DHT plays a key role in the process of sexual differentiation in the external genitalia and prostate during the development of the male fetus.
Affected individuals exhibit a broad spectrum of presentation including atypical genitalia (ranging from female-appearing to underutilized male), hypospadias, and isolated micropenis.
The internal reproductive structures (vasa deferentia, seminal vesicles, epididymides and ejaculatory ducts) are normal but testes are usually undescended and prostate hypoplasia is common.
[3][4] Although people who are genetically female (with two X chromosomes in each cell) may inherit variants in both copies of the SRD5A2 gene, their sexual development is not affected.
The development of female sex characteristics does not require DHT, so a lack of steroid 5-alpha reductase 2 activity does not cause physical changes in these individuals.
[1] Virilization of genitalia with voice deepening, development of muscle mass occurs at puberty in affected individuals, and height is not impaired.
Gynecomastia is uncommon and bone density is normal in contrast to 46,XY DSD from other causes such as partial androgen insensitivity syndrome and 17β-hydroxysteroid dehydrogenase 3 deficiency.
The human 5α-reductase-2 gene (SRD5A2) is located on the short arm of chromosome 2 at band 23 and encodes a 254 amino acid protein, called 5α-reductase type 2.
The 5α-reductase-1 gene (SRD5A1) is located in band 15 on the short arm of chromosome 5 and encodes a 259 amino acid protein, called 5α-reductase type 1.
The high amino acid sequence identity of their proteins (approximately 60%) indicates the possibility of a common precursor gene during evolution.
[10] 5α-Reductase type 2 (5αR2) is an enzyme, encoded by the SRD5A2 gene, that is expressed in specific tissues in the male body from fetal development to adulthood.
[13] Upon binding, the DHT-AR complex translocates from cytoplasm to the nucleus and activates the androgen receptor-regulated genes involved in processes that include male sexual differentiation.
The objective clinical evaluation of dysmorphic features to diagnose 46,XY DSD for apparent female genitalia includes enlarged clitoris, posterior labial fusion, and inguinal/labial mass.
Interpreting T/DHT ratios in male newborns is especially challenging due to neonatal testosterone surge[16] and higher than normal 5a-reductase type 1 activity.
[19] 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.
[22] Female sex rearing in 5αR2D individuals involves surgical procedures such as childhood gonadectomy (to prevent virilization at puberty) and vaginoplasty.
[7] The intersection of the child's well-being, parental wishes, recommendations of the associated medical team, and local laws makes decision-making challenging in these cases.
[9] Many SRD5A2 mutations come from areas with high coefficients of inbreeding,[3] including the Dominican Republic (where people with the condition are called güevedoces – "testes at twelve"),[33] Papua New Guinea (where it is known as kwolu-aatmwol – suggesting a person's transformation "into a male thing"),[34] and Turkey.
[37] The main feature of this syndrome was a vulva with the presence of bilateral testes and male urogenital tracts in which the ejaculatory ducts terminate in a blind-ending vagina.