5α-Reductase 2 deficiency

Mutations in the SRD5A2 gene can result in a 46,XY disorder of sex development[1] (46,XY DSD) called 5α-reductase 2 deficiency (5αR2D). The mutations are inherited in an autosomal recessive pattern can be either homozygous or, less frequently, compound heterozygous loss-of-function. Affected males exhibit a broad spectrum of presentation including atypical genitalia (ranging from female appearing to undervirilized 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. Males with the same mutations in SRD5A2 can have different phenotypes suggesting additional factors that are involved in clinical presentation. Females with the same mutations in SRD5A2 as affected males (as seen in siblings) are unaffected and have normal female phenotypes and reproductive function.[2][3]

Virilization of genitalia with voice deepening, development of muscle mass occur at puberty in affected males 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. Hair on the face and body is reduced and male pattern baldness does not occur.[2]

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.[2][4][5] The enzyme catalyzes the transformation of testosterone (T) to 5α-dihydrotestosterone (DHT) intracellularly. DHT is the most potent ligand to the androgen receptor (AR).[6] 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.[7]

Two of three isozymes of 5αR can catalyze the transformation of T to DHT, but it is only 5αR2D that causes 46XY, DSD. 5αR2 is encoded by the gene SRD5A2 which is located on the short arm of chromosome 2 and contains five exons and four introns. 5αR2 consists of 254 amino acid residues with reported mutations at 67 of them with multiple different mutations at some residues.[8][2]

The first known mutation SRD5A2 was almost a complete deletion which was discovered from analysis of affected males in Papua New Guinean tribe.[9] The majority of SRD5A2 mutations are missense mutations but small deletions, splice junction mutations, and gross deletions were also observed.[10] Mutations result in a spectrum of activity effects ranging from destabilizing 5αR2 to complete loss of activity.[2]

SRD5A2 mutations are inherited in an autosomal recessive pattern. Homozygous defects are more common than compound heterozygous ones. A phenotype-genotype correlation is not known to exist for many of the most common mutations, and affected males with the same 5αR2 mutations have variable phenotypes suggesting other interacting genetic factors that determine phenotype.[11]

Diagnosis is usually made between birth and puberty. Pseudovaginal perineoscrotal hypospadias presenting with female appearing genitalia and pubertal virilization is the classical syndrome attributed to 5αR2D, but modern diagnostic methods can diagnose the deficiency shortly after birth and recognize the broad spectrum of presentation.[2]

The initial diagnosis of 46,XY DSD is indicated by overt genital abnormality. The objective clinical evaluation of dysmorphic features to diagnose 46,XY DSD for apparent female genitalia include: enlarged clitoris, posterior labial fusion, and inguinal/labial mass. For apparent male genitalia: nonpalpable testes, micropenis, isolated perineal hypospadias, or mild hypospadias with undescended testis. Family history and prenatal history are also taken into account in evaluation. Karyotyping and SRY gene analysis on samples from peripheral leukocytes will exclude sex chromosome abnormalities. With the determination of an XY karyotype and normal SRY, the differential diagnosis of 46,XY DSD is made with endocrinological measurements of T/DHT ratios[12] (which indicate 5αR2 activity) and precise anatomical imaging since 5αR2D can be difficult to distinguish from other causes of 46,XY DSD (e.g., partial androgen insensitivity syndrome and 17β- hydroxysteroid dehydrogenase type 3 enzyme deficiencies).[13]

The measurement of the serum DHT concentration is challenging since the concentrations are low and DHT has a high level of cross-reactivity. A high level of assay specificity is required to measure concentrations of DHT since serum T levels are generally 10 fold higher than DHT in young males. Endocrinological tests for T/DHT ratios can be difficult to interpret since the normal ratio level varies according to age and severity of 5αR2 activity impairment. Affected young males of at least pubertal age with normal serum T levels demonstrate elevated T/DHT levels (normal T, lower than normal DHT). Stimulation with human chorionic gonadotropin (hCG) (alternatively, testosterone enanthate) is required in prepubertal children (with stimulation and samples taken over several days) to increase serum testosterone levels for measurement. Interpreting T/DHT ratios in male newborns is especially challenging due to neonatal testosterone surge[14] and higher than normal 5a-reductase type 1 activity. SRD5A2 gene analysis is recommended for diagnosis in newborns.[15][16] Broadly, 5αR2D is diagnosed with T/DHT ratios greater than 18 while ratios greater than 30 have been observed in severely affected individuals.[2] 5αR2D can also be indicated by low ratios of 5α- to 5ß- reduced steroids, as measured in urine measured via gas chromatography–mass spectrometry.[17]

