NR5A1-related sex development disorder

Mendelian MONDO:1060211 Pathograph 15 Show in embeddings browser Disorder of sex development Infertility disorder Primary ovarian insufficiency

NR5A1-related sex development disorder is a monogenic disorder caused by pathogenic variants in NR5A1, which encodes steroidogenic factor 1 (SF-1 / Ad4BP), a nuclear-receptor transcription factor that controls adrenal and gonadal development and steroidogenesis. Reduced SF-1 transactivational activity dysregulates a shared adrenogonadal transcriptional program, producing a strikingly wide, sex-dependent phenotypic spectrum from a single gene defect: 46,XY individuals present with disorders of sex development ranging from partial or complete gonadal dysgenesis and undervirilized external genitalia to oligo/azoospermia, while 46,XX individuals present with primary ovarian insufficiency, and—less commonly with the recurrent p.Arg92Trp variant—46,XX testicular or ovotesticular DSD. Severe or biallelic loss can additionally cause primary adrenal insufficiency. Inheritance is most often autosomal dominant with sex-limited, variable expressivity; some severe cases are recessive.

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2
Inheritance
5
Pathophys.
7
Phenotypes
15
Pathograph
1
Genes
4
Medical Actions
1
References
1
Deep Research
👪

Inheritance

2
Autosomal dominant inheritance HP:0000006
Most reported NR5A1 variants are heterozygous and segregate dominantly with sex-limited, variable expressivity: the same heterozygous variant can cause 46,XY DSD in one relative and primary ovarian insufficiency in a 46,XX relative of the same family.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:19246354 SUPPORT Human Clinical
"Sequence analysis of the NR5A1 gene from the proband and her mother revealed a heterozygous frameshift mutation, c.666delC, in codon 222"
A heterozygous frameshift transmitted from an affected mother (POI) to her 46,XY DSD daughter documents dominant transmission with sex-limited expression.
PMID:28033660 SUPPORT Human Clinical
"Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling."
Carrier mothers and sisters developing POI illustrates dominant inheritance with sex-dependent, variable expressivity.
Autosomal recessive inheritance HP:0000007
A minority of families, particularly consanguineous pedigrees and some severe phenotypes with adrenal involvement, show recessive segregation with homozygous NR5A1 variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:19246354 SUPPORT Human Clinical
"Mutational analysis of the NR5A1 gene revealed a homozygous c.877G→A transition, predicted to cause a p.Asp293Asn amino acid change"
A homozygous NR5A1 variant in the affected offspring of consanguineous first-cousin parents documents recessive segregation in some families.
⚙

