DECEMBER 2021 Question: A neonate with ambiguous genitalia is being evaluated in the newborn nursery. The neonate was born today via an uncomplicated spontaneous vaginal delivery at 39 weeks of gestation, with a birthweight of 3.2 kg. The pregnancy was uncomplicated and maternal medication consisted only of prenatal vitamins. The neonate is breastfeeding well and has normal vital signs for age. Physical examination findings are normal except for the genitalia.. The neonate has a 1.5-cm long phallic structure, complete fusion of the labioscrotal folds, and no palpable gonads. Pelvic ultrasonography shows a uterus. A karyotype is ordered. Of the following, the BEST next test to determine the neonate’s diagnosis is
A. adrenocorticotropic hormone
B. cortisol C. 17-hydroxyprogesterone D. Testosterone Answer: C The neonate described in the vignette has congenital adrenal hyperplasia (CAH) arising from 21-hydroxylase deficiency. The findings of no palpable gonads and a uterus noted on ultrasonography are consistent with a virilized female or 46, XX disorder of sex development (DSD). Congenital adrenal hyperplasia arising from 21-hydroxylase deficiency is the most common 46, XX DSD. The best next test to determine the diagnosis for the neonate in the vignette is a 17-hydroxyprogesterone level. 17-hydroxyprogesterone is an intermediate steroid in the adrenal glucocorticoid pathway, which is a substrate for 21- hydroxylase and builds up in 21-hydroxylase deficiency. This defect in adrenal glucocorticoid production results in an elevated adrenocorticotropic hormone (ACTH) level, which stimulates the adrenal gland to make excess androgen. Adrenal mineralocorticoid production is also negatively affected by this enzyme defect. The excess androgen exposure in utero causes virilization of female external genitalia. Congenital adrenal hyperplasia should be suspected in a neonate with virilized, atypical genitalia and no palpable gonads. Male (46,XY) neonates with 21-hydroxylase deficiency have normal male genitalia. Unlike affected females, males have no physical findings to identify them at birth. Therefore, they are at risk of presenting with an adrenal salt-wasting crisis, which occurs after age 1 week. Signs and symptoms may include failure-to-thrive, vomiting, hypotension, hyponatremia, hyperkalemia,
hypoglycemia, and metabolic acidosis. The newborn screen is critically important for identification of male infants with CAH before an adrenal salt-wasting crisis occurs. If measured, an ACTH level would be high, cortisol level would be low, and testosterone level would be high in CAH, but none of these is the best next diagnostic test for this neonate, because the results would not be specific for the diagnosis.