A novel homozygous Q334X mutation in the HSD3B2 gene causing classic 3β-hydroxysteroid dehydrogenase deficiency: an unexpected diagnosis after a positive newborn screen for 21-hydroxylase deficiency.

BACKGROUND: 3β-hydroxysteroid dehydrogenase (3βHSD) type 2 (encoded by HSD3B2) is expressed in the adrenals and gonads. HSD3B2 mutations cause the rare form of congenital adrenal hyperplasia '3βHSD deficiency'. In its classic form, affected individuals have salt wasting early in infancy and may have ambiguous genitalia in both sexes. The presence of peripheral type 1 3βHSD often complicates the hormonal diagnosis of this disorder, in that very high 17α-hydroxypregnenolone levels can be converted extra-adrenally to 17α-hydroxyprogesterone (17OHP).

PATIENT AND METHODS: A 46,XX female newborn with no signs of virilization was referred for evaluation of positive 17OHP newborn screening, and developed a salt-wasting crisis at 13 days of age. The confirmatory test revealing highly elevated 17OHP suggested a 21-hydroxylase deficiency, but sequencing of the CYP21A2 gene was not consistent. Further family history suggested a 3βHSD deficiency. The HSD3B2 gene was then sequenced.

RESULTS: The patient was homozygous for the novel nonsense mutation Q334X in the HSD3B2 gene, inherited from both parents.

CONCLUSIONS: We report a novel mutation of the HSD3B2 gene, Q334X, responsible for a classic 3βHSD deficiency. The clinical and hormonal phenotypes can be complicated in this disorder, and this supports the benefits of 17OHP newborn screening to detect various forms of congenital adrenal hyperplasia.