Pathophysiology

5
NR5A1/SF-1 transcription factor haploinsufficiency
NR5A1 encodes steroidogenic factor 1 (SF-1, also called Ad4BP), a nuclear-receptor transcription factor expressed in steroidogenic and gonadal tissue. Heterozygous loss-of-function (haploinsufficiency), and in some families biallelic, variants reduce SF-1 transactivational activity on its target-gene promoters, the proximal molecular lesion shared across all NR5A1-related presentations.
NR5A1 hgnc:7983
regulation of transcription by RNA polymerase II GO:0006357 ↓ DECREASED
Downstream
Impaired adrenogonadal developmental and steroidogenic program Reduced SF-1 transactivation dysregulates the adrenal and gonadal developmental and steroidogenic transcriptional program.
Show evidence (2 references)
PMID:31513305 SUPPORT Human Clinical
"Nuclear receptor subfamily 5 group A member 1 (NR5A1), also named steroidogenic factor 1, is an essential transcription factor that regulates a number of target genes crucial for normal reproductive physiology and endocrine function."
Establishes SF-1 as a transcription factor whose loss disrupts the reproductive and endocrine target-gene program.
PMID:19246354 SUPPORT In Vitro
"Functional studies indicated that these mutations substantially impaired NR5A1 transactivational activity."
Functional assays directly demonstrate that the disease variants reduce NR5A1 transactivation, supporting loss of function as the mechanism.
Impaired adrenogonadal developmental and steroidogenic program
SF-1 transcriptionally controls multiple steps of adrenal and gonadal development and steroidogenesis, regulating target genes including STAR, CYP17A1, CYP11A1, CYP19A1, AMH, LHB, and INHA. Reduced SF-1 dosage dysregulates this shared program, simultaneously impairing testis determination and differentiation, ovarian development and maintenance, and steroid-hormone biosynthesis. The same molecular lesion is therefore channeled into divergent, sex-dependent clinical outcomes.
Sertoli cell CL:0000216 Leydig cell CL:0000178 granulosa cell CL:0000501
gonad development GO:0008406 ↓ DECREASED steroid biosynthetic process GO:0006694 ↓ DECREASED
Downstream
46,XY testicular dysgenesis and undervirilization In 46,XY individuals the impaired program disrupts testis determination and androgen output.
46,XX ovarian dysgenesis and insufficiency In 46,XX individuals the impaired program disrupts ovarian development and follicle maintenance.
Impaired steroidogenesis and adrenal insufficiency Reduced SF-1 control of steroidogenic genes can additionally impair adrenal steroid output in severe cases.
Show evidence (2 references)
PMID:28033660 SUPPORT Human Clinical
"Steroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function."
Defines the adrenogonadal developmental program that SF-1 governs and that is dysregulated when its activity falls.
PMID:28033660 SUPPORT Human Clinical
"Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum."
Links NR5A1 dysfunction to gonadal-development disorders across a broad, sex-dependent phenotypic range.
46,XY testicular dysgenesis and undervirilization
In 46,XY individuals, reduced SF-1 activity impairs testis determination and Sertoli/Leydig-cell function, producing a spectrum from partial or complete gonadal dysgenesis to undervirilized external genitalia; milder alleles instead present later as oligo/azoospermia from spermatogenic failure with otherwise typical genitalia.
Sertoli cell CL:0000216 Leydig cell CL:0000178
male gonad development GO:0008584 ↓ DECREASED male gamete generation GO:0048232 ↓ DECREASED
Downstream
Gonadal dysgenesis Impaired testis determination produces gonadal dysgenesis.
Ambiguous genitalia Reduced fetal androgen output undervirilizes the external genitalia.
Azoospermia Milder alleles impair spermatogenesis, presenting as spermatogenic failure with azoospermia.
Oligozoospermia Milder alleles impair spermatogenesis, presenting as spermatogenic failure with oligozoospermia.
Show evidence (2 references)
PMID:28033660 SUPPORT Human Clinical
"In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI)."
Documents the 46,XY range from DSD to oligo/azoospermia as the male output of impaired SF-1-dependent testis development.
PMID:28033660 SUPPORT Human Clinical
"Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty."
Describes the characteristic undervirilization at birth in 46,XY NR5A1-related DSD.
46,XX ovarian dysgenesis and insufficiency
In 46,XX individuals, reduced SF-1 activity impairs ovarian development and follicle maintenance, depleting the follicle pool and producing primary ovarian insufficiency with hypoestrogenism and elevated gonadotropins. The recurrent p.Arg92Trp variant can instead drive variable testis development in 46,XX individuals (46,XX testicular/ovotesticular DSD).
granulosa cell CL:0000501 oocyte CL:0000023
female gonad development GO:0008585 ↓ DECREASED
Downstream
Premature ovarian insufficiency Follicle depletion presents clinically as primary ovarian insufficiency.
Primary amenorrhea Ovarian failure in adolescent carriers presents as primary amenorrhea with absent secondary sexual characteristics.
Show evidence (2 references)
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."
Directly attributes 46,XX gonadal dysgenesis and primary ovarian insufficiency to NR5A1 mutations.
PMID:28033660 SUPPORT Human Clinical
"the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients."
Documents the distinctive 46,XX testicular-DSD arm driven by the recurrent p.Arg92Trp variant.
Impaired steroidogenesis and adrenal insufficiency
Because SF-1 also regulates adrenal steroidogenic genes, severe or biallelic NR5A1 loss can impair adrenal steroid biosynthesis and cause primary adrenal insufficiency. This is the least frequent arm of the spectrum and was the presentation in the first reported human NR5A1 mutation.
steroid biosynthetic process GO:0006694 ↓ DECREASED
Downstream
Adrenal insufficiency Impaired adrenal steroidogenesis presents clinically as adrenal insufficiency in severe cases.
Show evidence (1 reference)
PMID:19246354 SUPPORT Human Clinical
"Mutation of NR5A1 causes 46,XY disorders of sex development, with or without adrenal failure"
Establishes that adrenal failure can accompany NR5A1 mutations, defining the adrenal arm of the phenotype spectrum.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for NR5A1-related sex development disorder 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

7
Endocrine 1
Adrenal insufficiency Adrenal insufficiency HP:0000846
Show evidence (1 reference)
PMID:19246354 SUPPORT Human Clinical
"Mutation of NR5A1 causes 46,XY disorders of sex development, with or without adrenal failure"
Establishes adrenal failure as part of the NR5A1 phenotype spectrum.
Genitourinary 4
Gonadal dysgenesis Gonadal dysgenesis HP:0000133
Context-specific annotations (1)
MALE
Reported in 46,XY individuals with NR5A1 variants (karyotypic males).
Show evidence (1 reference)
PMID:19246354 SUPPORT Human Clinical
"Gonadal histologic analysis revealed homogeneous fibrous tissue, and 46,XY complete gonadal dysgenesis was diagnosed"
Documents 46,XY complete gonadal dysgenesis on gonadal histology in an NR5A1-mutation carrier.
Azoospermia Azoospermia HP:0000027
Context-specific annotations (1)
MALE
46,XY men with idiopathic severe spermatogenic failure.
Show evidence (1 reference)
PMID:20887963 SUPPORT Human Clinical
"NR5A1 mutations are found in approximately 4% of men with otherwise unexplained severe spermatogenic failure."
Quantifies NR5A1 as a recurrent monogenic cause of severe male spermatogenic failure.
Premature ovarian insufficiency Premature ovarian insufficiency HP:0008209
Context-specific annotations (1)
FEMALE
Reported in 46,XX individuals carrying NR5A1 variants.
Show evidence (1 reference)
PMID:28033660 SUPPORT Human Clinical
"In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels."
Directly documents primary ovarian insufficiency and its features as the 46,XX presentation of NR5A1 mutations.
Primary amenorrhea Primary amenorrhea HP:0000786
Context-specific annotations (1)
FEMALE
Common presenting complaint in adolescents with NR5A1-related gonadal failure.
Show evidence (1 reference)
PMID:19246354 SUPPORT Human Clinical
"presented at the age of 17 years with primary amenorrhea and an absence of secondary sex characteristics."
Documents primary amenorrhea with absent secondary sexual characteristics as a presenting feature in an NR5A1-mutation carrier.
Other 2
Ambiguous genitalia Ambiguous genitalia HP:0000062
Context-specific annotations (1)
MALE
46,XY individuals; undervirilization is frequently noted at birth.
Show evidence (1 reference)
PMID:28033660 SUPPORT Human Clinical
"The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives."
Describes the characteristic atypical/undervirilized external genitalia of 46,XY NR5A1-related DSD.
Oligozoospermia Oligozoospermia HP:0000798
Context-specific annotations (1)
MALE
46,XY men with idiopathic severe spermatogenic failure.
Show evidence (1 reference)
PMID:28033660 SUPPORT Human Clinical
"In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia"
Splits the reviewed combined oligo/azoospermia phenotype into a term-specific oligozoospermia entry.
🧬

