46,XY difference of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency

46,XY difference of sex development (DSD) due to 17-beta-hydroxysteroid dehydrogenase 3 (17β-HSD3) deficiency is a rare autosomal recessive disorder of sex development caused by mutations in the HSD17B3 gene. This enzyme is responsible for converting androstenedione to testosterone in the testes, and its deficiency leads to impaired testosterone biosynthesis during fetal development. The condition is also known as 17-beta-hydroxysteroid dehydrogenase 3 deficiency or 17β-HSD3 deficiency. Affected individuals have a 46,XY karyotype (genetically male) but are typically born with female-appearing or ambiguous external genitalia due to insufficient prenatal virilization. Internal male structures such as the epididymis, vas deferens, and seminal vesicles are usually present because anti-Müllerian hormone production is unaffected, and Müllerian structures (uterus, fallopian tubes) are typically absent. At puberty, significant virilization often occurs due to peripheral conversion of androstenedione to testosterone by other isoenzymes, as well as increased testicular androstenedione production. This can result in deepening of the voice, increased muscle mass, clitoromegaly or phallic growth, and development of a more masculine body habitus. Gynecomastia may also occur. Many individuals raised as female experience gender role changes at puberty. The testes may be located in the inguinal canal or labioscrotal folds, and there is an increased risk of gonadal tumors if the testes remain undescended. Management depends on the gender of rearing and individual circumstances. For individuals raised female, treatment may include gonadectomy (to prevent virilization at puberty and reduce tumor risk) followed by estrogen replacement therapy. For those raised male or who transition to a male gender role, testosterone supplementation and surgical correction of the genitalia may be offered. Psychological support and multidisciplinary care involving endocrinologists, urologists, psychologists, and geneticists are essential components of management. The condition is particularly prevalent in certain populations, including the Gaza Strip and parts of the Dominican Republic, where consanguinity rates are higher.

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