👪

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.

◆

Subtypes

1

46,XY sex reversal 3 (NR5A1-related 46,XY gonadal dysgenesis, with or without adrenal failure) MONDO:0013066

NR5A1 hgnc:7983 Autosomal dominant inheritance

SRXY3 is the 46,XY arm of the NR5A1/SF-1 spectrum: reduced SF-1 transactivation impairs testis determination and fetal androgen output, so a 46,XY fetus undervirilizes. The gonadal lesion ranges from partial to complete gonadal dysgenesis and the external genitalia from penoscrotal hypospadias with micropenis through ambiguous genitalia to an entirely female appearance; Mullerian derivatives may persist when Sertoli-cell AMH output fails. The first two reported NR5A1 patients had the severe end of this range together with primary adrenal failure, which is why the OMIM entity is named "with or without adrenal failure", but adrenal involvement is in fact exceptional and most SRXY3 patients have normal adrenal function. NR5A1 is among the most frequently identified causes of 46,XY DSD, commonly cited at 8-15% and reported at 9% and 13% in the two cohorts cited here. Two features distinguish SRXY3 from the other 46,XY gonadal dysgenesis subtypes and drive management: gonads retained into adolescence carry a raised germ-cell-tumour risk, and severely undervirilized infants may nevertheless virilize spontaneously at puberty, so the neonatal phenotype is a poor guide to adult androgen status. Inheritance is usually heterozygous and sex-limited dominant; a carrier mother may be unaffected or present with primary ovarian insufficiency.

Show evidence (5 references)

PMID:17200175 SUPPORT Human Clinical

"Heterozygous missense mutations in NR5A1 were found in four individuals (four of 30, 13%) with this phenotype."

Establishes heterozygous NR5A1 variants as a recurrent cause of the 46,XY DSD phenotype that defines this subtype, at 13% of a screened cohort.

PMID:22549935 SUPPORT Human Clinical

"SF-1/NR5A1 mutations are frequently found in 46,XY DSD individuals (9%) and manifest with a broad phenotype."

Independently quantifies the NR5A1 yield in 46,XY DSD and records the phenotypic breadth that makes this a spectrum subtype rather than a single presentation.

PMID:29151085 SUPPORT Human Clinical

"cases of SF1 deficiency associated with adrenal failure are exceptionally rare"

Supports the "with or without adrenal failure" scope of this subtype while establishing that the adrenal arm is the exception, not the rule.

+ 2 more references

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Pathophysiology

7

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

nuclear receptor activity GO:0004879 ↓ DECREASED

Downstream

Impaired adrenogonadal developmental and steroidogenic program Reduced SF-1 transactivation dysregulates the adrenal and gonadal developmental and steroidogenic transcriptional program.

Show evidence (3 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.

PMID:29190620 SUPPORT In Vitro

"Transfection of different mutations revealed altered subcellular localization of the mutant SF-1 protein in the case of the frameshift mutations, indicating an impaired protein function."

Adds a second route to loss of function beyond reduced transactivation: frameshift alleles mislocalize the protein, so functional SF-1 does not reach the nucleus in the first place.

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.

Female external genitalia in individual with 46,XY karyotype At the severe end of the 46,XY range, fetal androgen output is low enough that the external genitalia remain entirely female.

Hypospadias Partial undervirilization short of ambiguity presents as penoscrotal hypospadias with a small phallus.

Micropenis Reduced fetal androgen output limits phallic growth.

Sertoli-cell AMH transcription failure Dysgenetic Sertoli cells lose SF-1-driven transcription of anti-Mullerian hormone.

Testicular neoplasm Gonadal dysgenesis is the substrate for germ-cell malignancy and its precursor lesions when the gonad is retained into adolescence.

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.

Sertoli-cell AMH transcription failure

SF-1 activates transcription of anti-Mullerian hormone in the Sertoli cell. Where SF-1 activity falls far enough, AMH output drops below the level needed to signal the paramesonephric ducts, and circulating AMH and inhibin B fall below their reference ranges.

Sertoli cell CL:0000216

SF-1-dependent activation of AMH transcription GO:0045944 ↓ DECREASED

Downstream

Mullerian duct persistence Without sufficient AMH the paramesonephric ducts receive no regression signal.

Show evidence (2 references)

PMID:34613524 SUPPORT INDIRECT Human Clinical

"Here, SF-1 activates the expression of the Anti-Müllerian hormone (AMH) and consequently, it influences the regression of the paramesonephric ducts"

Establishes the SF-1-dependent AMH transcription step that this node reports as failing.

PMID:34613524 SUPPORT Human Clinical

"the Sertoli cell markers AMH and inhibin B were below the reference ranges in nine patients"

Measures the Sertoli-cell output directly in an NR5A1 46,XY cohort, confirming the failure is present in patients and not only inferred from the mouse.

Mullerian duct persistence

Absent the AMH signal, the paramesonephric (Mullerian) ducts fail to regress in the 46,XY fetus and a uterus and upper vagina remain alongside the dysgenetic testis. Persistence is partial and variable across SRXY3 patients, which is why Mullerian status does not track with the degree of external undervirilization.

Mullerian duct regression GO:0001880 ↓ DECREASED

Downstream

Presence of uterus in 46,XY individual Failed duct regression leaves a uterus in place in the 46,XY individual.

Show evidence (2 references)

PMID:17200175 SUPPORT INDIRECT Model Organism

"Targeted deletion of Nr5a1 (Sf1) in the mouse results in adrenal and gonadal agenesis, XY sex-reversal, and persistent Müllerian structures in males."

The Sf1-null mouse retains Mullerian structures in XY animals, showing that loss of SF-1 is sufficient to abolish duct regression.

PMID:8187173 SUPPORT INDIRECT Model Organism

"Male and female Ftz-F1 null mice had female internal genitalia, despite complete gonadal agenesis."

