Delayed diagnosis of congenital adrenal hyperplasia with salt wasting due to type II 3β-hydroxysteroid dehydrogenase deficiency

Classical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency is a rare cause of congenital adrenal hyperplasia. We report two sisters presenting with delayed diagnoses of classical 3 beta-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 17 alpha-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 3 beta-HSD deficiency because of increased dehydroepiandrosterone sulfate levels. Further hormonal studies showed markedly elevated Delta(5)-steroids, in particular 17 alpha-hydroxypregnenolone greater than 100 nmol/liter ( the clue to the diagnosis) and elevated Delta(5)-/Delta(4)-steroid ratios. Sequencing of the type II 3 beta-HSD gene documented that both girls were compound heterozygotes for T181I and 1105delA mutations. Retrospectively, elevated levels of 17 alpha-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 3 beta-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.