α-Reductase 2 Deficiency

5α-Reductase 2 deficiency (5αR2D) is an autosomal recessive disorder resulting from mutations that disrupt the function of SRD5A2, a gene situated on chromosome 2 that encodes the enzyme 5α-reductase type 2 (5αR2). This enzyme is expressed in specific tissues and facilitates the conversion of testosterone (T) into 5α-dihydrotestosterone (DHT). DHT is crucial for sexual differentiation.

This rare deficiency leads to atypical sex development in genetic males (individuals with a 46XY karyotype), showing a wide range of presentations, particularly in the genitalia. Many individuals with 5-alpha reductase deficiency are assigned female at birth based on their external genitalia. In other instances, affected infants are assigned male at birth due to external genitalia, often characterized by a small penis (micropenis) and a urethra opening on the underside of the penis (hypospadias). Some infants may be assigned either female or male at birth as their genitalia are ambiguous.

During puberty, increased levels of male sex hormones lead to the development of secondary sex characteristics, such as increased muscle mass, a deeper voice, pubic hair growth, and a growth spurt. The penis and scrotum may enlarge. People with 5-alpha reductase deficiency typically do not develop much facial or body hair.

Signs and symptoms

Affected individuals show a variety of presentations, including atypical genitalia (ranging from female-like to underdeveloped male), hypospadias, and isolated micropenis. The internal reproductive structures (vasa deferentia, seminal vesicles, epididymides, and ejaculatory ducts) are normal, but testes are often undescended, and prostate hypoplasia is common. Males with identical mutations in SRD5A2 may have varying phenotypes, suggesting additional factors influencing clinical presentation. Although genetically female individuals (with two X chromosomes) may inherit variants in both copies of the SRD5A2 gene, their sexual development is unaffected. Female sex characteristics do not require DHT, so a lack of steroid 5-alpha reductase 2 activity does not cause physical changes in these individuals.

Virilization of genitalia, voice deepening, and muscle mass development occur during puberty in affected individuals, and height is not affected. Gynecomastia is rare, and bone density remains normal, unlike in 46,XY DSD from other causes such as partial androgen insensitivity syndrome and 17β-hydroxysteroid dehydrogenase 3 deficiency. Facial and body hair is reduced, and male pattern baldness does not occur.

Spontaneous fertility in individuals with 5αR2D is very rare (though documented) due to semen abnormalities, including reduced sperm counts, high semen viscosity, and sometimes a lack of primary spermatocytes. This indicates that DHT is important for spermatocyte differentiation. The wide range of presentations aligns with highly variable sperm counts among affected individuals. Testicular function may also be impaired by incomplete descent and the genetic mutation itself.

Genetics

Two distinct genes, each comprising five exons and four introns, named SRD5A1 and SDR5A2, encode two different 5α-reductases. The human 5α-reductase-2 gene (SRD5A2) is found on the short arm of chromosome 2 at band 23, encoding a 254 amino acid protein, known as 5α-reductase type 2. The 5α-reductase-1 gene (SRD5A1) is located in band 15 on the short arm of chromosome 5, encoding a 259 amino acid protein, called 5α-reductase type 1. The high amino acid sequence identity of their proteins (approximately 60%) suggests a common ancestral gene during evolution. However, the role of 5α-reductase type 1 is not well understood.

Mutations in the SRD5A2 gene can lead to a 46,XY disorder of sex development (46,XY DSD) known as 5α-reductase-2 deficiency. These mutations are more prevalent in regions with specific ethnic backgrounds and high inbreeding coefficients. They produce proteins with varying degrees of enzymatic activity, from an unstable isoenzyme to complete loss of activity. Among the 254 amino acids in the 5α-reductase type 2 protein, mutations in codons specifying 67 different residues have been identified, with multiple mutations in several amino acid codons.

The first identified SRD5A2 mutation was nearly a complete deletion discovered through analysis of affected individuals in a Papua New Guinean tribe. Most SRD5A2 mutations are missense mutations, but small deletions, splice junction mutations, and large deletions have also been observed. These mutations result in a range of effects from destabilizing 5αR2 to complete loss of activity.

