial hyperplasia and carcinoma, which will increase due to
      long-term application of estrogen without opposition.
    explanation: >-
      Supports cyclic progestogen addition to estrogen replacement when uterine
      tissue is present.
- name: Bone-health monitoring and calcium-vitamin D support
  description: >-
    Delayed diagnosis and prolonged hypoestrogenism can cause osteopenia or
    osteoporosis, so bone-density monitoring plus calcium and vitamin D support
    should accompany hormone replacement.
  treatment_term:
    preferred_term: Dual-energy X-ray absorptiometry procedure
    term:
      id: MAXO:0020004
      label: Dual-energy X-ray absorptiometry procedure
  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: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early initiation of estrogen therapy is essential to minimize bone loss.
      Moreover, lifelong oral calcium and vitamin D supplement should be given to
      maintain bone health.
    explanation: >-
      Supports bone-focused management in hypoestrogenic 46,XX gonadal
      dysgenesis.
  - reference: PMID:24945456
    reference_title: "Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The goals of hormonal therapy extend beyond simply symptom relief to levels
      that support bone, cardiovascular, and sexual health.
    explanation: >-
      General adolescent POI guidance supports bone-health goals for hormone
      therapy.
- name: Fertility and reproductive counseling
  description: >-
    Counseling should cover infertility expectations, reproductive endocrinology
    referral, donor-oocyte or gestational-surrogacy pathways when relevant, and
    recurrence-risk implications for inherited subtypes.
  treatment_term:
    preferred_term: behavioral counseling
    term:
      id: MAXO:0000077
      label: behavioral counseling
  target_phenotypes:
  - preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  evidence:
  - reference: PMID:24945456
    reference_title: "Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients and their families should be counseled on the effect of the
      patient's condition on future fertility, on the risk of comorbidities
      associated with primary ovarian insufficiency, and on the condition's
      potential for genetic inheritance.
    explanation: >-
      Supports fertility and inheritance counseling in adolescent ovarian
      insufficiency.
  - 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: >-
      She has been informed about future options for having children by adoption
      or gestational surrogacy.
    explanation: >-
      Case-level evidence supports reproductive-option counseling, though it is
      not a comparative intervention study.
- name: Psychologic support and longitudinal follow-up
  description: >-
    Diagnosis can affect self-esteem, emotional health, fertility expectations,
    and identity; longitudinal care should include psychologic counseling and at
    least annual follow-up for ovarian-insufficiency consequences.
  treatment_term:
    preferred_term: behavioral counseling
    term:
      id: MAXO:0000077
      label: behavioral counseling
  evidence:
  - reference: PMID:24945456
    reference_title: "Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Psychologic counseling also should be offered because impaired self-esteem
      and emotional distress have been reported after diagnosis of primary
      ovarian insufficiency.
    explanation: >-
      Supports psychologic counseling after diagnosis.
  - reference: PMID:24945456
    reference_title: "Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Once primary ovarian insufficiency is diagnosed, patients should be
      evaluated at least annually.
    explanation: >-
      Supports longitudinal follow-up.
- name: Audiology and hearing-support management for Perrault-spectrum cases
  description: >-
    Perrault-spectrum patients need multidisciplinary hearing assessment and
    intervention planning in parallel with endocrine surveillance.
  treatment_term:
    preferred_term: audiologist evaluation
    term:
      id: MAXO:0000734
      label: audiologist evaluation
  target_phenotypes:
  - preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:32423379
    reference_title: "LARS2-Perrault syndrome: a new case report and literature review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hearing loss should be assessed and treated by a multidisciplinary team
      including an audiologist and otolaryngologist.
    explanation: >-
      Supports audiology-led hearing management for the Perrault-spectrum
      subtype.

📚

References & Deep Research

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Summary

gpt-5 8 citations 2026-04-14T05:40:11Z

Summary

MONDO:0009299 provides a dedicated disease-level anchor for 46 XX gonadal dysgenesis. The literature consistently treats this as a rare, genetically heterogeneous ovarian developmental failure state in phenotypically female individuals with a normal 46,XX karyotype, with the core phenotype defined by streak or underdeveloped ovaries, absent spontaneous puberty, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism.

Disease-Anchor Decision

Anchor chosen: 46 XX gonadal dysgenesis (MONDO:0009299)
Why this anchor: the disease has its own MONDO term and multiple primary human papers describe it as a coherent clinical entity rather than only as a phenotype mention inside broader DSD literature.
Why not a generic 46,XX DSD bucket: the core disease definition here is ovarian developmental failure with phenotypically female external genitalia, not generic 46,XX sex-development variation such as prenatal androgen excess.
Why not lump fully with broader primary ovarian insufficiency: NR5A1 demonstrates overlap with 46,XX primary ovarian insufficiency, but the 46,XX gonadal dysgenesis literature is narrower and emphasizes congenital streak/underdeveloped ovaries, absent spontaneous puberty, and uterine hypoplasia.
Why not split into single-gene disorders for this issue: NUP107, PSMC3IP, FSHR, and NR5A1 all support the same disease-level anchor, and the issue explicitly asked for a disease-level dismech entry rather than a single-gene subtype.

Mechanistic Themes

Shared proximal theme: disrupted female gonad development.
Shared intermediate theme: impaired ovarian hormonal signaling and folliculogenesis.
Shared downstream theme: streak or severely underdeveloped ovaries leading to hypoestrogenic hypergonadotropic ovarian failure.

Papers Used for YAML Evidence

PMID	Use in YAML	Key contribution
23087880	prevalence framing	Rare genetically heterogeneous disease framing
26485283	case definition, pathophysiology, phenotypes, genetics	Strong disease-definition abstract plus ovarian-development mechanism
21963259	progression, pathophysiology, phenotypes, genetics	Streak gonads, estrogenic signaling, follicular-pool mechanism
7553856	pathophysiology, genetics	Direct FSHR signaling defect causing ovarian dysgenesis
8855829	pathophysiology, phenotypes	Elevated FSH/LH and amenorrhea in mechanistically defined subset
19246354	pathophysiology, genetics	Overlap boundary with broader ovarian insufficiency
35142292	treatment	Hormone replacement therapy for secondary sexual characteristics and osteoporosis prevention
31809259	PR framing / differential context	MRKH misdiagnosis pitfall and estrogen-dependent uterine visualization

Curation Notes

Evidence snippets were restricted to exact quoted text from the cached PMID records.
The YAML intentionally avoids generic DSD-management statements as primary treatment evidence; management is limited to hormone replacement therapy with direct PMID-backed wording.
The YAML intentionally avoids assigning phenotype frequency bands because the available abstracts support association but not robust quantitative frequency.

46,XX Gonadal Dysgenesis

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References & Deep Research

Deep Research

Summary

Disease-Anchor Decision

Mechanistic Themes

Papers Used for YAML Evidence

Curation Notes