Studies of 3 beta-hydroxysteroid dehydrogenase genes in infants and children manifesting premature pubarche and increased adrenocorticotropin-stimulated Delta(5)-steroid levels

Classic 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) deficiency congenital adrenal hyperplasia (CAH) results from a mutation in the type II 3 beta HSD gene encoding adrenal and gonadal 3 beta HSD. We investigated the type II and type I 3 beta HSD gene sequences in 15 infants and children with premature pubarche (PP; mean/range of age at PP, 4/0.08-9 yr) and elevated ACTH-stimulated Delta(5) precursor steroid levels. Compared to Tanner I control subjects of similar age, ACTH-stimulated hormonal levels were at 2.3-10.7 SD for 17-hydroxypregnenolone (Delta(5)-17P) in all PP subjects, at 2.2-17 SD for dehydroepiandrosterone (DHEA) and 2.4-5.6 SD for the Delta(5)-17P/cortisol(F) ratio in all PP subjects except 1 infant, and at 2.3-10 SD for the DHEA/androstenedione (Delta(4)-A) ratio in 8 PP subjects. Compared to Tanner II normal children, the hormonal levels were at 3-8 SD for Delta(5)-17P in all 13 PP children, at 2.3-4.7 so for the Delta(5)-17P/F ratio in 6 PP children, and at 2.3-6.5 SD for DHEA and 3.5-9 SD for the DHEA/Delta(4)-A ratio in 7 PP children. Type II 3 beta HSD gene sequences, including regions of a putative promoter, all exons (I, II, III, and IV), and exon-intron boundaries, were normal in all subjects. Sequences of the type I 3 beta HSD gene encoding extraadrenal and extragonadal 3 beta HSD were normal in the 6 patients tested. The ACTH-stimulated Delta(5)-17P levels and Delta(5)-17P/F ratios in the PP children without type II 3 beta HSD gene mutation were exceedingly lower than the respective reported hormonal data for children with 3 beta HSD deficiency CAH with proven type II 3 beta HSD gene mutation. The ACTH-stimulated DHEA levels and DHEA/Delta(4)-A ratios were not exceedingly different between the children with and without type II 3 beta HSD gene mutation. These findings suggest that the degree of ACTH-stimulated Delta(5) precursor steroid abnormality, such as Delta(5)-17P levels up to 10 SD above the normal mean level found in our PP patients, is not caused by a mild variant of 3 beta HSD deficiency CAH resulting from type II or type I 3 beta HSD gene mutation. The hormonal criterion for ACTH-stimulated Delta(5)-17P levels in patients with mild variant 3 beta HSD deficiency, therefore, is predicted to be higher than 10 SD above the normal mean value.