Genetic Associations

1
NR5A1 (Causative (Primary))
Gene: NR5A1 hgnc:7983
Autosomal dominant inheritance
Show evidence (2 references)
PMID:31513305 SUPPORT Human Clinical
"NR5A1 mutations are associated with a wide phenotypic spectrum of disorders/differences of sex development (DSD), a group of conditions in which development of chromosomal, gonadal, or anatomic sex is atypical."
Establishes NR5A1 as the causal gene across the DSD phenotype spectrum.
PMID:20887963 SUPPORT Human Clinical
"Mutations of NR5A1 have been reported in 46,XY disorders of sex development and in 46,XX primary ovarian insufficiency."
Confirms the causal role of NR5A1 variants across both 46,XY DSD and 46,XX ovarian insufficiency.
💊

Medical Actions

4
Estrogen replacement therapy
Action: estrogen replacement therapy Ontology label: pharmacotherapy MAXO:0000058
Agent: estradiol CHEBI:23965
Estrogen-based hormone replacement treats the hypoestrogenism of the 46,XX primary-ovarian-insufficiency arm (and of 46,XY individuals raised female after gonadectomy), supporting pubertal development and reducing long-term bone and cardiovascular risk.
Show evidence (1 reference)
PMID:28033660 PARTIAL Human Clinical
"In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels."
Anchors the hypoestrogenic ovarian-insufficiency arm for which estrogen replacement is the standard management.
Androgen replacement therapy
Action: androgen replacement therapy Ontology label: pharmacotherapy MAXO:0000058
Agent: testosterone CHEBI:17347
Testosterone replacement is used in 46,XY individuals with undervirilization and Leydig-cell insufficiency to induce or support virilization and secondary sexual characteristics, individualized to the assigned sex and degree of androgen deficiency.
Show evidence (1 reference)
PMID:28033660 PARTIAL Human Clinical
"Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty."
Anchors the undervirilized 46,XY arm for which androgen replacement is a management option depending on assigned sex.
Adrenal hormone replacement therapy
Action: adrenal hormone replacement therapy Ontology label: pharmacotherapy MAXO:0000058
Agent: corticosteroid CHEBI:50858
Glucocorticoid replacement, with mineralocorticoid replacement when clinically indicated, treats primary adrenal insufficiency in severe NR5A1-related adrenal involvement.
Target Phenotypes: Adrenal insufficiency HP:0000846
Show evidence (1 reference)
PMID:19246354 PARTIAL Human Clinical
"Mutation of NR5A1 causes 46,XY disorders of sex development, with or without adrenal failure"
Anchors the adrenal-failure arm for which adrenal steroid replacement is the standard management.
Genetic counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling is indicated because NR5A1 variants segregate with sex-limited, variable expressivity: at-risk relatives—including carrier mothers and sisters of 46,XY DSD probands—may develop primary ovarian insufficiency and benefit from counseling and reproductive planning.
Show evidence (1 reference)
PMID:28033660 SUPPORT Human Clinical
"Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling."
Directly supports genetic counseling for at-risk relatives carrying heterozygous NR5A1 variants.
🔬

Biochemical Markers

1
Serum estradiol (DECREASED)
Context: Hypoestrogenism accompanies the 46,XX primary-ovarian-insufficiency arm of NR5A1-related disease.
Pathograph Readouts
Readout Of 46,XX ovarian dysgenesis and insufficiency Negative Diagnostic
Low estradiol reports the hypoestrogenic endocrine state in NR5A1-related primary ovarian insufficiency.
Show evidence (1 reference)
PMID:28033660 SUPPORT Human Clinical
"manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels."
Provides the POI biochemical context of hypoestrogenism with elevated gonadotropins.
{ }

