5-Alpha-Reductase Deficiency

Etiology

Although testosterone is considered a predominant male sex hormone, not all tissues are responsive to testosterone. The 5alpha-RD2 enzyme converts testosterone into a more potent form of the male sex hormone called dihydrotestosterone (DHT). During male fetal development, testosterone, and DHT have a specific predetermined role in sexual development. Testosterone is the driver for the development of male internal genitalia, including the Wolffian duct, whereas DHT has a role in the genesis of male external genitalia. At puberty, testosterone is responsible for aggressive psychosexual behavior, deepening of the voice, increased muscle mass, and initiating spermatogenesis. On the contrary, DHT has a role in the development of the prostate and male hair growth pattern at puberty.[3] 5α-RD2 deficiency is a rare disorder seen most commonly due to a mutation in the gene SRD5A2 located on the short arm of chromosome 2. Children with a deficiency of 5α-reductase will have decreased production of DHT during fetal development, and this leads to defective external genital development and ambiguous genitalia.[4]

Epidemiology

The disease is very rare among white patients. Due to a large number of consanguineous marriages, there is a high prevalence of 5α-RD2 deficiency in the population of the Dominican Republic; the first reported case of 5α-RD2 deficiency was also from the same island. Apart from the Caribbean, this disease is also present in southern Lebanon and Papua New Guinea.[5] This condition was identified in patients in 1993. Two forms of 5α-reductase deficiency were described, and 2 genes were cloned.[6]

Pathophysiology

The human embryo can develop and differentiate into male and female reproductive systems. By the 6th week of gestation, the fetus would have developed the primordial structures that could form a male or female reproductive system. In the absence of testosterone, the fetus would develop the female reproductive system. Differentiation of the primordial undifferentiated gonadal ridge into the male reproductive system initiates during embryonic life by the SRY gene located on the short arm of the Y chromosome. Testosterone produced by the testes leads to differentiation of the Wolffian duct in males to form the male internal genitalia, including seminal vesicles, epididymis, and vas deferens. The overlying skin on the external genitalia has the activity of 5α-RD2 activity, which helps in the conversion of testosterone to di-hydro testosterone. DHT then starts forming the external genitalia. By 12 weeks of gestation, the male external genitalia differentiates. After 12 weeks, the penis starts to grow in size, and the testes begin their descent into the scrotum.[7] 

5α-RD2 deficiency is an inherited autosomal recessive disease. The deficiency is due to mutations in the gene that encodes for the enzyme 5α-RD2 on the short arm of chromosome 2. Up to 40 mutations have been reported, leading to this disease. The levels of DHT are low in these children, which affects the sexual differentiation of male external genitalia. Although the genotype of these children is 46 XY, the phenotype varies from case to case.[5]

History and Physical

The presentation of patients with a deficiency of 5α-RD2 can vary. This condition is an autosomal recessive disorder of sex development associated with the mutation in the SRD5A2 gene. No direct association has been seen between the phenotype and the genotype in this disorder. Two individuals with the same gene defects in SRD5A2 can present with completely different phenotypes. This shows that other additional genes probably control the phenotype and the gene under discussion.[8]

The newborns might have genitalia resembling labia majora, which would be unfused labioscrotal folds. The phallus in these children may look more like a clitoris than a penis.[9] At the same time, the internal genitalia in these children include seminal vesicles, epididymis, vas deferens, and ejaculatory duct, and one may not see any Mullerian structures. The testes in these children might be present in the inguinal sac, and very rarely, they can also be found within the abdomen. These children tend to be raised as females until puberty, when they start exhibiting virilization.[5] At puberty, the phallus may grossly enlarge to form a penis, the testes may descend into the unfused labioscrotal folds, the voice deepens, and a beard starts growing. The development of all these secondary sexual characteristics during puberty does not need the presence of DHT but only the presence of testosterone.[9]

Gender Identity Problems in Children with 5α-RD2 Deficiency

Although some children with this enzyme deficiency are raised as girls, many would change their gender to males at puberty after virilization. There are multiple factors, such as culture and environmental pressures, which can influence the gender changes in these children. Still, the most significant factor responsible for the gender change is the exposure of the child's brain to androgen, including testosterone, and not to the female sex hormone. A brain exposed to androgens develops more masculine behavior and influences the child to identify itself as a male child rather than a female.[10]

Evaluation

The evaluation of 5α-RD2 deficiency includes biochemical assays and gene analysis.

