Abstract
Classical 3β-hydroxysteroid dehydrogenase (3β-HSD) deficiency is a rare cause of congenital adrenal hyperplasia. We report two sisters presenting with delayed diagnoses of classical 3β-HSD, despite salt wasting (SW) episodes in infancy. Sibling 1 was referred for premature pubarche, slight growth acceleration, and advanced bone age, whereas sibling 2 had no signs of virilization.
At referral, increased 17α-hydroxyprogesterone associated with premature pubarche at first suggested a nonclassical 21-hydroxylase deficiency. Sequencing of the CYP21 gene showed both girls only heterozygotes (V281L mutation). This result, combined with SW in infancy, suggested a 3β-HSD deficiency because of increased dehydroepiandrosterone sulfate levels. Further hormonal studies showed markedly elevated Δ5-steroids, in particular 17α-hydroxypregnenolone greater than 100 nmol/liter (the clue to the diagnosis) and elevated Δ5-/Δ4-steroid ratios. Sequencing of the type II 3β-HSD gene documented that both girls were compound heterozygotes for T181I and 1105delA mutations. Retrospectively, elevated levels of 17α-hydroxyprogesterone were found on blood spots from Guthrie’s test.
There is no previous report of the combination of SW and premature pubarche due to mutations in the type II 3β-HSD gene. Because neonatal diagnosis could have prevented life-threatening crises in these girls, this report further supports the benefits for neonatal screening for congenital adrenal hyperplasia whatever the etiology.
A Novel Nonstop Mutation in the Stop Codon and a Novel Missense Mutation in the Type II 3β-Hydroxysteroid Dehydrogenase (3β-HSD) Gene Causing, Respectively, Nonclassic and Classic 3β-HSD Deficiency Congenital Adrenal Hyperplasia
