5α-Reductase 2 deficiency (5αR2D) is an autosomal recessive condition caused by a mutation in SRD5A2, a gene encoding the enzyme 5α-reductase type 2 (5αR2). The condition is rare, affects only genetic males, and has a broad spectrum of presentations, most apparent in the genitalia where a male is born with an underdeveloped penis that might develop to various extents in puberty and hence be raised as female up to a certain age. 5αR2 is expressed in specific tissues and catalyzes the transformation of testosterone (T) to 5α-dihydrotestosterone (DHT). DHT plays a key role in the process of sexual differentiation in the external genitalia and prostate during development of the male fetus. 5αR2D is a result of impaired 5αR2 activity resulting in decreased DHT levels. This defect results in a spectrum of phenotypes including overt genital ambiguity, female appearing genitalia, hypospadias, and isolated micropenis. Affected males still develop typical masculine features at puberty (deep voice, facial hair, muscle bulk) since most aspects of pubertal virilization are driven by testosterone, not DHT. Management of this condition in the context of sex assignment is a challenging and controversial area. Diagnostic availability, local laws, parental anxiety all play roles in treatment decisions. The investigation of 5αR2D as a disease has played a key role in the biochemical characterization of the SRD5A2 gene, the 5αR2 enzyme, and DHT in male sexual differentiation. Presentation
Mutations in the SRD5A2 gene can result in a 46,XY disorder of sex development (46,XY DSD) called 5α-reductase 2 deficiency (5αR2D).
5αR2D can also be indicated by low ratios of 5α- to 5ß- reduced steroids, as measured in urine measured via gas chromatography–mass spectrometry.Ultrasonography is the primary means for assessing internal reproductive organs for diagnosis while genitography and voiding cystourethrography are used to resolve structures such as urethral and vaginal tracts. The use of pelvic MRI for diagnostic imaging for 5αR2D remains controversial. Management
One of the most clinically challenging and controversial topics with 46,XY DSD is the practice of "sex assignment" or "sex of rearing". This is especially so in 5αR2D, since most affected individuals have undervirilized genitalia at birth but virilize to varying degrees at puberty. Historically most 5αR2D individuals have been "raised as females", but later reports show that over half of patients who underwent virilizing puberty adopted a male gender identity thus challenging historical practices.The goal of sex assignment/of rearing is to facilitate the greatest likelihood of a concordant gender identity in the patients adulthood. The factors that contribute to gender identity are complex and not easy to report but some factors that contribute include sex chromosomes, androgen exposure, psychosocial development, cultural expectations, family dynamics and social situation.Female sex of rearing in 5αR2D individuals involves surgical procedures such as childhood gonadectomy (to prevent virilization at puberty) and vaginoplasty. Life-long hormonal treatments as also required for the development and maintenance of female secondary sex characteristics. Male sex of rearing avoids lifelong hormonal treatments and allow for the potential of fertility.