Classical 3-hydroxysteroid dehydrogenase (3-HSD) deficiency is a rare cause of congenital adrenal hyperplasia (CAH). We report two sisters presenting with delayed diagnoses of classical 3-HSD, despite salt wasting (SW) episodes in infancy. Sibling 1 was referred for premature pubarche, slight growth acceleration and advanced bone age, while sibling 2 had no signs of virilization.

At referral, increased 17-hydroxyprogesterone (17-OHP) associated with premature pubarche at first suggested a non-classical 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-HSD deficiency because of increased DHAS levels. Further hormonal studies showed markedly elevated (5)-steroids, in particular 17-hydroxypregnenolone > 100 nmol/liter (the clue to the diagnosis) and elevated (5)-/ (4)-steroid ratios. Sequencing of the type II 3-HSD gene documented that both girls were compound heterozygotes for T181I and 1105delA mutations. Retrospectively, elevated levels of 17-OHP 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-HSD gene. As neonatal diagnosis could have prevented life threatening crises in these girls, this report further supports the benefits for neonatal screening for CAH whatever the etiology.