Mutations in the type II 3 beta-hydroxysteroid dehydrogenase (HSD3B2) genecan cause premature pubarche in girls

OBJECTIVE Most previous studies have failed to demonstrate any mutations in the type II 3 beta hydroxysteroid dehydrogenase (HSD3B2) gene in patients satisfying the hormonal criteria of nonclassic 3 beta-hydroxysteroid dehydr ogenase deficiency, suggesting that a mutant 3 beta-hydroxysteroid dehydrog enase protein is not the cause of this disorder. We screened the HSD3B2 gen e for mutations in girls with premature pubarche and a hormonal diagnosis o f 3 beta-hydroxysteroid dehydrogenase deficiency. DESIGN From 30 girls with premature pubarche, we selected 9 whose ACTH-stim ulated 17-hydroxypregnenolone levels were elevated (greater than or equal t o 6 SD) and screened the HSD3B2 gene for mutations. MEASUREMENTS All patients were submitted to a standard ACTH stimulation tes t. Serum steroids were measured and compared to the mean level of pubertal stage matched control subjects. The four exons and exon-intron boundaries o f the HSD3B2 gene were amplified by polymerase chain reaction and screened for mutations by denaturing gradient gel electrophoresis. The fragments wit h abnormal migration on denaturing gradient gel electrophoresis were direct ly sequenced. RESULTS A homozygous T259M mutation was identified in one girl and a new co mpound heterozygous G129R/P222H mutation was identified in two sisters. The highest ACTH-stimulated 17-hydroxypregnenolone levels, 147, 339 and 351 nm ol/l, were found in those patients with mutations in the HSD3B2 gene. In th e patients without mutations, ACTH-stimulated 17-hydroxypregnenolone ranged from 48 to 111 nmol/l. ACTH-stimulated dehydroepiandrosterone levels had a n overlap among the girls with and without mutations and the normal control s. CONCLUSIONS Premature pubarche can be caused by mutations in the type II 3 beta hydroxysteroid dehydrogenase gene.