title: 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.
authors.affiliation: Department of Pediatrics, University of Illinois College of Medicine, Chicago 60612, USA.
authors.forename: H
authors.initials: H
authors.lastname: Sakkal-Alkaddour
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.forename: Y T
authors.initials: YT
authors.lastname: Chang
authors.forename: M
authors.initials: M
authors.lastname: Kappy
authors.forename: R S
authors.initials: RS
authors.lastname: Slover
authors.forename: V
authors.initials: V
authors.lastname: Jorgensen
authors.forename: S
authors.initials: S
authors.lastname: Pang
mesh_terms: D006907:17-alpha-Hydroxypregnenolone / Q000097:blood; D015096:3-Hydroxysteroid Dehydrogenases / Q000172:deficiency / Q000235:genetics*; D000312:Adrenal Hyperplasia, Congenital / Q000097:blood / Q000201:enzymology / Q000235:genetics; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000735:Androstenedione / Q000097:blood; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003687:Dehydroepiandrosterone / Q000097:blood; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007223:Infant; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D011629:Puberty, Precocious / Q000097:blood / Q000201:enzymology* / Q000235:genetics*
chemical_list: D006907:17-alpha-Hydroxypregnenolone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D000324:Adrenocorticotropic Hormone; D015096:3-Hydroxysteroid Dehydrogenases; D006854:Hydrocortisone