Differences of sex development (DSD)
• Embryology: the gonad is initially bipotential. • The testes develop under active control of SRY and other genes. Disorders of sex development (DSDs) are classified according to the karyotype: • 46,XY DSD (incomplete masculinization of a male fetus): ◦ The commonest cause is androgen insensitivity syndrome (AIS): ■ mutations in androgen receptor (AR) gene on X chromosome in complete forms ■ alterations in androgen binding in partial forms. ◦ Abnormalities of testosterone synthesis and conversion, may be: ■ isolated, e.g. 17βHSD, 5αRD ■ occur in association with defects in steroid biosynthesis, e.g. StAR, 3βHSD. • Pure 46,XY gonadal dysgenesis (Swyer syndrome): ◦ phenotype unambiguously female; may present with delayed puberty ◦ Müllerian structures are present but only streak gonads are seen. • Mixed gonadal dysgenesis: ◦ usually asymmetrical, e.g. ovary/streak gonad or ovotestis ◦ karyotype is 45,X/46,XY or 46,XX/46,XY. • Pure 46,XX gonadal dysgenesis: ◦ absent puberty in a phenotypically normal female ◦ intact Müllerian structures but streak ovaries; normal genitalia. • 46,XX DSD (masculinization of a female fetus): ◦ the commonest cause is congenital adrenal hyperplasia, with the vast majority (>90%) due to 21-hydroxylase deficiency (21OHD). • Ovotesticular DSD is rare: ◦ aetiology is unknown, and karyotype usually 46,XX ◦ asymmetrical gonad development; ovary and testis or ovotestis. • DSD may also be part of other genetic syndromes, e.g. Antley–Bixler, Smith–Lemli–Opitz, trisomy 13. • Management requires careful evaluation and counselling, working as part of a multidisciplinary team.