The primary Ftz-F1 knockout report: XY nulls retain female internal genitalia, the original demonstration that Mullerian regression fails without SF-1.

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.

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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

12

Endocrine 1

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 11

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.

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.

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.

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.

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 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.

Female external genitalia in individual with 46,XY karyotype HP:0008730

Show evidence (1 reference)

PMID:17200175 SUPPORT Human Clinical

"human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian structures (uterus), and primary adrenal failure"

The founding SRXY3 cases are described as 46,XY individuals with female external genitalia, which is the phenotype asserted here.

Presence of uterus in 46,XY individual HP:0034546

Show evidence (2 references)

PMID:17200175 SUPPORT Human Clinical

"human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian structures (uterus), and primary adrenal failure"

Records a retained uterus in the originally reported 46,XY SF-1 patients.

PMID:34613524 SUPPORT Human Clinical

"Neither the extent of virilization at birth nor the presence of Müllerian structures reliably correlated with the degree of virilization during puberty."

Confirms that Mullerian structures occur in this cohort and establishes that their presence carries no prognostic weight for pubertal virilization.

Hypospadias HP:0000047

Show evidence (1 reference)

PMID:17200175 SUPPORT Human Clinical

"noted at birth to have a small phallus with severe penoscrotal hypospadias and chordee"

Documents severe penoscrotal hypospadias in a molecularly confirmed NR5A1 46,XY patient (heterozygous L437Q).

Micropenis HP:0000054

Show evidence (2 references)

PMID:34613524 SUPPORT Human Clinical

"ambiguous external genitalia with a scrotum bipartitum and/or micropenis"

Places micropenis in the reported 46,XY NR5A1 genital spectrum.

PMID:17200175 SUPPORT Human Clinical

"noted at birth to have a small phallus with severe penoscrotal hypospadias and chordee"

A molecularly confirmed NR5A1 46,XY patient with a small phallus alongside hypospadias.

Testicular neoplasm HP:0010788

Show evidence (2 references)

PMID:22080441 SUPPORT Human Clinical

"Patients with SF-1 mutations are at increased risk for malignant germ cell tumors."

States the increased germ-cell-tumour risk in SF-1 mutation carriers that this phenotype records.

PMID:22080441 SUPPORT Human Clinical

"gonadectomy at 13 years revealed incomplete spermatogenesis and bilateral precursor lesions of testicular carcinoma in situ"

Provides the histological observation of bilateral precursor lesions behind the risk statement.

🧬

Genetic Associations

1

NR5A1 (Causative (Primary))

Gene: NR5A1 hgnc:7983 gene page

Autosomal dominant inheritance

Show evidence (5 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.

PMID:28033660 SUPPORT Human Clinical

"Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients."

Records the one recurrent NR5A1 allele, p.Arg92Trp, and its distinctive behaviour: it drives testis development in 46,XX individuals rather than the 46,XY undervirilization typical of the gene.

+ 2 more references

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Medical Actions

5

Estrogen replacement therapy

Action: estrogen replacement therapy Ontology label: Estrogen Replacement Therapy NCIT:C15231

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 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."

Anchors the hypoestrogenic ovarian-insufficiency arm for which estrogen replacement is the standard management.

Androgen replacement therapy

Action: androgen replacement therapy Ontology label: Androgen Therapy NCIT:C15482

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 SUPPORT 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: Hormone Replacement Therapy NCIT:C15599

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 SUPPORT 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.

Orchidopexy and germ cell tumour surveillance

Action: orchidopexy with germ-cell tumour surveillance Ontology label: Orchiopexy NCIT:C111066

Platform: Surgery

Where the gonads are preserved in a 46,XY (SRXY3) patient, they should be brought into a palpable position by early orchidopexy and then kept under germ-cell-tumour surveillance, because dysgenetic gonads carry a raised risk of malignant germ cell tumour and of carcinoma-in-situ precursor lesions. Finding premalignant or malignant change is what prompts gonadectomy. The corollary is that reflex gonadectomy in infancy is not the default: because severely undervirilized SRXY3 infants may still virilize spontaneously at puberty, irreversible procedures should be deferred until sex assignment has been considered carefully.

Target Phenotypes: Testicular neoplasm HP:0010788

Show evidence (3 references)

PMID:22080441 SUPPORT Human Clinical

"In case of preserved gonads, early orchidopexy and germ cell tumor screening is warranted."

States the orchidopexy-plus-surveillance recommendation for preserved gonads that this treatment entry records.

PMID:22080441 SUPPORT Human Clinical

"The finding of premalignant and/or malignant changes should prompt gonadectomy or possibly irradiation."

Gives the escalation rule that surveillance feeds into, distinguishing this from routine prophylactic gonadectomy.

PMID:34613524 SUPPORT Human Clinical

"Therefore, it is important to consider sex assignment carefully and avoid irreversible procedures during infancy."

Supports deferring irreversible gonadal surgery in infancy, the caution attached to this management approach.

🔬

Biochemical Markers

3

Serum anti-Mullerian hormone (DECREASED)

Context: AMH is the Sertoli-cell product whose loss leaves the Mullerian ducts un-regressed, so it reads out the Sertoli-cell arm of SRXY3 directly.

Pathograph Readouts

Readout Of Sertoli-cell AMH transcription failure Negative Diagnostic

Low serum AMH reports failed Sertoli-cell AMH output, the mechanism node it is measured against.

Show evidence (1 reference)

PMID:34613524 SUPPORT Human Clinical

"the Sertoli cell markers AMH and inhibin B were below the reference ranges in nine patients"

Measures AMH below the reference range in nine of ten 46,XY NR5A1 patients.

Serum inhibin B (DECREASED)

Context: Inhibin B is the second Sertoli-cell marker and falls with AMH in the same cohort, independently of whether Mullerian structures are present.