Biochemical Assay

Traditionally, the biochemical test of choice for diagnosing 5α-RD2 enzyme deficiency has been estimating the ratio between testosterone and DHT after human chorionic gonadotropin (hCG) stimulation. With this disorder, the children show an increase in the ratio of testosterone to DHT after hCG administration.[11] It merits recall that this disorder cannot be ruled out entirely if the testosterone to DHT ratio does not rise with hCG stimulation, making it more difficult to diagnose this condition.[12] Furthermore, this test is not very reliable as the ratio of testosterone to DHT may vary based on factors like the severity of enzyme deficiency and the age of the children. This biochemical test is also not useful in case of partial enzyme deficiencies. 

Gene Analysis

The human SRD5A2 gene encodes for a protein that makes up enzyme 5α-RD2 containing 254 amino acids. This variant has more affinity to testosterone than 5α-RD1. At least 54 mutations have been seen involving this gene, among which the primary type is missense mutations. The severity of the disease depends on the degree of loss of enzymatic activity due to a gene mutation. About half of these missense mutations result in an enzyme with no functional biological activity, and the rest half of the time, the gene may produce an enzyme with very little measurable biological activity.[5]

Treatment / Management

The treatment of a child with 5α-RD2 deficiency depends on many factors, the most important being the phenotypic findings and gender of the child when the physician diagnoses the problem. If there is a critical defect in the formation of external male genitalia, then it is better if the child is raised as a female. Further, if the child wants to be raised as a female, then the testes have to be removed, and corrective surgery is necessary. The testes must be removed before the child attains puberty and virilization.[13] The surgical correction if the child opts to be a female would be external genitalia reconstruction, creating a vaginal opening in the perineum with a clear separation of the urethra and vagina. When the child becomes a teenager, then vaginoplasty would be a potential treatment option.[14](B3)

If the child is raised as a male, then corrective surgery should be done depending on the phenotype of the child. The developmental size of the penis at the time of diagnosis and its ability to develop into a functional penis is the main criteria of consideration before raising the child as a male.[15] The corrective procedures in males include hypospadias correction, correction of chordee, and reconstruction of the urethra. These surgeries are normally performed during the first or second year of life.[14](B3)

The parents of the child with ambiguous genitalia have legal rights to seek assistance, support, and any information on the child's problem. They can take adequate time to decide the treatment options and the gender of the child.[16]

Differential Diagnosis

The differential diagnosis in ambiguous genitalia should be considered after a precise anatomical examination and hormonal assay. The significant differentials that can present similarly to 5α-RD2 deficiency include androgen insensitivity syndrome (AIS) and insufficiency of 17 beta-hydroxysteroid dehydrogenase type 3.[17][18] Diagnosing 5α-RD2 deficiency and AIS is critical because individuals with 5α-RD2 deficiency are usually raised as males and AIS as females. Sometimes, the phenotype of 5α-RD2 deficiency can be similar to Leydig cell hypoplasia associated with a mutation of LH receptor on the Leydig cells.[5]

Prognosis

The prognosis in individuals with 5α-RD2 deficiency is relatively good. There have been no reports of prostate malignancy and benign prostatic enlargement in these patients. These individuals have reduced facial and body hair but with normal sebum production. Most males with a deficiency of 5α-RD2 are infertile. The reasons for infertility could be undescended testes, decreased sperm count, urethral strictures, and urethroscrotal fistulas. The good news is that some individuals with 5α-RD2 deficiency can produce children, thanks to intrauterine insemination and in vitro fertilization procedures.[5]

Complications

The most significant complication associated with the deficiency of the 5α-RD2 enzyme is the altered phenotype of the genital organs. The incidence of tumors of testes in these individuals remains unreported. Some studies have looked at bone growth and development in these groups of patients, but the bone mineral density was normal in all these patients. Females with genotype 46 XX having a homozygous mutation of the SRD5A2 gene can have a delay in their menarche, but their reproductive functions are normal.[17][5]