ABSENCE OF MOLECULAR DEFECT IN THE TYPE-II 3-BETA-HYDROXYSTEROID DEHYDROGENASE (3-BETA-HSD) GENE IN PREMATURE PUBARCHE CHILDREN AND HIRSUTEFEMALE-PATIENTS WITH MODERATELY DECREASED ADRENAL 3-BETA-HSD ACTIVITY

To date the molecular basis and hormonal criteria for inherited mild l ate-onset 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency congenital adrenal hyperplasia (CAH) have not been defined. We have th us investigated the presence or absence of mutation in the type II 3 b eta-HSD gene encoding adrenal/gonadal 3 beta-HSD in each of five prema ture pubarche children and hirsute female patients manifesting moderat ely decreased adrenal 3 beta-HSD activity. ACTH-stimulated hormonal le vels in all patients compared with mean levels in pubertal stage-match ed normal subjects were between 2.5 and 6.5 SD for 17-hydroxypregnenol one 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 androstened ione ratios were between 3 and 8.6 SD, The type II 3 beta-HSD gene reg ions of a putative promoter, exons I, II, III, and IV, and exon-intron boundaries in all subjects were amplified by polymerase chain reactio n and then sequenced. All patients had normal sequences of the type II 3 beta-HSD gene in both alleles. Three female patients heterozygotic for severe 3 beta-HSD deficiency CAH with one allele mutation of the g ene demonstrated normal ACTH-stimulated hormone profiles. These data i ndicate that moderately decreased adrenal 3 beta-HSD activity resultin g in modestly increased Delta 5 precursor steroid levels and Delta 5 t o Delta 4 steroid ratios in premature pubarche and hirsute patients is not caused by a mutation in the type II 3 beta-HSD gene. This suggest s that the moderately decreased adrenal 3 beta-HSD activity in the pat ient is not due to mild late-onset variants of inherited 3 beta-HSD de ficiency CAH, whereas the carriers for true 3 beta-HSD deficiency CAH do not express decreased adrenal 3 beta-HSD activity.