Absence of molecular defect in the type II 3β-hydroxysteroid dehydrogenase (3β-HSD) gene in premature pubarche children and hirsute female patients with moderately decreased adrenal 3β-HSD activity

ABSTRACT: To date the molecular basis and hormonal criteria for inherited mild late-onset 3β-hydroxysteroid dehydrogenase (3β-HSD) deficiency congenital adrenal hyperplasia (CAH) have not been defined. We have thus investigated the presence or absence of mutation in the type II 3β-HSD gene encoding adrenal/gonadal 3β-HSD in each of five premature pubarche children and hirsute female patients manifesting moderately decreased adrenal 3β-HSD activity. ACTH-stimulated hormonal levels in all patients compared with mean levels in pubertal stage-matched normal subjects were between 2.5 and 6.5 SD for 17-hydroxypregnenolone levels, and between 2.5 and 7 SD for dehydroepiandrosterone levels in all except one patient. 17-Hydroxypregnenolone to cortisol ratios were between 2.5 and 4.3 SD, and dehydroepiandrosterone to androstenedione ratios were between 3 and 8.6 SD. The type II 3β-HSD gene regions of a putative promoter, exons I, II, III, and IV, and exon-intron boundaries in all subjects were amplified by polymerase chain reaction and then sequenced. All patients had normal sequences of the type II 3β-HSD gene in both alleles. Three female patients heterozygotic for severe 3β-HSD deficiency CAH with one allele mutation of the gene demonstrated normal ACTH-stimulated hormone profiles. These data indicate that moderately decreased adrenal 3β-HSD activity resulting in modestly increased Δ5 precursor steroid levels and Δ5 to Δ4 steroid ratios in premature pubarche and hirsute patients is not caused by a mutation in the type II 3β-HSD gene. This suggests that the moderately decreased adrenal 3β-HSD activity in the patient is not due to mild late-onset variants of inherited 3β-HSD deficiency CAH, whereas the carriers for true 3β-HSD deficiency CAH do not express decreased adrenal 3β-HSD activity.