Source YAML

click to show 
name: NR5A1-related sex development disorder
creation_date: "2026-05-29T12:00:00Z"
category: Mendelian
description: >-
  NR5A1-related sex development disorder is a monogenic disorder caused by
  pathogenic variants in NR5A1, which encodes steroidogenic factor 1 (SF-1 /
  Ad4BP), a nuclear-receptor transcription factor that controls adrenal and
  gonadal development and steroidogenesis. Reduced SF-1 transactivational
  activity dysregulates a shared adrenogonadal transcriptional program,
  producing a strikingly wide, sex-dependent phenotypic spectrum from a single
  gene defect: 46,XY individuals present with disorders of sex development
  ranging from partial or complete gonadal dysgenesis and undervirilized
  external genitalia to oligo/azoospermia, while 46,XX individuals present with
  primary ovarian insufficiency, and—less commonly with the recurrent
  p.Arg92Trp variant—46,XX testicular or ovotesticular DSD. Severe or biallelic
  loss can additionally cause primary adrenal insufficiency. Inheritance is most
  often autosomal dominant with sex-limited, variable expressivity; some severe
  cases are recessive.
disease_term:
  preferred_term: NR5A1-related sex development disorder
  term:
    id: MONDO:1060211
    label: NR5A1-related sex development disorder
parents:
- Disorder of sex development
- Infertility disorder
- Primary ovarian insufficiency
synonyms:
- SF-1 deficiency
- Steroidogenic factor 1 deficiency
- NR5A1-related disorder of sex development
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Most reported NR5A1 variants are heterozygous and segregate dominantly with
    sex-limited, variable expressivity: the same heterozygous variant can cause
    46,XY DSD in one relative and primary ovarian insufficiency in a 46,XX
    relative of the same family.
  evidence:
  - reference: PMID:19246354
    reference_title: "Mutations in NR5A1 associated with ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of the NR5A1 gene from the proband and her mother
      revealed a heterozygous frameshift mutation, c.666delC, in codon 222
    explanation: >-
      A heterozygous frameshift transmitted from an affected mother (POI) to her
      46,XY DSD daughter documents dominant transmission with sex-limited
      expression.
  - reference: PMID:28033660
    reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1
      mutations may develop POI, and therefore require appropriate counseling.
    explanation: >-
      Carrier mothers and sisters developing POI illustrates dominant
      inheritance with sex-dependent, variable expressivity.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    A minority of families, particularly consanguineous pedigrees and some
    severe phenotypes with adrenal involvement, show recessive segregation with
    homozygous NR5A1 variants.
  evidence:
  - reference: PMID:19246354
    reference_title: "Mutations in NR5A1 associated with ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutational analysis of the NR5A1 gene revealed a homozygous c.877G→A
      transition, predicted to cause a p.Asp293Asn amino acid change
    explanation: >-
      A homozygous NR5A1 variant in the affected offspring of consanguineous
      first-cousin parents documents recessive segregation in some families.
notes: >-
  MONDO:1060211 (NR5A1-related sex development disorder) is a gene-axis disease
  entity that unifies the NR5A1/SF-1 phenotype spectrum (46,XY DSD, 46,XX POI,
  46,XX testicular/ovotesticular DSD, spermatogenic failure, and adrenal
  insufficiency) under a single transcription-factor mechanism. NR5A1 disease
  was first established by Achermann et al. 1999 (PMID:10369247), who reported a
  heterozygous NR5A1 mutation causing 46,XY sex reversal with adrenal failure;
  the abstract is not available in the local cache, so that founding report is
  cited here for historical provenance rather than as an evidence snippet.
  Unlike the synaptonemal-complex and meiotic-recombination genes in the
  gametogenic-failure series (e.g., SYCE1, MCM9), NR5A1 acts upstream of meiosis
  on gonadal organogenesis and steroidogenesis, so this entry intentionally does
  not conform to the meiotic_prophase_failure module, which explicitly excludes
  steroidogenic transcription-factor disorders. Structuring the clinical bins as
  formal has_subtypes is deferred to a follow-up (issue 3310, open question 2).
pathophysiology:
- name: NR5A1/SF-1 transcription factor haploinsufficiency
  description: >-
    NR5A1 encodes steroidogenic factor 1 (SF-1, also called Ad4BP), a
    nuclear-receptor transcription factor expressed in steroidogenic and
    gonadal tissue. Heterozygous loss-of-function (haploinsufficiency), and in
    some families biallelic, variants reduce SF-1 transactivational activity on
    its target-gene promoters, the proximal molecular lesion shared across all
    NR5A1-related presentations.
  genes:
  - preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DECREASED
  evidence:
  - reference: PMID:31513305
    reference_title: "Mutation update for the NR5A1 gene involved in DSD and infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nuclear receptor subfamily 5 group A member 1 (NR5A1), also named
      steroidogenic factor 1, is an essential transcription factor that
      regulates a number of target genes crucial for normal reproductive
      physiology and endocrine function.
    explanation: >-
      Establishes SF-1 as a transcription factor whose loss disrupts the
      reproductive and endocrine target-gene program.
  - reference: PMID:19246354
    reference_title: "Mutations in NR5A1 associated with ovarian insufficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional studies indicated that these mutations substantially impaired
      NR5A1 transactivational activity.
    explanation: >-
      Functional assays directly demonstrate that the disease variants reduce
      NR5A1 transactivation, supporting loss of function as the mechanism.
  downstream:
  - target: Impaired adrenogonadal developmental and steroidogenic program
    description: >-
      Reduced SF-1 transactivation dysregulates the adrenal and gonadal
      developmental and steroidogenic transcriptional program.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31513305
      reference_title: "Mutation update for the NR5A1 gene involved in DSD and infertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "where it controls several steps of adrenal and gonadal development."
      explanation: >-
        SF-1 controls multiple steps of adrenal and gonadal development, so
        reduced activity perturbs that developmental program.
