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Steroid 5-alpha-reductase 2 deficiency is a rare disorder leading to male pseudohermaphroditism (MPH), a condition characterized by incomplete differentiation of male genitalia in 46X,Y patients. The enzyme 5-alpha-reductase 2 catalyses the conversion of testosterone (T) to dihydrotestosterone (DHT), which is essential for normal differentiation of the external male genitalia and development of the urogenital sinus. The classical syndrome (pseudovaginal perineoscrotal hypospadias) is characterized at birth by ambiguous external genitalia with a clitoral-like phallus, hypospadias, bifid scrotum and persistent urogenital sinus with a perineal blind vaginal pouch. However, external genitalia phenotypes may range from complete female to male with hypospadias and/or micropenis. Testes are found in the labioscrotal folds or inguinal canals. The internal urogenital tract is well developed and Müllerian duct derived structures are absent. At puberty, unless gonadectomy has already been performed, significant virilization without gynecomastia occurs, due to the action of testosterone. Most patients are infertile. The disorder is transmitted as an autosomal recessive trait. The enzyme 5-alpha-reductase 2 is encoded by the SRD5A2 gene localized to 2p23. More than 40 mutations have been reported in all five exons of the SRD5A2 gene. These are mainly amino-acid substitutions, but complete gene deletion, small deletions, nonsense mutations and splice site mutations have also been detected. Baseline and post-hCG (human chorionic gonadotropin) stimulation hormonal investigations reveal normal or elevated testosterone levels, low DHT and an increased T/DHT ratio (> 20). The conversion of T to DHT can be assessed in cultured genital skin fibroblasts, but false negative results are frequent. Gender assignment is still debated and must be carefully discussed for each patient, depending on the expected results of masculinizing genitoplasty. If female assignment is selected, feminizing genitoplasty and gonadectomy should be performed. Prenatal diagnosis is available for the kindred of affected patients if the causal mutations have been characterized. |