46,XY partial gonadal dysgenesis

46,XY partial gonadal dysgenesis (also known as 46,XY PGD, partial testicular dysgenesis, or ambiguous genitalia due to partial gonadal dysgenesis) is a rare disorder of sex development (DSD) in which individuals have a 46,XY karyotype but their gonads (testes) do not develop fully. Unlike complete gonadal dysgenesis where the testes fail to form entirely, in partial gonadal dysgenesis there is some residual testicular tissue that produces variable amounts of testosterone and anti-Müllerian hormone (AMH). This results in ambiguous genitalia at birth, with features that may range from predominantly female to predominantly male external appearance, depending on the degree of testicular function during fetal development. The condition primarily affects the reproductive and endocrine systems. Key clinical features include ambiguous external genitalia (such as micropenis, hypospadias, bifid scrotum, or clitoromegaly), the possible presence of both Müllerian structures (such as a rudimentary uterus or fallopian tubes) and Wolffian duct derivatives, and dysgenetic gonads that may appear as streak gonads or partially formed testes. Cryptorchidism (undescended testes) is common. Individuals with this condition are at increased risk for gonadal tumors, particularly gonadoblastoma and dysgerminoma, especially if dysgenetic gonadal tissue is retained. Several genes have been implicated in 46,XY partial gonadal dysgenesis, including mutations in SRY, NR5A1 (SF1), DHH, MAP3K1, and other genes involved in testicular determination and differentiation. The inheritance pattern varies depending on the underlying genetic cause. Management is individualized and may include hormone replacement therapy (testosterone or estrogen depending on the sex of rearing), surgical correction of genital ambiguity, gonadectomy to reduce tumor risk in retained dysgenetic gonads, and psychological support. Sex assignment decisions are made collaboratively with families and a multidisciplinary team, taking into account the degree of virilization, potential for fertility, and psychosocial considerations.

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