- name: Impaired adrenogonadal developmental and steroidogenic program
  description: >-
    SF-1 transcriptionally controls multiple steps of adrenal and gonadal
    development and steroidogenesis, regulating target genes including STAR,
    CYP17A1, CYP11A1, CYP19A1, AMH, LHB, and INHA. Reduced SF-1 dosage
    dysregulates this shared program, simultaneously impairing testis
    determination and differentiation, ovarian development and maintenance, and
    steroid-hormone biosynthesis. The same molecular lesion is therefore
    channeled into divergent, sex-dependent clinical outcomes.
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
  - preferred_term: granulosa cell
    term:
      id: CL:0000501
      label: granulosa cell
  biological_processes:
  - preferred_term: gonad development
    term:
      id: GO:0008406
      label: gonad development
    modifier: DECREASED
  - preferred_term: steroid biosynthetic process
    term:
      id: GO:0006694
      label: steroid biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:28033660
    reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Steroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator
      of genes involved in adrenal and gonadal development and function.
    explanation: >-
      Defines the adrenogonadal developmental program that SF-1 governs and that
      is dysregulated when its activity falls.
  - reference: PMID:28033660
    reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in NR5A1 have been among the most frequently identified genetic
      causes of gonadal development disorders and are associated with a wide
      phenotypic spectrum.
    explanation: >-
      Links NR5A1 dysfunction to gonadal-development disorders across a broad,
      sex-dependent phenotypic range.
  downstream:
  - target: 46,XY testicular dysgenesis and undervirilization
    description: >-
      In 46,XY individuals the impaired program disrupts testis determination
      and androgen output.
    causal_link_type: DIRECT
  - target: 46,XX ovarian dysgenesis and insufficiency
    description: >-
      In 46,XX individuals the impaired program disrupts ovarian development and
      follicle maintenance.
    causal_link_type: DIRECT
  - target: Impaired steroidogenesis and adrenal insufficiency
    description: >-
      Reduced SF-1 control of steroidogenic genes can additionally impair
      adrenal steroid output in severe cases.
    causal_link_type: DIRECT
- name: 46,XY testicular dysgenesis and undervirilization
  description: >-
    In 46,XY individuals, reduced SF-1 activity impairs testis determination and
    Sertoli/Leydig-cell function, producing a spectrum from partial or complete
    gonadal dysgenesis to undervirilized external genitalia; milder alleles
    instead present later as oligo/azoospermia from spermatogenic failure with
    otherwise typical genitalia.
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
  biological_processes:
  - preferred_term: male gonad development
    term:
      id: GO:0008584
      label: male gonad development
    modifier: DECREASED
  - preferred_term: male gamete generation
    term:
      id: GO:0048232
      label: male gamete generation
    modifier: DECREASED
  evidence:
  - reference: PMID:28033660
    reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 46,XY individuals, NR5A1-related phenotypes may range from disorders of
      sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from
      46,XX ovotesticular and testicular DSD to primary ovarian insufficiency
      (POI).
    explanation: >-
      Documents the 46,XY range from DSD to oligo/azoospermia as the male
      output of impaired SF-1-dependent testis development.
  - reference: PMID:28033660
    reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, an undervirilized external genitalia is frequently seen at birth,
      while spontaneous virilization may occur later, at puberty.
    explanation: >-
      Describes the characteristic undervirilization at birth in 46,XY
      NR5A1-related DSD.
  downstream:
  - target: Gonadal dysgenesis
    description: Impaired testis determination produces gonadal dysgenesis.
    causal_link_type: DIRECT
  - target: Ambiguous genitalia
    description: Reduced fetal androgen output undervirilizes the external genitalia.
    causal_link_type: DIRECT
  - target: Azoospermia
    description: >-
      Milder alleles impair spermatogenesis, presenting as spermatogenic failure
      with azoospermia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20887963
      reference_title: "Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified seven men with severe spermatogenic failure who carried
        missense mutations in NR5A1.
      explanation: >-
        Ties NR5A1 missense variants to severe spermatogenic failure in 46,XY
        men with otherwise unexplained infertility.
  - target: Oligozoospermia
    description: >-
      Milder alleles impair spermatogenesis, presenting as spermatogenic failure
      with oligozoospermia.
    causal_link_type: DIRECT
- name: 46,XX ovarian dysgenesis and insufficiency
  description: >-
    In 46,XX individuals, reduced SF-1 activity impairs ovarian development and
    follicle maintenance, depleting the follicle pool and producing primary
    ovarian insufficiency with hypoestrogenism and elevated gonadotropins. The
    recurrent p.Arg92Trp variant can instead drive variable testis development
    in 46,XX individuals (46,XX testicular/ovotesticular DSD).
  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: female gonad development
    term:
      id: GO:0008585
      label: female gonad development
    modifier: DECREASED
  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: >-
      Directly attributes 46,XX gonadal dysgenesis and primary ovarian
      insufficiency to NR5A1 mutations.
  - reference: PMID:28033660
    reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with
      variable degrees of testis development in 46,XX patients.
    explanation: >-
      Documents the distinctive 46,XX testicular-DSD arm driven by the recurrent
      p.Arg92Trp variant.
  downstream:
  - target: Premature ovarian insufficiency
    description: >-
      Follicle depletion presents clinically as primary ovarian insufficiency.
    causal_link_type: DIRECT
  - target: Primary amenorrhea
    description: >-
      Ovarian failure in adolescent carriers presents as primary amenorrhea
      with absent secondary sexual characteristics.
    causal_link_type: DIRECT
- name: Impaired steroidogenesis and adrenal insufficiency
  description: >-
    Because SF-1 also regulates adrenal steroidogenic genes, severe or biallelic
