46,XY 5-Alpha-Reductase Deficiency in a Phenotypic Female

5-alpha-reductase deficiency (5aRD) is a rare genetic sex disorder seen in 46, XY individuals inherited as an autosomal recessive mutation of the 5aR type 2 gene (SRD5A2) resulting in dihydrotestosterone deficiency during sexual characteristic development.

Case Description:

A 36-year-old Pakistani phenotypic female with history of pre-diabetes presented with a new onset type II diabetes mellitus, weight gain, and acne. She had unremarkable surgical and family history. She had never been sexually active and denied ever having a normal menstrual cycle, but did describe intermittent spotting. Physical examination showed BP 130/86 mmHg, BMI 29 kg/m2, thin, pale abdominal striae, central obesity, facial acne, mild hirsutism and moon facies. A low-dose dexamethasone suppression test was negative with cortisol suppressing to < 1.0mcg/dL. Further biochemical assessment included normal thyroid function tests, prolactin, DHEA-S and negative hCG. Total testosterone level was elevated to 427 ng/dL (normal 10-55 ng/dL). Dihydrotestosterone (DHT) level was 9.0 ng/dL (normal 4-22 ng/dL). Karyotype revealed a 46XY genotype. Patient denied clitoromegaly or virilization, but endorsed primary amenorrhea. MRI (Figure 1) showed an absent uterus, cervix and ovaries with a blind vaginal pouch posterior to the bladder and anterior to the rectum. Figure 2 showed rudimentary undescended gonads in the proximal inguinal canal bilaterally. The patient was referred for genetic testing and found to be homozygous for a pathogenic variant of the SRD5A2 gene, consistent with autosomal recessive 5ARD.

Discussion:

DHT is a main factor in the development of the external male genitalia. Testosterone is important in the development of internal male genitalia and secondary sexual characteristics. 5-alpha-reductase type 2 enzyme catalyzes the reduction of testosterone to DHT during embryogenesis.
Generally, 46,XY patients with 5ARD present at birth with female features and varying degree of hypospadias, normal female genitourinary anatomy or with clitomegaly. 5ARD has been described in 46,XX females; these individuals have an elevated urinary testosterone-to-DHT ratio, normal female phenotype, absent arm and leg hair with a decrease in axillary and pubic hair due to low DHT (references…). They have late menarche but normal menstrual function and fertility. Management for 5ARD may include initial gender assignment, trial of androgen supplementation, or DHT. This case is atypical as this patient presented at age 36. This was due to her lack of sexual activity and conservative upbringing. Typically, these patients are identified much earlier as they present with amenorrhea and infertility. This unique case highlights the need for medical providers to consider rare sexual development disorders in the differential for obesity, hirsutism, infertility and amenorrhea.