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Delayed Diagnosis of Congenital Adrenal Hyperplasia with Salt Wasting Due to Type II 3ß-Hydroxysteroid Dehydrogenase Deficiency

University Department of Growth and Reproduction (T.H.J., J.M., K.M.M.), Rigshospitalet, DK-2100 Copenhagen, Denmark; Laboratoire de Biologie Endocrinienne et Moléculaire (D.M., Y.M., M.G.F.), Hôpital Debrousse, 69322 Lyon Cedex 05, France; and University Department of Clinical Physiological and Nuclear Medicine (H.D.-P.), Glostrup University Hospital, DK-2600 Glostrup, Denmark

Address all correspondence and requests for reprints to: Trine Holm Johannsen, University Department of Growth and Reproduction, GR-5064, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: trinejohannsen{at}rh.dk.

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