Mutations in the Type II 3β-Hydroxysteroid Dehydrogenase (HSD3B2) Gene Can Cause Premature Pubarche in Girls

Abstract

Congenital adrenal hyperplasia (CAH) caused by a deficiency of 3β-hydroxysteroid dehydrogenase (3β-HSD) is a rare autosomal recessive disorder affecting both boys and girls. The clinical presentation is heterogeneous. Girls with premature pubarche as well as hirsute women with increased ACTH-stimulated delta-5 steroid levels were previously thought to have nonclassic or mild CAH secondary to 3β-HSD deficiency. Most efforts have failed to reveal mutations in the type II 3β-HSD gene (HSD3B 2) in these patients, apparently ruling out a mutant 3β-HSD protein as the cause. This study screened HSD3B2 for mutations in nine girls with premature pubarche who had a hormonal diagnosis of 3β-HSD deficiency. All of them had a circulating level of 17-hydroxypregnenolone 6 or more standard deviations above the mean (range = 48–351 nmol/liter). ACTH-stimulated levels of dehydroepiandrosterone were elevated in four of the nine girls. A homozygous T259M mutation was found in one girl, and a new mixed heterozygous G129R/P222H mutation was found in two sisters. Individuals with mutations had the highest levels of stimulated 17-hydroxypregnenolone, but levels of stimulated dehydroepiandrosterone (DHEA) overlapped between the girls with or without mutations and normal control subjects. The investigators concluded that mutations in HSD3B2 may cause premature pubarche in girls with elevated levels of ACTH-stimulated 17-hydroxypregnenolone. The cutoff level in the present series was 147 nmol/liter. Genotyping patients with premature pubarche will help to make a correct endocrine diagnosis of 3β-HSD deficiency.