An infant is born at 39 weeks gestation to a 26-year-old woman. The delivery was uncomplicated, and Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. The mother had gestational diabetes during pregnancy, which was controlled by diet alone. Physical examination of the infant shows clitoromegaly and partial fusion of the labioscrotal folds. Cytogenetic analysis reveals a 46,XX karyotype. Abdominal imaging shows bilateral adrenal hyperplasia. This patient is most likely deficient for an enzyme normally responsible for which of the following reactions?
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This patient's abdominal imaging and ambiguous genitalia are consistent with congenital adrenal hyperplasia (CAH). The most common cause of CAH is 21-hydroxylase deficiency, accounting for 90% of all cases. This enzyme catalyzes the conversion of progesterone to 11-deoxycorticosterone (aldosterone precursor) in the zona glomerulosa, and 17-hydroxyprogesterone to 11-deoxycortisol (cortisol precursor) in the zona fasciculata.
In 21-hydroxylase deficiency, the adrenal gland cannot synthesize aldosterone and cortisol efficiently. ACTH levels increase as a result of low cortisol levels, stimulating increased adrenal androgen production by diverting the accumulating aldosterone and cortisol precursors toward the androgen biosynthetic pathway. Genetic females (46,XX) affected with classic 21-hydroxylase deficiency are usually identified at birth as increased androgen levels lead to ambiguous genitalia (virilization). However, genetic males (46,XY) have normal genitalia and therefore typically present later with symptoms of salt-wasting or precocious puberty.
Infants with 21-hydroxylase deficiency are often detected during routine newborn screening, and a high serum level of 17-hydroxyprogesterone confirms the diagnosis.
(Choice A) Side-chain cleavage enzyme catalyzes the conversion of cholesterol into pregnenolone. Lack of this enzyme leads to absent steroid hormone synthesis. Complete enzyme deficiency is lethal due to absent placental progesterone synthesis.
(Choice B) Dehydroepiandrosterone is converted to androstenedione by 3β-hydroxysteroid dehydrogenase, an enzyme that also converts pregnenolone to progesterone and 17-hydroxypregnenolone to 17-hydroxyprogesterone. Although deficiency of this enzyme can result in adrenal insufficiency and ambiguous genitalia (in both sexes), it is a very rare cause of CAH.
(Choice D) Synthesis of 17-hydroxyprogesterone from progesterone is catalyzed by 17α-hydroxylase. Deficiency of this enzyme causes mineralocorticoid excess and impaired androgen synthesis. Genetic males have ambiguous genitalia, whereas genetic females appear phenotypically normal.
(Choice E) 5α-reductase deficiency prevents the conversion of testosterone to dihydrotestosterone, the hormone responsible for the development of male external genitalia. Affected genetic males, not females, are born with ambiguous genitalia.
Educational objective:
The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency. Genetically female infants typically have ambiguous genitalia (virilization) at birth, whereas males have phenotypically normal genitalia, with salt-wasting or precocious puberty appearing later. Elevated 17-hydroxyprogesterone is diagnostic.