Pathograph Readouts

Readout Of Sertoli-cell AMH transcription failure Negative Diagnostic

Low inhibin B corroborates loss of Sertoli-cell function at the same node.

Show evidence (1 reference)

PMID:34613524 SUPPORT Human Clinical

"the Sertoli cell markers AMH and inhibin B were below the reference ranges in nine patients"

Reports inhibin B below the reference range in the same nine patients, alongside AMH.

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.

🔬

Diagnosis

1

Targeted molecular testing

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.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:20887963 SUPPORT Human Clinical

"To test the hypothesis that mutations in NR5A1 cause male infertility, we sequenced NR5A1 in 315 men with idiopathic spermatogenic failure."

Demonstrates NR5A1 sequencing as the diagnostic route in individuals with unexplained gonadal/reproductive phenotypes.

PMID:17488792 SUPPORT Human Clinical

"Screening for SF-1 mutation should be performed in subjects with apparent partial androgen insensitivity syndrome and no mutation in the AR gene."

Extends the testing indication: because normal Sertoli and Leydig markers do not exclude SRXY3, NR5A1 must be sequenced in AR-negative apparent partial androgen insensitivity.

📈

Progression

2

Fetal and neonatal undervirilization

SRXY3 Age: Birth to early infancy

SRXY3 declares itself at birth as undervirilized 46,XY external genitalia, anywhere from penoscrotal hypospadias with micropenis to ambiguous genitalia to an entirely female appearance. The rare patients who also have primary adrenal insufficiency usually present in this window with the adrenal failure rather than the genital finding.

Show evidence (2 references)

PMID:34613524 SUPPORT Human Clinical

"ambiguous external genitalia with a scrotum bipartitum and/or micropenis"

Describes the neonatal genital spectrum this phase records in 46,XY NR5A1 patients.

PMID:29151085 SUPPORT Human Clinical

"We describe the clinical characteristics of a phenotypically female patient presenting at 2 months with signs of adrenal insufficiency. DSD 46,XY was diagnosed at 4 years."

Illustrates the adrenal-first infantile presentation, in which the 46,XY DSD is recognised only years later.

Spontaneous virilization at puberty

SRXY3 Age: Pubertal age

A substantial share of SRXY3 patients virilize spontaneously at puberty, including some who showed no discernible androgen effect in utero, because Leydig-cell function can recover as gonadotropin drive rises. Gonadotropins sit at or above the upper reference range, and testosterone can reach the adult male range despite reduced gonadal volume. Neither the neonatal genital phenotype nor the presence of Mullerian structures predicts how far an individual will virilize, which is the argument against irreversible infant surgery and early gonadectomy in this subtype.

Show evidence (5 references)

PMID:34613524 SUPPORT Human Clinical

"Patients who first presented in early infancy due to ambiguous genitalia showed spontaneous virilization at pubertal age accompanied by a significant testosterone production despite the decreased gonadal volume."

Documents spontaneous pubertal virilization with real testosterone production, which is the defining feature of this phase.

PMID:30224582 SUPPORT Human Clinical

"severe under-virilization in utero followed by spontaneous virilization around puberty in NR5A1-related 46,XY DSD"

A literature review of thirteen cases establishes this trajectory as a recognised pattern rather than an isolated observation.

PMID:30224582 SUPPORT Human Clinical

"Gonadal histology revealed bilateral dysplastic testes consisting of mostly Sertoli cell-only tubules and Leydig cell hyperplasia."

Leydig cell hyperplasia in a dysplastic testis is the histological correlate of the recovered androgen output described in this phase.