    NR5A1 loss can impair adrenal steroid biosynthesis and cause primary adrenal
    insufficiency. This is the least frequent arm of the spectrum and was the
    presentation in the first reported human NR5A1 mutation.
  biological_processes:
  - preferred_term: steroid biosynthetic process
    term:
      id: GO:0006694
      label: steroid biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:19246354
    reference_title: "Mutations in NR5A1 associated with ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation of NR5A1 causes 46,XY disorders of sex development, with or
      without adrenal failure
    explanation: >-
      Establishes that adrenal failure can accompany NR5A1 mutations, defining
      the adrenal arm of the phenotype spectrum.
  downstream:
  - target: Adrenal insufficiency
    description: >-
      Impaired adrenal steroidogenesis presents clinically as adrenal
      insufficiency in severe cases.
    causal_link_type: DIRECT
phenotypes:
- name: Gonadal dysgenesis
  category: Reproductive
  description: >-
    46,XY individuals show partial to complete gonadal (testicular) dysgenesis
    due to impaired SF-1-dependent testis determination.
  phenotype_term:
    preferred_term: Gonadal dysgenesis
    term:
      id: HP:0000133
      label: Gonadal dysgenesis
  phenotype_contexts:
  - sex: MALE
    notes: Reported in 46,XY individuals with NR5A1 variants (karyotypic males).
    evidence:
    - reference: PMID:19246354
      reference_title: "Mutations in NR5A1 associated with ovarian insufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Gonadal histologic analysis revealed homogeneous fibrous tissue, and
        46,XY complete gonadal dysgenesis was diagnosed
      explanation: >-
        Documents 46,XY complete gonadal dysgenesis on gonadal histology in an
        NR5A1-mutation carrier.
- name: Ambiguous genitalia
  category: Reproductive
  description: >-
    Reduced fetal androgen output produces undervirilized or atypical external
    genitalia in 46,XY individuals, ranging to female-appearing genitalia with
    clitoromegaly and palpable gonads.
  phenotype_term:
    preferred_term: Ambiguous genitalia
    term:
      id: HP:0000062
      label: Ambiguous genitalia
  phenotype_contexts:
  - sex: MALE
    notes: 46,XY individuals; undervirilization is frequently noted at birth.
    evidence:
    - reference: PMID:28033660
      reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most common 46,XY phenotype is atypical or female external genitalia
        with clitoromegaly, palpable gonads, and absence of Müllerian
        derivatives.
      explanation: >-
        Describes the characteristic atypical/undervirilized external genitalia
        of 46,XY NR5A1-related DSD.
- name: Azoospermia
  category: Reproductive
  description: >-
    Milder NR5A1 alleles can cause severe spermatogenic failure presenting as
    azoospermia in 46,XY men with otherwise unexplained infertility.
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  phenotype_contexts:
  - sex: MALE
    notes: 46,XY men with idiopathic severe spermatogenic failure.
    evidence:
    - reference: PMID:20887963
      reference_title: "Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        NR5A1 mutations are found in approximately 4% of men with otherwise
        unexplained severe spermatogenic failure.
      explanation: >-
        Quantifies NR5A1 as a recurrent monogenic cause of severe male
        spermatogenic failure.
- name: Oligozoospermia
  category: Reproductive
  description: >-
    Milder NR5A1 alleles can cause severe spermatogenic failure presenting as
    oligozoospermia in 46,XY men with otherwise unexplained infertility.
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  phenotype_contexts:
  - sex: MALE
    notes: 46,XY men with idiopathic severe spermatogenic failure.
    evidence:
    - reference: PMID:28033660
      reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In 46,XY individuals, NR5A1-related phenotypes may range from disorders
        of sex development (DSD) to oligo/azoospermia
      explanation: >-
        Splits the reviewed combined oligo/azoospermia phenotype into a
        term-specific oligozoospermia entry.
- name: Premature ovarian insufficiency
  category: Reproductive
  description: >-
    46,XX individuals present with primary ovarian insufficiency manifesting as
    amenorrhea, infertility, hypoestrogenism, and elevated gonadotropins.
  phenotype_term:
    preferred_term: Premature ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
  phenotype_contexts:
  - sex: FEMALE
    notes: Reported in 46,XX individuals carrying NR5A1 variants.
    evidence:
    - reference: PMID:28033660
      reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI,
        manifesting as primary or secondary amenorrhea, infertility,
        hypoestrogenism, and elevated gonadotropin levels.
      explanation: >-
        Directly documents primary ovarian insufficiency and its features as the
        46,XX presentation of NR5A1 mutations.
- name: Primary amenorrhea
  category: Reproductive
  description: >-
    46,XX (and phenotypically female 46,XY DSD) individuals may present at
    adolescence with primary amenorrhea and absent secondary sexual
    characteristics.
  phenotype_term:
    preferred_term: Primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  phenotype_contexts:
  - sex: FEMALE
    notes: Common presenting complaint in adolescents with NR5A1-related gonadal failure.
    evidence:
    - reference: PMID:19246354
      reference_title: "Mutations in NR5A1 associated with ovarian insufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        presented at the age of 17 years with primary amenorrhea and an absence
        of secondary sex characteristics.
      explanation: >-
        Documents primary amenorrhea with absent secondary sexual characteristics
        as a presenting feature in an NR5A1-mutation carrier.
- name: Adrenal insufficiency
  category: Endocrine
  description: >-
    Severe or biallelic NR5A1 loss can impair adrenal steroidogenesis and cause
    primary adrenal insufficiency, the least common arm of the spectrum and the
    presentation of the first reported human NR5A1 mutation.
  phenotype_term:
    preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  evidence:
  - reference: PMID:19246354
    reference_title: "Mutations in NR5A1 associated with ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation of NR5A1 causes 46,XY disorders of sex development, with or
      without adrenal failure
    explanation: >-
      Establishes adrenal failure as part of the NR5A1 phenotype spectrum.
