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

Abstract

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 dehydroepi-androsterone (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 5-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 SD 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.

Pronounced Adrenarche and Precocious Pubarche in Boys

“…Boys with PP were included in the study, if PP was attributable to premature adrenarche, as suggested by elevated serum concentrations of androstenedione (Δ 4 -A) and/or dehydroepiandrosterone sulfate (DHEAS) at prepubertal diagnosis of PP [15]and by lack of evidence for nonclassic adrenal hyperplasia (serum 17-OHP and 17-hydroxypregnenolone measurements after adrenocorticotropic hormone – ACTH – administration) [16, 17]and for precocious puberty (testicular volume at PP diagnosis ≤2 ml). None of the subjects had acanthosis nigricans, thyroid dysfunction, Cushing’s syndrome, hyperprolactinemia, or a family or personal history of diabetes mellitus.…”

Increased Bone Mineral Density and Serum Leptin in Non-Obese Girls with Precocious Pubarche: Relation to Low Birthweight and Hyperinsulinism

“…All subjects were receiving a standard Mediterranean diet; none presented evidence for thyroid dysfunction, hyperprolactinemia, a family or personal history of diabetes mellitus, late-onset congenital adrenal hyperplasia [26, 27]; none was receiving an oral contraceptive treatment or a medication known to affect gonadal function or carbohydrate metabolism.…”