46,XX difference of sex development

46,XX difference of sex development (46,XX DSD), also known as 46,XX testicular disorder of sex development or 46,XX sex reversal, is a rare condition in which an individual has a female chromosomal complement (46,XX) but develops male or ambiguous external genitalia. This condition encompasses a spectrum of presentations, including 46,XX testicular DSD (formerly called XX male syndrome) and 46,XX ovotesticular DSD. The underlying mechanisms vary and may include translocation of the SRY gene (the sex-determining region of the Y chromosome) onto an X chromosome or an autosome, or mutations in other genes involved in sex determination such as SOX9, SOX3, RSPO1, or WNT4. In SRY-positive cases, individuals typically present as phenotypic males with small testes, azoospermia, and infertility, often diagnosed in adulthood. In SRY-negative cases, ambiguous genitalia may be present at birth, and the condition may be identified during the neonatal period. The condition primarily affects the reproductive and endocrine systems. Key clinical features can include ambiguous or male-appearing external genitalia, gynecomastia (breast development), small testes, hypospadias, infertility, and variable degrees of virilization. Some individuals may have ovotestes (gonads containing both ovarian and testicular tissue). Hormonal profiles may show elevated gonadotropins and low testosterone levels, similar to patterns seen in Klinefelter syndrome. Psychosocial support and appropriate gender identity assessment are important components of care. Management is multidisciplinary and individualized, involving endocrinologists, urologists, psychologists, and geneticists. Treatment may include hormone replacement therapy (testosterone supplementation in those raised male, or estrogen in those raised female), surgical correction of genital ambiguity if desired, and gonadal monitoring due to a potential risk of gonadal tumors in certain subtypes. Genetic counseling is recommended for affected individuals and their families. There is no cure, but with appropriate medical and psychological support, individuals can lead healthy lives.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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