46, XY disorder of sex development (DSD; see this term) due to 5-alpha-reductase 2 (SRD5A2) deficiency is a disorder of sex development due to a defect in testosterone (T) metabolism resulting in incomplete intrauterine masculinization. Patients present an ambiguous external genitalia which varies from a female with a blind vaginal pouch to a fully male phenotype with pseudovaginal posterior hypospadias (see this term) or only micropenis.
The disease has been described in >50 families and is prevalent in the Dominican Republic, Southern Lebanon and the Eastern Highlands Province of Papua New Guinea. It is relatively rare among Caucasians.
Patients present at birth characteristics of dihydrotestosterone (DHT) deficiency, such as posterior hypospadias, micropenis/clitoris-like phallus, bifid scrotum, cryptorchid (with normal or reduced spermatogenesis), and rudimentary prostate. The clinical spectrum is heterogeneous, ranging from a female with a blind vaginal pouch to a fully male phenotype with hypospadias and micropenis. 2/3 patients with SRD5A2 are initially assigned female gender. However, during puberty, scarce facial and body hair (with normal sebum production) and virilization without breast development are observed. Wolffian duct differentiation and regression of Müllerian structures are not involved.
The disease is caused by mutations in SRD5A2 (2p23.1) leading to a reduced or absent function of the steroid 5a-reductase type 2 enzyme which converts T into DHT in the external genitalia. As a result, male differentiation fails to occur during fetal development, despite high circulating T levels. Manifestations at birth vary according to the levels of residual enzymatic function.
Diagnostic criteria include genital ambiguity, a family history of DSD, and genital/karyotype discordance. Biochemical findings reveal increase in the T/DHT ratio after HCG stimulation and normal T and anti-Müllerian hormone concentration. Diagnosis also relies on 5-alpha-reductase activity assessment using the urinary steroid profiling (ratio of androsterone to etiocholanolone and 5-alpha-tetrahydrocortisol/tetrahydrocortisol and 5-alpha-tetrahydrocorticosterone to tetrahydrocorticosterone below the lower limit of normal). Diagnosis is confirmed by genetic screening.
Differential diagnosis includes complete androgen insensitivity syndrome, partial androgen insensitivity syndrome, 17-beta-hydroxysteroid dehydrogenase 3 deficiency and Leydig cell hypoplasia (see these terms).
Transmission is autosomal recessive and genetic counseling should be offered to at-risk couples.
For patients raised as male, management includes administration of androgens prior to surgery: topical DHT cream above the pubic area (prior to puberty for phallic growth), and use of donor-grafting tissue for urethra and penis elongation. Surgical repair of hypospadias (chordee correction, orchidopexia, and urethral reconstruction) should be performed at 6-18 months of age. For patients raised as female, management includes surgical correction of the external genitalia (vaginal opening into the perineum with early separation of the vagina and urethra), early removal of gonadal tissue to prevent masculinization before puberty, clitoral reduction (if severe masculinization) and cyclic hormonal therapy at puberty for development of secondary sexual characteristics.
The risk of gonadal tumors in individuals with SRD5A2 is quite low. Prostate diseases (prostate cancer, benign prostate hyperplasia) have not been reported in affected males. Most men are infertile due to azospermia or oligospermia associated with undescended testes.
Last update: August 2014