+ 2 more references

{ }

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
has_subtypes:
- name: SRXY3
  display_name: 46,XY sex reversal 3 (NR5A1-related 46,XY gonadal dysgenesis, with or
    without adrenal failure)
  classification: clinical_phenotype
  subtype_term:
    preferred_term: 46,XY sex reversal 3
    term:
      id: MONDO:0013066
      label: 46,XY sex reversal 3
  genes:
  - preferred_term: NR5A1
    term:
      id: hgnc:7983
      label: NR5A1
  description: >-
    SRXY3 is the 46,XY arm of the NR5A1/SF-1 spectrum: reduced SF-1
    transactivation impairs testis determination and fetal androgen output, so a
    46,XY fetus undervirilizes. The gonadal lesion ranges from partial to
    complete gonadal dysgenesis and the external genitalia from penoscrotal
    hypospadias with micropenis through ambiguous genitalia to an entirely
    female appearance; Mullerian derivatives may persist when Sertoli-cell AMH
    output fails. The first two reported NR5A1 patients had the severe end of
    this range together with primary adrenal failure, which is why the OMIM
    entity is named "with or without adrenal failure", but adrenal involvement
    is in fact exceptional and most SRXY3 patients have normal adrenal function.
    NR5A1 is among the most frequently identified causes of 46,XY DSD, commonly
    cited at 8-15% and reported at 9% and 13% in the two cohorts cited here. Two features distinguish SRXY3 from the other
    46,XY gonadal dysgenesis subtypes and drive management: gonads retained into
    adolescence carry a raised germ-cell-tumour risk, and severely
    undervirilized infants may nevertheless virilize spontaneously at puberty,
    so the neonatal phenotype is a poor guide to adult androgen status.
    Inheritance is usually heterozygous and sex-limited dominant; a carrier
    mother may be unaffected or present with primary ovarian insufficiency.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      SRXY3 probands typically carry a single heterozygous NR5A1 variant that is
      either de novo or inherited in a sex-limited dominant manner from a
      heterozygous mother.
    evidence:
    - reference: PMID:17200175
      reference_title: "Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two mutations appeared to be de novo or germline changes. The other two mutations appeared to be inherited in a sex-limited dominant manner because the mother is heterozygous for the change."
      explanation: >-
        Documents both the de novo and the sex-limited dominant maternal
        transmission routes in molecularly confirmed 46,XY NR5A1 cases.
  evidence:
  - reference: PMID:17200175
    reference_title: "Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous missense mutations in NR5A1 were found in four individuals (four of 30, 13%) with this phenotype."
    explanation: >-
      Establishes heterozygous NR5A1 variants as a recurrent cause of the 46,XY
      DSD phenotype that defines this subtype, at 13% of a screened cohort.
  - reference: PMID:22549935
    reference_title: "Ten novel mutations in the NR5A1 gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SF-1/NR5A1 mutations are frequently found in 46,XY DSD individuals (9%) and manifest with a broad phenotype."
    explanation: >-
      Independently quantifies the NR5A1 yield in 46,XY DSD and records the
      phenotypic breadth that makes this a spectrum subtype rather than a single
      presentation.
  - reference: PMID:29151085
    reference_title: "A Novel Mutation in the Critical P-Box Residue of Steroidogenic Factor-1 Presenting with XY Sex Reversal and Transient Adrenal Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cases of SF1 deficiency associated with adrenal failure are exceptionally rare"
    explanation: >-
      Supports the "with or without adrenal failure" scope of this subtype while
      establishing that the adrenal arm is the exception, not the rule.
  - reference: PMID:15070943
    reference_title: "A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "may be relevant to the cohort of patients who present with 46, XY sex reversal but normal adrenal function"
    explanation: >-
      Names the adrenal-sparing 46,XY sex-reversal presentation that constitutes
      the bulk of this subtype.
  - reference: PMID:32738419
    reference_title: "Identification and functional analysis of fourteen NR5A1 variants in patients with the 46 XY disorders of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 8-15% of 46,XY DSD are caused by variants in the NR5A1 gene."
    explanation: >-
      Gives the commonly cited share of 46,XY DSD attributable to NR5A1, the
      range this subtype description reports.
  review_notes: >-
    Parent entry is NR5A1-related sex development disorder (MONDO:1060211).
    MONDO:0013066 is a subclass of that gene-axis term and of both
    MONDO:0010765 (46,XY complete gonadal dysgenesis) and MONDO:0016674 (46,XY
    partial gonadal dysgenesis), all three of which are already curated; it is
    therefore recorded here as the 46,XY clinical bin of the gene-axis entry
    rather than as a fourth standalone entry, following the SRXX3/SRXX4
    precedent in 46_XX_Testicular_DSD.yaml. Isolated NR5A1 spermatogenic failure
    is deliberately excluded: it is a separate OMIM entity (SPGF8) and the
    Azoospermia and Oligozoospermia phenotypes in this entry are left untagged.
    Named-entity trap for future curators: SRXY3 (OMIM 612965) is the NR5A1
    entity, while SRXY6 (OMIM 618973) is MAP3K1. Both are numbered "46,XY sex
    reversal" entries and a literature search on the phrase returns MAP3K1
    papers freely, so a MAP3K1 cohort must not be cited here.
    Considered and deferred: streak gonad (HP:0000813) and cryptorchidism
    (HP:0000028) are both reported for this subtype in the deep-research report,
    but no reference cached for this entry yields an exact quote for either in
    an NR5A1 46,XY context. They need a dedicated source rather than a
    re-derivation from the same cache.
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. The clinical bins are being
  structured as formal has_subtypes incrementally (issue 3310, open question 2);
  the 46,XY bin is now recorded as the SRXY3 subtype, anchored to MONDO:0013066
  (46,XY sex reversal 3, OMIM 612965), and the 46,XX POI and 46,XX
  testicular/ovotesticular bins remain to be structured the same way.
  MONDO:0013066 was curated here as a subtype rather than as its own entry
  because it is a subclass of this term and of both MONDO:0010765 (46,XY
  complete gonadal dysgenesis) and MONDO:0016674 (46,XY partial gonadal
  dysgenesis), all three already curated, so a standalone entry would have
  duplicated content across three parents; the parallel 46,XX sex-reversal
  terms are handled the same way as SRXX3/SRXX4 in 46_XX_Testicular_DSD.yaml.
  Phenotypes, progression phases, and the Sertoli-cell AMH node added for that
  bin carry subtype: SRXY3; the Azoospermia and Oligozoospermia phenotypes are
  deliberately left untagged because isolated NR5A1 spermatogenic failure is a
  separate OMIM entity (SPGF8) and is not within MONDO:0013066.
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
  molecular_functions:
  - preferred_term: nuclear receptor activity
    term:
      id: GO:0004879
      label: nuclear receptor activity
    modifier: DECREASED
  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.
  - reference: PMID:29190620
    reference_title: "Four Novel NR5A1 Mutations in 46,XY Gonadal Dysgenesis Patients Including Frameshift Mutations with Altered Subcellular SF-1 Localization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transfection of different mutations revealed altered subcellular localization of the mutant SF-1 protein in the case of the frameshift mutations, indicating an impaired protein function."