SRD5A2 mutations are inherited in an autosomal recessive manner. Homozygous defects are more frequent than compound heterozygous ones. For many common mutations, a phenotype-genotype correlation is not established, and individuals with the same 5αR2 mutations exhibit variable phenotypes, suggesting other genetic factors influence phenotype.

Mechanism

5α-Reductase type 2 (5αR2) is an enzyme encoded by the SRD5A2 gene, expressed in specific tissues in the male body from fetal development to adulthood. It catalyzes the conversion of testosterone (T) into 5α-dihydrotestosterone (DHT) within cells. DHT is the most potent ligand for the androgen receptor (AR). Once bound, the DHT-AR complex moves from the cytoplasm to the nucleus, activating androgen receptor-regulated genes involved in processes such as male sexual differentiation.

Diagnosis

Diagnosis typically occurs between birth and puberty. Pseudovaginal perineoscrotal hypospadias with female-appearing genitalia and pubertal virilization is the classic syndrome linked to 5αR2D, but modern diagnostic techniques can identify the deficiency shortly after birth and recognize its broad spectrum of presentations.

The initial diagnosis of 46,XY DSD is suggested by obvious genital abnormalities. Clinical evaluation for diagnosing 46,XY DSD with apparent female genitalia includes enlarged clitoris, posterior labial fusion, and inguinal/labial mass. For apparent male genitalia, it includes nonpalpable testes, micropenis, isolated perineal hypospadias, or mild hypospadias with undescended testis. Family and prenatal history are also considered.

Karyotyping and SRY gene analysis on peripheral leukocytes exclude sex chromosome abnormalities. With an XY karyotype and normal SRY, 46,XY DSD is differentiated through endocrinological measurements of T/DHT ratios (indicating 5αR2 activity) and precise anatomical imaging, as 5αR2D can be difficult to distinguish from other 46,XY DSD causes (e.g., partial androgen insensitivity syndrome and 17β-hydroxysteroid dehydrogenase type 3 enzyme deficiencies).

Measuring serum DHT concentration is challenging due to low concentrations and high cross-reactivity. High assay specificity is needed to measure DHT concentrations since serum T levels are generally 10 times higher than DHT in young males. Endocrinological tests for T/DHT ratios can be difficult to interpret as the normal ratio level varies with age and severity of 5αR2 activity impairment.

Affected young males of at least pubertal age with normal serum T levels show elevated T/DHT levels (normal T, lower than normal DHT). Stimulation with human chorionic gonadotropin (hCG) (or testosterone enanthate) is needed 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 particularly challenging due to neonatal testosterone surge and higher than normal 5α-reductase type 1 activity. SRD5A2 gene analysis is recommended for newborn diagnosis. Generally, 5αR2D is diagnosed with T/DHT ratios over 18, with ratios over 30 seen in severely affected individuals. 5αR2D can also be indicated by low ratios of 5α- to 5β-reduced steroids, measured in urine via gas chromatography–mass spectrometry.

Ultrasonography is the primary method 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 is still debated.

Management

One of the most challenging and controversial topics in 46,XY DSD is "sex assignment" or "sex of rearing". This is particularly true in 5αR2D, as 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 those experiencing virilizing puberty adopted a male gender identity, challenging historical practices.

The aim of sex assignment/rearing is to maximize the likelihood of a concordant gender identity in adulthood. Factors influencing gender identity are complex and not easily reported, but include sex chromosomes, androgen exposure, psychosocial development, cultural expectations, family dynamics, and social circumstances.

Female sex rearing in 5αR2D individuals involves surgical procedures like childhood gonadectomy (to prevent virilization at puberty) and vaginoplasty. Lifelong hormonal treatments are also needed for the development and maintenance of female secondary sex characteristics. Male sex of rearing avoids lifelong hormonal treatments and allows for potential fertility. Cryptorchidism and hypospadias must be addressed to prevent damage to the seminiferous tubules, which are essential for spermatogenesis and fertility. Some approaches advocate for diagnosis during infancy before any gender assignment or surgical interventions.

The intersection of the child's well-being, parental wishes, recommendations of the 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 have been seriously questioned.

Assisted reproduction methods involving sperm extraction and concentration for intrauterine insemination, intracytoplasmic sperm injection, and in vitro fertilization have all shown successful fertility outcomes for those with 5αR2D.