Hyperandrogenism in carriers of CYP21 mutations: the role of genotype

• Published in: Clinical endocrinology (Oxford) 2006-06, Vol.64 (6), p.645-651
• Main Authors: Admoni, Osnat, Israel, Shosh, Lavi, Idit, Gur, Michal, Tenenbaum-Rakover, Yardena
• Format: Article
• Language: English
• Subjects: 17-alpha-Hydroxyprogesterone - blood; Adolescent; Adrenal Hyperplasia, Congenital - blood; Adrenal Hyperplasia, Congenital - genetics; Adrenocorticotropic Hormone; Biological and medical sciences; Chi-Square Distribution; Child; Child, Preschool; Endocrinopathies; Female; Fundamental and applied biological sciences. Psychology; Genetic Testing; Genotype; Heterozygote; Humans; Hydrocortisone - blood; Hyperandrogenism - blood; Hyperandrogenism - genetics; Infant, Newborn; Israel; Male; Medical sciences; Phenotype; Point Mutation; Polymerase Chain Reaction; Steroid 21-Hydroxylase - genetics; Vertebrates: endocrinology
• ISSN: 0300-0664; 1365-2265
• DOI: 10.1111/j.1365-2265.2006.02521.x

Summary Objective  It has been hypothesized that carriers of CYP21 mutations are at increased risk of developing clinically evident hyperandrogenism. In the present study, we assessed the risk for symptoms of androgen excess in carriers of CYP21 gene mutations and the effect of different mutations on phenotype. Design  All subjects underwent clinical evaluation, ACTH stimulation testing, and molecular analysis of the CYP21 gene. Patients  One hundred and eighty‐seven subjects were included in the study. Five groups were defined according to genotype: A, 38 patients with classical‐congenital adrenal hyperplasia (CAH); B, 16 patients with non classical CAH; C, 66 family member carriers; D, 24 children and adolescents with symptoms suggestive of hyperandrogenism who were found to be heterozygous and E, 43 subjects with androgen excess symptoms who had normal genotype. Measurements  Cortisol and 17‐hydroxyprogesterone (17OHP) were measured basally and 60 min after ACTH stimulation. Analysis of seven common mutations of the CYP21 gene, which collectively cover 95% of the mutations in the Israeli population, was performed. The hormonal results were correlated with the genotype. Results  The symptomatic carriers had a significantly higher rate of the mild mutation V281L compared with the family members (58% vs. 22%) and significantly higher levels of ACTH‐stimulated 17OHP (mean 37·2 and 21 nmol/l, respectively; P = 0·025). Higher values of peak 17OHP levels were found in the carriers of the V281L mutation compared with carriers of other mutations (P = 0·025). Stimulated 17OHP levels were significantly higher in carriers compared with normal genotype subjects (P