biochemical:
- name: Serum estradiol
  presence: DECREASED
  context: >-
    Hypoestrogenism accompanies the 46,XX primary-ovarian-insufficiency arm of
    NR5A1-related disease.
  biomarker_term:
    preferred_term: estradiol
    term:
      id: CHEBI:23965
      label: estradiol
  readouts:
  - target: 46,XX ovarian dysgenesis and insufficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Low estradiol reports the hypoestrogenic endocrine state in NR5A1-related
      primary ovarian insufficiency.
  evidence:
  - reference: PMID:28033660
    reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      manifesting as primary or secondary amenorrhea, infertility,
      hypoestrogenism, and elevated gonadotropin levels.
    explanation: >-
      Provides the POI biochemical context of hypoestrogenism with elevated
      gonadotropins.
genetic:
- name: NR5A1
  association: Causative (Primary)
  gene_term:
    preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  inheritance:
  - name: Autosomal dominant inheritance
    evidence:
    - reference: PMID:28033660
      reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1
        mutations may develop POI, and therefore require appropriate counseling.
      explanation: >-
        Heterozygous variants segregating with disease across relatives support
        dominant inheritance at the gene level.
  evidence:
  - reference: PMID:31513305
    reference_title: "Mutation update for the NR5A1 gene involved in DSD and infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NR5A1 mutations are associated with a wide phenotypic spectrum of
      disorders/differences of sex development (DSD), a group of conditions in
      which development of chromosomal, gonadal, or anatomic sex is atypical.
    explanation: >-
      Establishes NR5A1 as the causal gene across the DSD phenotype spectrum.
  - reference: PMID:20887963
    reference_title: "Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations of NR5A1 have been reported in 46,XY disorders of sex development
      and in 46,XX primary ovarian insufficiency.
    explanation: >-
      Confirms the causal role of NR5A1 variants across both 46,XY DSD and 46,XX
      ovarian insufficiency.
  notes: >-
    NR5A1 encodes steroidogenic factor 1 (SF-1 / Ad4BP), a nuclear-receptor
    transcription factor regulating adrenal and gonadal development and
    steroidogenesis. Most disease variants are heterozygous with sex-limited,
    variable expressivity; biallelic variants occur in some severe and
    consanguineous cases.
treatments:
- name: Estrogen replacement therapy
  description: >-
    Estrogen-based hormone replacement treats the hypoestrogenism of the 46,XX
    primary-ovarian-insufficiency arm (and of 46,XY individuals raised female
    after gonadectomy), supporting pubertal development and reducing long-term
    bone and cardiovascular risk.
  treatment_term:
    preferred_term: estrogen replacement therapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: estradiol
      term:
        id: CHEBI:23965
        label: estradiol
  evidence:
  - reference: PMID:28033660
    reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI,
      manifesting as primary or secondary amenorrhea, infertility,
      hypoestrogenism, and elevated gonadotropin levels.
    explanation: >-
      Anchors the hypoestrogenic ovarian-insufficiency arm for which estrogen
      replacement is the standard management.
- name: Androgen replacement therapy
  description: >-
    Testosterone replacement is used in 46,XY individuals with undervirilization
    and Leydig-cell insufficiency to induce or support virilization and secondary
    sexual characteristics, individualized to the assigned sex and degree of
    androgen deficiency.
  treatment_term:
    preferred_term: androgen replacement therapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: testosterone
      term:
        id: CHEBI:17347
        label: testosterone
  evidence:
  - reference: PMID:28033660
    reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, an undervirilized external genitalia is frequently seen at birth,
      while spontaneous virilization may occur later, at puberty.
    explanation: >-
      Anchors the undervirilized 46,XY arm for which androgen replacement is a
      management option depending on assigned sex.
- name: Adrenal hormone replacement therapy
  description: >-
    Glucocorticoid replacement, with mineralocorticoid replacement when
    clinically indicated, treats primary adrenal insufficiency in severe
    NR5A1-related adrenal involvement.
  treatment_term:
    preferred_term: adrenal hormone replacement therapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_phenotypes:
  - preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  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
    explanation: >-
      Anchors the adrenal-failure arm for which adrenal steroid replacement is
      the standard management.
- name: Genetic counseling
  description: >-
    Genetic counseling is indicated because NR5A1 variants segregate with
    sex-limited, variable expressivity: at-risk relatives—including carrier
    mothers and sisters of 46,XY DSD probands—may develop primary ovarian
    insufficiency and benefit from counseling and reproductive planning.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:28033660
    reference_title: "Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1
      mutations may develop POI, and therefore require appropriate counseling.
    explanation: >-
      Directly supports genetic counseling for at-risk relatives carrying
      heterozygous NR5A1 variants.
diagnosis:
- name: Targeted molecular testing
  description: >-
    Sequencing of NR5A1 (gene panel or exome) confirms the diagnosis by
    identifying a pathogenic variant in individuals presenting with 46,XY DSD,
    46,XX primary ovarian insufficiency, 46,XX testicular DSD, or unexplained
    severe spermatogenic failure.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:20887963
    reference_title: "Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To test the hypothesis that mutations in NR5A1 cause male infertility, we
      sequenced NR5A1 in 315 men with idiopathic spermatogenic failure.
    explanation: >-
      Demonstrates NR5A1 sequencing as the diagnostic route in individuals with
      unexplained gonadal/reproductive phenotypes.
references:
- reference: PMID:20301589
  title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:20301589
Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development.
No top-level findings curated for this source.

