Disorder of sex development (46,XY-DSD)

Clinical presentation of 46,XY DSD ranges from atypical external genitalia identified in the newborn period to female-appearing external genitalia diagnosed at puberty or in adulthood owing to absent menarche or virilisation. The clinical spectrum is broad. Complete gonadal dysgenesis produces phenotypically female external genitalia. Intermediate forms show ambiguous genitalia. Milder presentations include isolated hypospadias, micropenis or undervirilisation, and some individuals present only with male infertility. Certain subtypes instead, present at puberty, for example, virilisation in 5-alpha-reductase 2 or 17-beta-hydroxysteroid dehydrogenase 3 deficiency. Steroidogenic subtypes may additionally involve the adrenal axis. NR5A1-related disease illustrates this variability, spanning partial and complete gonadal dysgenesis, undervirilisation, vanishing testes and male infertility.

The estimated incidence of 46,XY DSD is approximately 1 in 20,000 births. This figure applies to the 46,XY karyotype specifically and excludes isolated cryptorchidism and hypospadias; the broader DSD incidence is higher, at roughly 1 in 4,500 live births.

The genes associated with 46,XY DSD are grouped by biological function. The most frequently implicated are SRD5A2, AR, NR5A1, MAP3K1, and HSD17B3, alongside others. One group governs gonadal (testicular) development and includes NR5A1, MAP3K1, SOX9, SRY, WT1, DMRT1, DHH and NR0B1. NR5A1 accounts for 10 to 15% and MAP3K1 for 10 to 18% of non-syndromic 46,XY testicular-development disorders. A second group, comprising SRD5A2, HSD17B3, and HSD3B2, disrupts androgen biosynthesis and metabolism. Germline pathogenic variants in AR impair androgen action, causing .

The genetic conditions associated with 46,XY DSD follow heterogeneous inheritance patterns. Mode of inheritance is determined at the level of the identified entity and varies by gene. Androgen biosynthesis defects (SRD5A2, HSD17B3, HSD3B2) and DHH-related gonadal dysgenesis are autosomal recessive. Most gonadal-development genes (NR5A1, MAP3K1, SOX9, WT1, DMRT1) are autosomal dominant. , NR0B1 duplication and MAMLD1 are X-linked, and the SRY is located on the Y chromosome. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Diagnosis rests on integrated clinical, biochemical and molecular assessment rather than a single criterion. A 46,XY karyotype is confirmed and external masculinisation scored, with pelvic and gonadal imaging. Endocrine profiling supports subtype assignment: anti-müllerian hormone and inhibin B assess testicular tissue, while LH, FSH and hCG-stimulation testing assess gonadal steroidogenesis.

Main differential diagnoses include:

• Steroidogenic defects not on this panel: adrenal insufficiency with an abnormal steroid profile; STAR, CYP17A1, CYP11A1, POR
• Leydig cell hypoplasia: low testosterone, elevated LH/FSH, reduced hCG response; LHCGR
• Sex-chromosome DSD: mosaic karyotype (e.g., 45,X/46,XY), distinguished cytogenetically
• 46,XX testicular or ovotesticular DSD: 46,XX karyotype with testicular tissue; SRY, NR5A1, SOX9
• Syndromic gonadal dysgenesis: extragenital features present; SOX9, WT1

• Genetic testing establishes the molecular diagnosis and confirms the clinical suspicion.
• Identification of the germline pathogenic variant supports condition-specific monitoring and management, including gonadal management where dysgenetic or streak gonads carry an increased risk of gonadoblastoma, made by the treating physicians in consultation with the affected individual.
• Once the familial variant is known, testing of at-risk relatives can clarify their genetic status and inform reproductive planning.

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