    explanation: >-
      Adds a second route to loss of function beyond reduced transactivation:
      frameshift alleles mislocalize the protein, so functional SF-1 does not
      reach the nucleus in the first place.
  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
  - target: Female external genitalia in individual with 46,XY karyotype
    description: >-
      At the severe end of the 46,XY range, fetal androgen output is low enough
      that the external genitalia remain entirely female.
    causal_link_type: DIRECT
  - target: Hypospadias
    description: >-
      Partial undervirilization short of ambiguity presents as penoscrotal
      hypospadias with a small phallus.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17200175
      reference_title: "Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "noted at birth to have a small phallus with severe penoscrotal hypospadias and chordee"
      explanation: >-
        Records hypospadias as the presenting undervirilization in an NR5A1
        46,XY patient, linking the testicular lesion to this genital outcome.
  - target: Micropenis
    description: >-
      Reduced fetal androgen output limits phallic growth.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17200175
      reference_title: "Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "noted at birth to have a small phallus with severe penoscrotal hypospadias and chordee"
      explanation: >-
        The same patient is recorded as having a small phallus, tying the
        testicular lesion to reduced phallic growth as well as to the
        hypospadias.
  - target: Sertoli-cell AMH transcription failure
    description: >-
      Dysgenetic Sertoli cells lose SF-1-driven transcription of anti-Mullerian
      hormone.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34613524
      reference_title: "Pubertal development in 46,XY patients with NR5A1 mutations."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, SF-1 activates the expression of the Anti-Müllerian hormone (AMH) and consequently, it influences the regression of the paramesonephric ducts"
      explanation: >-
        States the SF-1 to AMH to duct-regression axis that this edge asserts,
        so loss of SF-1 activity in Sertoli cells removes the regression signal.
  - target: Testicular neoplasm
    description: >-
      Gonadal dysgenesis is the substrate for germ-cell malignancy and its
      precursor lesions when the gonad is retained into adolescence.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22080441
      reference_title: "Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with SF-1 mutations are at increased risk for malignant germ cell tumors."
      explanation: >-
        Directly ties SF-1 deficiency, whose gonadal expression is the
        dysgenesis node, to increased germ-cell-tumour risk.
- name: Sertoli-cell AMH transcription failure
  description: >-
    SF-1 activates transcription of anti-Mullerian hormone in the Sertoli cell.
    Where SF-1 activity falls far enough, AMH output drops below the level
    needed to signal the paramesonephric ducts, and circulating AMH and inhibin
    B fall below their reference ranges.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  biological_processes:
  - preferred_term: SF-1-dependent activation of AMH transcription
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    modifier: DECREASED
  evidence:
  - reference: PMID:34613524
    reference_title: "Pubertal development in 46,XY patients with NR5A1 mutations."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, SF-1 activates the expression of the Anti-Müllerian hormone (AMH) and consequently, it influences the regression of the paramesonephric ducts"
    explanation: >-
      Establishes the SF-1-dependent AMH transcription step that this node
      reports as failing.
  - reference: PMID:34613524
    reference_title: "Pubertal development in 46,XY patients with NR5A1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the Sertoli cell markers AMH and inhibin B were below the reference ranges
      in nine patients
    explanation: >-
      Measures the Sertoli-cell output directly in an NR5A1 46,XY cohort,
      confirming the failure is present in patients and not only inferred from
      the mouse.
  downstream:
  - target: Mullerian duct persistence
    description: >-
      Without sufficient AMH the paramesonephric ducts receive no regression
      signal.
    causal_link_type: DIRECT
- name: Mullerian duct persistence
  description: >-
    Absent the AMH signal, the paramesonephric (Mullerian) ducts fail to regress
    in the 46,XY fetus and a uterus and upper vagina remain alongside the
    dysgenetic testis. Persistence is partial and variable across SRXY3
    patients, which is why Mullerian status does not track with the degree of
    external undervirilization.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: Mullerian duct regression
    term:
      id: GO:0001880
      label: Mullerian duct regression
    modifier: DECREASED
  evidence:
  - reference: PMID:17200175
    reference_title: "Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Targeted deletion of Nr5a1 (Sf1) in the mouse results in adrenal and gonadal agenesis, XY sex-reversal, and persistent Müllerian structures in males."
    explanation: >-
      The Sf1-null mouse retains Mullerian structures in XY animals, showing
      that loss of SF-1 is sufficient to abolish duct regression.
  - reference: PMID:8187173
    reference_title: "A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Male and female Ftz-F1 null mice had female internal genitalia, despite complete gonadal agenesis."
    explanation: >-
      The primary Ftz-F1 knockout report: XY nulls retain female internal
      genitalia, the original demonstration that Mullerian regression fails
      without SF-1.
  downstream:
  - target: Presence of uterus in 46,XY individual
    description: >-
      Failed duct regression leaves a uterus in place in the 46,XY individual.
    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
  subtype: SRXY3
  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
  subtype: SRXY3
  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
  subtype: SRXY3
  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.
- name: Female external genitalia in individual with 46,XY karyotype
  category: Reproductive
  subtype: SRXY3
  description: >-
    At the severe end of the SRXY3 range, fetal androgen output is low enough
    that the external genitalia are entirely female, and the 46,XY karyotype is
    discovered incidentally or at investigation for absent puberty.
  phenotype_term:
    preferred_term: Female external genitalia in individual with 46,XY karyotype
    term:
      id: HP:0008730
      label: Female external genitalia in individual with 46,XY karyotype
  evidence:
  - reference: PMID:17200175
    reference_title: "Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian structures (uterus), and primary adrenal failure"
    explanation: >-
      The founding SRXY3 cases are described as 46,XY individuals with female
      external genitalia, which is the phenotype asserted here.
- name: Presence of uterus in 46,XY individual
  category: Reproductive
  subtype: SRXY3
  description: >-
    Mullerian derivatives persist in a subset of SRXY3 patients because
    dysgenetic Sertoli cells fail to produce enough anti-Mullerian hormone to
    drive paramesonephric duct regression. Persistence is variable, and its
    presence does not predict how far the patient will virilize at puberty.
  phenotype_term:
    preferred_term: Presence of uterus in 46,XY individual
    term:
      id: HP:0034546
