5-Alpha-Reductase Deficiency 

5-alpha-reductase type 2 deficiency (5-ARD) is an autosomal recessive sex-limited condition resulting in the inability to convert testosterone to the more physiologically active dihydrotestosterone (DHT). Because DHT is required for the normal masculinization of the external genitalia in utero, genetic males with 5-alpha-reductase type 2 deficiency are born with ambiguous genitalia (ie, 46,XY disorder of sex development).^[1]

Patients with 5-alpha-reductase type 2 deficiency usually present with striking ambiguity of the genitalia, with a clitoral-like phallus, severely bifid scrotum, pseudovaginal perineoscrotal hypospadias, and a rudimentary prostate. Occasionally, patients can appear more masculinized; they may lack a separate vaginal opening, have a blind vaginal pouch that opens into the urethra, and have isolated penile hypospadias^[2] or even a penile urethra.^[3]

The uterus and fallopian tubes are absent because of the normal secretion of the müllerian-inhibiting factor. Testes are intact and are usually found in the inguinal canal or scrotum; however, cryptorchidism is frequently described with testes occasionally located in the abdomen. Wolffian duct differentiation is normal with seminal vesicles, vasa differentia, epididymides, and ejaculatory ducts. The prostate is small, nonpalpable, and rudimentary in adulthood. Neither benign prostate hyperplasia (BPH) nor prostate cancer has been reported in these patients.^[4]

The root cause of this disorder is a deficiency in the 5-alpha-reductase type 2 isoenzyme, which transforms testosterone to DHT. DHT is a more potent androgen than testosterone and is bound selectively to the androgen receptors in genital skin and fibroblasts. The 5-alpha-reductase type 2 isoenzyme is expressed in external genital tissues early in gestation, making its action necessary for the development of normal male genital anatomy in the fetus.^[3] As with most single enzyme disorders, 5-alpha-reductase type 2 deficiency is autosomal recessive and sex limited because it only causes a clinically significant disorder in genetic males, with very subtle phenotypic changes in homozygous females. See the image below.

Two genes coding for 5-alpha-reductase have been identified, each for a slightly different isoenzyme. The gene for 5-alpha-reductase type 2 has been determined to be on chromosome 2. Lack of expression of this gene clinically correlates with the symptoms of 5-alpha-reductase type 2 deficiency. In adulthood, the 5-alpha-reductase type 2 isoenzyme is expressed in high levels in the prostate, genital skin, epididymis, seminal vesicle, and liver.^[3]

The gene for 5-alpha-reductase type 1 has been located on chromosome 5. Its product is expressed only in nongenital skin and liver at low levels from the time the individual is aged 3 years until puberty, at which time enzyme expression is measurable in sebaceous glands and scalp. Linkage analysis has demonstrated that the type 1 enzyme is unrelated to the clinical syndrome of 5-alpha-reductase type 2 deficiency. Interestingly, partial virilization of males with 5-alpha-reductase type 2 deficiency occurs at puberty and may be attributable to the rise in type 1 enzyme activity at that time.^[4]

More than 33 different mutations of this gene have been reported in people with clinical and biochemical evidence of the enzyme deficiency. Correlation between the severity of the syndrome and a particular gene defect has not been observed.^[3]

Frequency

United States

The carrier frequency and number of individuals with this disorder are not established.

International

Although frequencies for various countries are not established, increased frequency is reported in the Dominican Republic, some highland tribes in New Guinea, and in Turkey. The high frequency in these areas represents the effect of consanguinity in specific kindreds.^[3] Overall, more than 50 families with this disorder have been described in several parts of the world. In a few patients with 46,XY disorders of sexual development (DSD) due to 5-alpha-reductase type 2 deficiency diagnosed by clinical and hormonal findings, no mutations were identified in the SRD5A2.^[5] In general, intersex conditions as a whole are uncommon, with an overall incidence of 1:5500.^[6]

Mortality/Morbidity

This enzyme deficiency is not life threatening; however, if intra-abdominal testes are retained, an increased risk of gonadoblastoma is noted. Secondary issues include a risk of osteoporosis if hormone replacement therapy is not initiated in the patient with a gonadectomy and psychological morbidity due to gender or sexual identity (see Treatment).

Sex

Clinical 5-alpha-reductase type 2 deficiency is limited to genetic males. Although the enzyme deficiency can be documented in homozygous females, no clinical or developmental need for DHT is documented in women.

Age

Most individuals with 5-alpha-reductase type 2 deficiency are identified in the neonatal period because of ambiguous genitalia.^[7] However, some of these children are misdiagnosed as having partial or complete androgen insensitivity syndrome (AIS), which can produce almost identical phenotypes. As noted above, some patients with 5-alpha-reductase type 2 deficiency present with more masculinized genitalia including isolated hypospadias or penile urethra with micropenis, which can lead to a delay in diagnosis.^[3]

The clinical heterogeneity and unpredictable and varying outcome of patients with disorders of sexual development (DSD) associated with abnormalities in androgen response or synthesis places an ethical, and potentially legal, burden on the treatment team to ensure that standards of informed consent are met prior to medical or surgical intervention. This is especially true for gonadectomy and/or genitoplasty, irreversible procedures that result in loss of potential fertility and have life-long impact on gender satisfaction.

The health care team needs to clearly communicate to the parents that data are insufficient to absolutely predict adult gender satisfaction irrespective of initial medical or surgical treatment. Early genitoplasty with or without gonadectomy does not appear to be associated with increased gender assignment satisfaction or a decrease in the potential for gender role change. On the other hand, although delaying these procedures provides a greater opportunity for the patient's involvement in the decision process, this alternative approach is not without risk, because little data suggest the consequences of delayed repair of ambiguity on the development of self-esteem and gender satisfaction within cultures with low incidence of disease.^{[20, 21, 22]}

The more contemporary approach, to delay definitive therapy, has developed over the last 2 decades as adult intersex patients and advocates have voiced their dissatisfaction with life-changing procedures performed premature to their ability to consent.

The consequence is that the parents of the newborn with a 46,XY DSD are placed in a difficult situation. They must adapt to the diagnosis, acutely acquire an understanding of the issues of gender as well as the risks, benefits, and potential complications of treatment and nontreatment options. This education process, ultimately concluded with a statement of informed consent, should satisfy a "reasonable patient" standard: "a doctor must disclose those risks, benefits, and alternatives that a reasonable person in the patient's position would be likely to consider significant in deciding whether or not to undergo treatment, including diagnosis and prognosis, common risks of the proposed procedure, remote risks with grave consequences, probable outcomes and expected posttreatment course, and the risks, benefits and unknowns of alternative treatments and nontreatment."^{[12, 21]}