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.[18][19] The use of pelvic MRI for diagnostic imaging for 5αR2D remains controversial.[18]

One of the most clinically challenging and controversial topics with 46,XY DSD is the practice of "sex assignment" or "sex of rearing".[20] 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",[21] but later reports show that over half of patients who underwent virilizing puberty adopted a male gender identity thus challenging historical practices.[22][23][24]

The goal of sex assignment/of rearing is to facilitate the greatest likelihood of a concordant gender identity in the patient's 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.[20]

Female sex of rearing in 5αR2D individuals involves surgical procedures such as childhood gonadectomy (to prevent virilization at puberty) and vaginoplasty.[13] Life-long hormonal treatments as also required for the development and maintenance of female secondary sex characteristics.[25] Male sex of rearing avoids lifelong hormonal treatments and allow for the potential of fertility.[20] Cryptorchidism and hypospadias must be addressed to prevent damage to the seminiferous tubules that are essential for spermatogenesis and fertility.[26] Diagnosis in infancy is essential before any gender assignment or surgical intervention since patients should be considered males at birth.[13]

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. The necessity and ethics around consent and deception involved in administering such interventions has been seriously questioned.[27]

5αR2D is a rare condition, but has a worldwide distribution. A 2020 study identified 434 cases of 5αR2D across 44 countries including Turkey (23%), China (17%), Italy (9%), and Brazil (7%).[10] The same study also found that genitalia virilization influenced sex assignment while gender change was influenced by cultural aspects across the countries. Molecular diagnosis resulted in favoring male sex assignment in affected newborns.

Many SRD5A2 mutations come from areas with high coefficients of inbreeding,[2] including the Dominican Republic (where people with the condition are called güevedoces – "testes at twelve"),[33] and Papua New Guinea (where it is known as kwolu-aatmwol – suggesting a person's transformation "into a male thing"),[34] and Turkey.[35]

In the Dominican Republic, güevedoces are regarded as a third gender and experience ambivalent gender socialisation. In adulthood, they most commonly self-identify as men, but are not necessarily completely treated as such by society.[34] In the cases in Papua New Guinea, it has been said that the "girl" is shunned when he begins his natural transformation into a male body and socially assumes a male gender role.[36]

An autosomal recessive disorder of sex development, described as pseudovaginal perineoscrotal hypospadias (PPSH), was discovered in males in 1961.[37] The main feature of this syndrome was female appearing external genitalia with the presence of bilateral testes and male urogenital tracts in which the ejaculatory ducts terminate in a blind-ending vagina.[2] This disorder was consistent with 5αR2D as the underlying cause as observed in animal models.[28] 5αR2D was confirmed as the cause in humans in 1974, when studies of 24 participants in the Dominican Republic[38] and 2 in Dallas Texas, USA.[39] One of the cases in Dallas began to virilize at puberty and underwent surgery to remove testes and "repair" the apparent clitoromegaly. During surgery, a normal male urogenital tract was observed as well as other features consistent with PPSH. DHT was almost undetectable in cultured fibroblasts from foreskin,[40] epididymis and the presumed "labia majora" whereas in normal males DHT is detected, suggesting impaired DHT formation.[41] Similar conclusions were obtained for participants in a family in the Dominican Republic study in whom high serum concentration ratios of T to DHT and low concentrations of urinary 5a-reduced androgens were observed. This disorder is now known to be due to homozygous or compound heterozygous loss-of-function mutations of the SRD5A2 gene.[8]

• Caster Semenya[47]

• Intersex
• Disorders of sexual development, pseudohermaphroditism, and ambiguous genitalia
• Inborn errors of steroid metabolism
• 5α-Reductase (I, II)
• Androgen (testosterone and dihydrotestosterone)
• Ambiguous genitalia
• Intersex surgery
• Androgen insensitivity syndrome
• Congenital adrenal hyperplasia

• OMIM article
• 5-Alpha-Reductase Deficiency at eMedicine