      label: Presence of uterus in 46,XY individual
  evidence:
  - reference: PMID:17200175
    reference_title: "Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian structures (uterus), and primary adrenal failure"
    explanation: >-
      Records a retained uterus in the originally reported 46,XY SF-1 patients.
  - reference: PMID:34613524
    reference_title: "Pubertal development in 46,XY patients with NR5A1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neither the extent of virilization at birth nor the presence of Müllerian structures reliably correlated with the degree of virilization during puberty."
    explanation: >-
      Confirms that Mullerian structures occur in this cohort and establishes
      that their presence carries no prognostic weight for pubertal
      virilization.
- name: Hypospadias
  category: Reproductive
  subtype: SRXY3
  description: >-
    Milder SRXY3 alleles present as undervirilization short of ambiguity, with
    penoscrotal hypospadias and a small phallus in a boy raised male.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:17200175
    reference_title: "Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "noted at birth to have a small phallus with severe penoscrotal hypospadias and chordee"
    explanation: >-
      Documents severe penoscrotal hypospadias in a molecularly confirmed
      NR5A1 46,XY patient (heterozygous L437Q).
- name: Micropenis
  category: Reproductive
  subtype: SRXY3
  description: >-
    Reduced fetal androgen output leaves a small phallus. Micropenis sits beside
    hypospadias and bifid scrotum in the partially virilized part of the SRXY3
    range, short of frank ambiguity.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  evidence:
  - reference: PMID:34613524
    reference_title: "Pubertal development in 46,XY patients with NR5A1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ambiguous external genitalia with a scrotum bipartitum and/or micropenis"
    explanation: >-
      Places micropenis in the reported 46,XY NR5A1 genital spectrum.
  - reference: PMID:17200175
    reference_title: "Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "noted at birth to have a small phallus with severe penoscrotal hypospadias and chordee"
    explanation: >-
      A molecularly confirmed NR5A1 46,XY patient with a small phallus
      alongside hypospadias.
- name: Testicular neoplasm
  category: Neoplastic
  subtype: SRXY3
  description: >-
    Dysgenetic gonads retained into adolescence carry a raised risk of germ-cell
    malignancy and of its precursor lesion, so preserved gonads require
    orchidopexy and tumour surveillance rather than observation alone.
  phenotype_term:
    preferred_term: Testicular neoplasm
    term:
      id: HP:0010788
      label: Testicular neoplasm
  evidence:
  - reference: PMID:22080441
    reference_title: "Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with SF-1 mutations are at increased risk for malignant germ cell tumors."
    explanation: >-
      States the increased germ-cell-tumour risk in SF-1 mutation carriers that
      this phenotype records.
  - reference: PMID:22080441
    reference_title: "Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gonadectomy at 13 years revealed incomplete spermatogenesis and bilateral precursor lesions of testicular carcinoma in situ"
    explanation: >-
      Provides the histological observation of bilateral precursor lesions
      behind the risk statement.
biochemical:
- name: Serum anti-Mullerian hormone
  presence: DECREASED
  subtype: SRXY3
  context: >-
    AMH is the Sertoli-cell product whose loss leaves the Mullerian ducts
    un-regressed, so it reads out the Sertoli-cell arm of SRXY3 directly.
  biomarker_term:
    preferred_term: anti-Mullerian hormone (AMH)
    term:
      id: NCIT:C101737
      label: Muellerian-Inhibiting Factor
  readouts:
  - target: Sertoli-cell AMH transcription failure
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Low serum AMH reports failed Sertoli-cell AMH output, the mechanism node
      it is measured against.
  evidence:
  - reference: PMID:34613524
    reference_title: "Pubertal development in 46,XY patients with NR5A1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the Sertoli cell markers AMH and inhibin B were below the reference ranges
      in nine patients
    explanation: >-
      Measures AMH below the reference range in nine of ten 46,XY NR5A1
      patients.
- name: Serum inhibin B
  presence: DECREASED
  subtype: SRXY3
  context: >-
    Inhibin B is the second Sertoli-cell marker and falls with AMH in the same
    cohort, independently of whether Mullerian structures are present.
  biomarker_term:
    preferred_term: inhibin B
    term:
      id: NCIT:C2278
      label: Inhibin B
  readouts:
  - target: Sertoli-cell AMH transcription failure
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Low inhibin B corroborates loss of Sertoli-cell function at the same node.
  evidence:
  - reference: PMID:34613524
    reference_title: "Pubertal development in 46,XY patients with NR5A1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the Sertoli cell markers AMH and inhibin B were below the reference ranges
      in nine patients
    explanation: >-
      Reports inhibin B below the reference range in the same nine patients,
      alongside AMH.
- 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.
  - 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: >-
      Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is
      associated with variable degrees of testis development in 46,XX patients.
    explanation: >-
      Records the one recurrent NR5A1 allele, p.Arg92Trp, and its distinctive
      behaviour: it drives testis development in 46,XX individuals rather than
      the 46,XY undervirilization typical of the gene.
  - 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: >-
      A clear genotype-phenotype correlation is not seen in patients bearing
      NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic
      variants in other testis/ovarian-determining genes, may contribute to the
      phenotypic expression.
    explanation: >-
      States the absence of genotype-phenotype correlation, which is why an
      NR5A1 genotype does not predict where in the SRXY3 range a patient falls,
      and points at modifier variants as the proposed explanation.
  - reference: PMID:22549935
    reference_title: "Ten novel mutations in the NR5A1 gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found high variability and thus no apparent
      genotype-structure-function-phenotype correlation.
    explanation: >-
      An independent functional series reaches the same conclusion from
      transactivation assays, so the missing correlation is not an artefact of
      one cohort's ascertainment.
  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. Expressivity varies markedly even within a single
    pedigree carrying one allele, and no genotype-phenotype correlation has been
    established, so the variant does not predict where in the SRXY3 range a
    46,XY carrier will fall. The recurrent p.Arg92Trp allele is the notable
    exception to the gene's usual direction of effect, driving testis
    development in 46,XX individuals.
progression:
- phase: Fetal and neonatal undervirilization
  subtype: SRXY3
  age_range: Birth to early infancy
  notes: >-
    SRXY3 declares itself at birth as undervirilized 46,XY external genitalia,
    anywhere from penoscrotal hypospadias with micropenis to ambiguous genitalia
    to an entirely female appearance. The rare patients who also have primary
    adrenal insufficiency usually present in this window with the adrenal
    failure rather than the genital finding.
  evidence:
  - reference: PMID:34613524
    reference_title: "Pubertal development in 46,XY patients with NR5A1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ambiguous external genitalia with a scrotum bipartitum and/or micropenis"
    explanation: >-
      Describes the neonatal genital spectrum this phase records in 46,XY
      NR5A1 patients.
  - reference: PMID:29151085
    reference_title: "A Novel Mutation in the Critical P-Box Residue of Steroidogenic Factor-1 Presenting with XY Sex Reversal and Transient Adrenal Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe the clinical characteristics of a phenotypically female patient presenting at 2 months with signs of adrenal insufficiency. DSD 46,XY was diagnosed at 4 years."
    explanation: >-
      Illustrates the adrenal-first infantile presentation, in which the 46,XY
      DSD is recognised only years later.
- phase: Spontaneous virilization at puberty
  subtype: SRXY3
  age_range: Pubertal age
  notes: >-
    A substantial share of SRXY3 patients virilize spontaneously at puberty,
    including some who showed no discernible androgen effect in utero, because
    Leydig-cell function can recover as gonadotropin drive rises. Gonadotropins
    sit at or above the upper reference range, and testosterone can reach the
    adult male range despite reduced gonadal volume. Neither the neonatal
    genital phenotype nor the presence of Mullerian structures predicts how far
    an individual will virilize, which is the argument against irreversible
    infant surgery and early gonadectomy in this subtype.
  evidence:
  - reference: PMID:34613524
    reference_title: "Pubertal development in 46,XY patients with NR5A1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients who first presented in early infancy due to ambiguous genitalia showed spontaneous virilization at pubertal age accompanied by a significant testosterone production despite the decreased gonadal volume."
    explanation: >-
      Documents spontaneous pubertal virilization with real testosterone
      production, which is the defining feature of this phase.
  - reference: PMID:30224582
    reference_title: "Spontaneous virilization around puberty in NR5A1-related 46,XY sex reversal: additional case and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe under-virilization in utero followed by spontaneous virilization around puberty in NR5A1-related 46,XY DSD"
    explanation: >-
      A literature review of thirteen cases establishes this trajectory as a
      recognised pattern rather than an isolated observation.
  - reference: PMID:30224582
    reference_title: "Spontaneous virilization around puberty in NR5A1-related 46,XY sex reversal: additional case and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gonadal histology revealed bilateral dysplastic testes consisting of mostly Sertoli cell-only tubules and Leydig cell hyperplasia."
    explanation: >-
      Leydig cell hyperplasia in a dysplastic testis is the histological
      correlate of the recovered androgen output described in this phase.
  - reference: PMID:34613524
    reference_title: "Pubertal development in 46,XY patients with NR5A1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, it is important to consider sex assignment carefully and avoid irreversible procedures during infancy."
    explanation: >-
      States the management consequence that follows from unpredictable
      pubertal virilization.
  - reference: PMID:29668062
    reference_title: "Long-term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NR5A1 variants were the most prevalent molecular defects (n = 6), and four of five patients harbouring them developed spontaneous puberty."
    explanation: >-
      A long-term 46,XY partial gonadal dysgenesis cohort quantifies spontaneous
      puberty in NR5A1 carriers specifically, four of five.
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: NCIT:C15231
      label: Estrogen Replacement Therapy
    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: 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: >-
      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: NCIT:C15482
      label: Androgen Therapy
    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: 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: >-
      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: NCIT:C15599
      label: Hormone Replacement Therapy
    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: SUPPORT
    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.
- name: Orchidopexy and germ cell tumour surveillance
  description: >-
    Where the gonads are preserved in a 46,XY (SRXY3) patient, they should be
    brought into a palpable position by early orchidopexy and then kept under
    germ-cell-tumour surveillance, because dysgenetic gonads carry a raised risk
    of malignant germ cell tumour and of carcinoma-in-situ precursor lesions.
    Finding premalignant or malignant change is what prompts gonadectomy. The
    corollary is that reflex gonadectomy in infancy is not the default: because
    severely undervirilized SRXY3 infants may still virilize spontaneously at
    puberty, irreversible procedures should be deferred until sex assignment has
    been considered carefully.
  context: >-
    Applies to the SRXY3 (46,XY) arm of NR5A1-related disease in patients whose
    gonads are retained; not applicable to the 46,XX arms of the spectrum.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orchidopexy with germ-cell tumour surveillance
    term:
      id: NCIT:C111066
      label: Orchiopexy
  target_phenotypes:
  - preferred_term: Testicular neoplasm
    term:
      id: HP:0010788
      label: Testicular neoplasm
  evidence:
  - reference: PMID:22080441
    reference_title: "Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In case of preserved gonads, early orchidopexy and germ cell tumor screening is warranted."
    explanation: >-
      States the orchidopexy-plus-surveillance recommendation for preserved
      gonads that this treatment entry records.
  - reference: PMID:22080441
    reference_title: "Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The finding of premalignant and/or malignant changes should prompt gonadectomy or possibly irradiation."
    explanation: >-
      Gives the escalation rule that surveillance feeds into, distinguishing
      this from routine prophylactic gonadectomy.
  - reference: PMID:34613524
    reference_title: "Pubertal development in 46,XY patients with NR5A1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, it is important to consider sex assignment carefully and avoid irreversible procedures during infancy."
    explanation: >-
      Supports deferring irreversible gonadal surgery in infancy, the caution
      attached to this management approach.
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: NCIT:C15709
      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.
  - reference: PMID:17488792
    reference_title: "Heterozygous mutation of steroidogenic factor-1 in 46,XY subjects may mimic partial androgen insensitivity syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening for SF-1 mutation should be performed in subjects with apparent partial androgen insensitivity syndrome and no mutation in the AR gene."
    explanation: >-
      Extends the testing indication: because normal Sertoli and Leydig markers
      do not exclude SRXY3, NR5A1 must be sequenced in AR-negative apparent
      partial androgen insensitivity.
references:
- reference: PMID:20301589
  title: "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development."
  tags:
  - GeneReviews
- reference: PMID:20301714
  title: "Nonsyndromic Disorders of Testicular Development Overview."
  tags:
  - GeneReviews