Deep Research

1
NR5A1-Related Sex Development Disorder Manual Research Audit ▸

NR5A1-Related Sex Development Disorder Manual Research Audit

This manual research artifact was prepared during PR rescue for NR5A1_Related_Sex_Development_Disorder.yaml. It is not a provider-generated Falcon/OpenAI deep-research run; it records the source-backed literature audit used to address review coverage gaps without fabricating a provider artifact.

Sources Checked

  • PMID:19246354, Lourenco et al. 2009, establishes NR5A1 mutations across ovarian insufficiency, 46,XY DSD, and adrenal failure, including functional transactivation impairment.
  • PMID:20887963, Bashamboo et al. 2010, links NR5A1 variants to severe spermatogenic failure in otherwise unexplained male infertility.
  • PMID:28033660, Domenice et al. 2016, reviews the broad 46,XY and 46,XX NR5A1 phenotypic spectrum, including POI with hypoestrogenism and elevated gonadotropins.
  • PMID:31513305, Fabbri-Scallet et al. 2020, summarizes NR5A1 as a transcription factor regulating adrenal, gonadal, reproductive, and endocrine target genes.
  • PMID:20301589, GeneReviews for nonsyndromic 46,XX testicular DSD, was identified by broad GeneReviews/SF-1 search and covers heterozygous NR5A1 pathogenic variants as one cause of SRY-negative 46,XX testicular or ovotesticular DSD.

Coverage Assessment

The curated entry captures the central mechanism as reduced NR5A1/SF-1 transactivation disrupting adrenogonadal development and steroidogenesis. The model separates downstream branches for 46,XY testicular dysgenesis and undervirilization, 46,XX ovarian dysgenesis or primary ovarian insufficiency, and adrenal insufficiency.

The phenotype section covers gonadal dysgenesis, ambiguous genitalia, azoospermia, oligozoospermia, premature ovarian insufficiency, primary amenorrhea, and adrenal insufficiency. The prior combined oligo/azoospermia phenotype was split into term-specific HP entries because HP:0000027 covers azoospermia only.

The treatment section covers estrogen replacement, androgen replacement, adrenal hormone replacement, and genetic counseling. The adrenal entry is only partially supported by the cited NR5A1 clinical literature because the source documents adrenal failure as part of the disease spectrum, while hormone replacement is standard care for adrenal insufficiency rather than specifically trialed in NR5A1 cohorts.

The biochemical section captures decreased serum estradiol as a readout of the 46,XX primary ovarian insufficiency arm, supported by the Domenice et al. description of hypoestrogenism with elevated gonadotropins.

Remaining Notes

PubMed search for NR5A1 GeneReviews[TI] returned no article with NR5A1 in the title. The tagged GeneReviews chapter, PMID:20301589, is therefore not a complete NR5A1 gene-axis review; it is relevant to the 46,XX testicular DSD arm and to NR5A1 inheritance counseling.