A 22-year-old woman with no prenatal care has a normal vaginal delivery. On physical examination, the infant's external genitalia are atypical and ambiguous. There is an intermediate clitorophallic length and a perineal urethral opening. Well-circumscribed, mobile masses are palpable bilaterally in the inguinal area. Vital signs are normal. Serum testosterone level is within normal limits. A karyotype is performed and shows 46,XY. This infant most likely has a deficiency in which of the following enzymes?
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Sexual development is influenced predominantly by 3 steroid hormones:
Testosterone: development of internal male genitalia (except prostate), spermatogenesis, male sexual differentiation at puberty (eg, muscle mass, libido)
Dihydrotestosterone (DHT): development of external male genitalia, growth of prostate, male-pattern hair growth; also amplifies effects of testosterone due to high affinity for testosterone receptor
Estrogen: endometrial proliferation, development of ovarian granulosa cells, breast development
5α-reductase converts testosterone to DHT. There are 2 types of 5α-reductase: type 1 is present in postpubescent skin, whereas type 2 is found predominantly in the genitals.
5α-reductase type 2 deficiency results in diminished conversion of testosterone to DHT in the male urogenital tract. In the phenotypically (46,XY) male fetus with this genetic defect, the internal genitalia (ie, testes) develop normally under the influence of testosterone. However, due to the lack of DHT, the testicles remain undescended (cryptorchid testes presenting as inguinal masses) and the external genitalia do not develop properly, ranging from a small phallus with hypospadias to ambiguous or female-type genitalia.
Testosterone levels are within the normal range because of intact negative feedback. At puberty, physiologic increased levels of testosterone and the action of 5α-reductase type 1 result in masculinization with male-pattern muscle mass, voice deepening, penile and scrotal growth, and testicular descent.
(Choice B) 17-hydroxylase deficiency results in decreased secretion of cortisol and sex steroids and an increased level of mineralocorticoids. This manifests clinically with sodium retention, leading to hypertension, and undervirilization of male infants due to low testosterone.
(Choice C) 21-hydroxylase deficiency causes corticosteroid precursors to be shunted toward androgen production, resulting in virilization of the female fetus and salt wasting. Male children have normal genitalia.
(Choice D) Aromatase catalyzes the conversion of androgens to estrogens in the gonads and peripheral tissues. Aromatase deficiency presents with virilization of female infants; male patients are not affected phenotypically.
(Choice E) Dehydroepiandrosterone (DHEA) sulfate is a weak androgen produced by the adrenal cortex. Deficiency of DHEA sulfatase does not result in undervirilization of the male fetus.
Educational objective:
5α-reductase converts testosterone to dihydrotestosterone, which mediates development of the external genitalia in the male fetus. Male neonates with 5α-reductase deficiency are born with ambiguous genitalia that typically masculinize at puberty.