📚

References & Deep Research

References

2

PMID:20301589

Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development.

No top-level findings curated for this source.

PMID:20301714

Nonsyndromic Disorders of Testicular Development Overview.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Curate 46,XY sex reversal 3 (MONDO:0013066) as the SRXY3 subtype · 2026-09-01T06:44:48Z · View source

Curation target was the stub 46,XY sex reversal 3 (MONDO:0013066, OMIM 612965, SRXY3). Recorded as entry_type SUBTYPE rather than a new disorder entry, and the stub was deleted. Lump/split reasoning. OAK against sqlite:obo:mondo shows MONDO:0013066 is a subclass of three terms this KB already curates: MONDO:1060211 (NR5A1-related sex development disorder), MONDO:0010765 (46,XY complete gonadal dysgenesis) and MONDO:0016674 (46,XY partial gonadal dysgenesis). The latter two already carry NR5A1-specific has_subtypes blocks, so a standalone entry would have duplicated content across three parents. 46_XX_Testicular_DSD.yaml already handles the parallel MONDO terms 46,XX sex reversal 3 and 4 as the SRXX3/SRXX4 subtypes, which fixes the shape used here. Placing it on the gene-axis parent also begins the has_subtypes structuring that entry's notes had deferred (issue 3310, open question 2); the 46,XX POI and 46,XX testicular/ovotesticular bins remain unstructured. Deep research. Requested provider was falcon, which returned 403 Failed to authenticate; deep-research-client providers --check reported falcon UNREACHABLE. Rather than substitute by hand, the run was repeated with just dr_fallback='--fallback' research-disorder falcon, which escalated to openscientist; that job timed out after 3600s and was cancelled, and because the failure surfaced as a ValueError the fallback chain ended before reaching claude_code. claude_code was therefore invoked explicitly as a third attempt and produced the report used here, research/46_XY_Sex_Reversal_3-deep-research-claude_code.md (12 web searches, 16 turns, 45 citations). The report carried no validation sections, so both were retro-fitted with just validate-research-terms and just validate-research-reference. Term validation: 35 checked, 33 resolved, 0 unresolved, 0 mislabelled, 2 unverifiable (OMIM has no resolver). Reference validation: 28 checked, 28 resolved, 0 unresolved, 0 off topic; 1 quoted claim checked and not found, which is the report quoting PMID:17200175's title as though it were a sentence. No content was taken from that quote. Named Entity Confusion found in the report. Three of its nine PMIDs (21129722, 28504475, 35290982) are MAP3K1 papers. MAP3K1 is SRXY6 (OMIM 618973), not SRXY3, and the report flagged the risk itself in its section 1 before nonetheless citing them. None were used. The trap is now recorded in the SRXY3 subtype's review_notes so the next curator does not fall into it. A separate hazard worth recording: four PMIDs recalled from model memory during early scoping resolved to entirely unrelated papers (20674172 TiO2 nanoparticles, 11994345 adipose IL-6, 8033209 Fmr1 knockout, 17179197 a PCOS review). All were caught by fetching before use, nothing from them reached the entry, and their cache files were deleted. Every citation in this edit was instead found by PubMed esearch and verified against the cached abstract. What was added to kb/disorders/NR5A1_Related_Sex_Development_Disorder.yaml: the SRXY3 has_subtypes entry bound to MONDO:0013066 with NR5A1, sex-limited dominant inheritance and five evidence items; a pathophysiology node 'Sertoli-cell AMH failure and Mullerian duct persistence' (GO:0001880, CL:0000216) wired downstream of the 46,XY testicular dysgenesis node, plus new edges to the genital phenotypes and to germ-cell tumour risk; four phenotypes (HP:0008730, HP:0034546, HP:0000047, HP:0010788) and subtype: SRXY3 tags on the three existing 46,XY phenotypes; two progression phases covering neonatal undervirilization and spontaneous pubertal virilization; an orchidopexy-plus-tumour-surveillance treatment; a subcellular-mislocalization loss-of-function mechanism on the haploinsufficiency node (PMID:29190620, from the report); and the GeneReviews baseline PMID:20301714. Scope boundary. Azoospermia and Oligozoospermia are deliberately left untagged because isolated NR5A1 spermatogenic failure is a separate OMIM entity (SPGF8) and is not within MONDO:0013066. Known gap, not filled. The report describes streak gonads in the complete form and anorchia/vanishing testes at the mild end. Neither was added: no cached reference yields an exact quote for either in an NR5A1 46,XY context, and manufacturing one is precisely the failure the evidence SOP forbids. Both are good candidates for a follow-up with a dedicated source. PMID:10369247 (Achermann 1999, the founding SRXY3 report) has no abstract in PubMed, so it remains cited in notes for historical provenance only and carries no snippet. GeneReviews baseline. PMID:20301714 'Nonsyndromic Disorders of Testicular Development Overview' is the applicable chapter and is now tagged GeneReviews in the top-level references. Its PubMed record contains only the chapter's scope statement, not Clinical Characteristics, so it supplied no phenotype snippets; phenotype coverage came from the primary literature instead. Validation. just validate passes (schema clean, term validation passed, 60/60 snippets verified against the local cache). Also run and clean: check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, and the batched just validate-disorders. Weighted compliance rose from 84.8% to 88.5%.

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.

NR5A1-related sex development disorder

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NR5A1-Related Sex Development Disorder Manual Research Audit

Sources Checked

Coverage Assessment

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