46,XY difference of sex development due to 5-alpha-reductase 2 deficiency

46,XY difference of sex development (DSD) due to 5-alpha-reductase 2 deficiency, also known as 5-alpha-reductase type 2 deficiency or pseudovaginal perineoscrotal hypospadias, is a rare autosomal recessive condition caused by mutations in the SRD5A2 gene. This enzyme normally converts testosterone to dihydrotestosterone (DHT), a more potent androgen that is essential for the development of male external genitalia during fetal life. Individuals with this condition have a 46,XY karyotype and normally functioning testes, but because DHT production is impaired, the external genitalia are undervirilized at birth. Affected newborns typically present with ambiguous genitalia, including a clitoris-like phallus, bifid scrotum, perineoscrotal hypospadias, a blind-ending vaginal pouch, and undescended or inguinal testes. Internal male structures such as the epididymis, vas deferens, and seminal vesicles develop normally because their formation depends on testosterone rather than DHT. At puberty, a significant rise in testosterone levels leads to notable virilization, including deepening of the voice, increased muscle mass, phallic growth, testicular descent, and development of male-pattern body hair, though facial hair growth is typically sparse and the prostate remains small. Gynecomastia is generally absent. This pubertal virilization often prompts a gender role change from female to male in individuals who were raised as girls, a phenomenon well-documented in certain populations such as the Dominican Republic and Papua New Guinea, where the condition is more prevalent due to consanguinity. Management is individualized and depends on the gender of rearing, timing of diagnosis, and patient/family preferences. For individuals raised male, treatment may include surgical correction of hypospadias, orchidopexy, and DHT or testosterone supplementation. For those raised female, options may include gonadectomy (to prevent virilization at puberty), estrogen replacement therapy, and feminizing genitoplasty. Psychological support and long-term endocrine follow-up are essential components of care. Fertility is generally reduced but not always absent in individuals raised as males. Genetic counseling is recommended for affected families.

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