HYPERANDROGENISM AND MANIFESTING HETEROZYGOTES FOR 21-HYDROXYLASE DEFICIENCY

Premature adrenarche and functional adolescent androgen excess are com mon disorders which may evolve into polycystic ovary syndrome (PCOS). In all three disorders, ACTH-stimulated 17-hydroxyprogesterone concent rations are often somewhat elevated, To determine the role of 21-hydro xylase (CYP21) gene mutations in these disorders, we performed molecul ar genotype analysis on 48 children and adolescents referred for evalu ation of hyperandrogenic findings and, diagnosed as having premature a drenarche or functional androgen excess. For comparison, DNA samples f rom 80 healthy adults were genotyped. Seventeen of the 48 hyperandroge nic patients were found to be heterozygotic carriers of CYP21 mutation s. The frequency of heterozygosity was significantly greater among sym ptomatic patients (35%) than among the healthy controls (6%), P < 0.00 1. Seven mutation-positive patients (50%) and only one mutation-negati ve patient had ACTH-stimulated 17-hydroxyprogesterone concentrations t ypical for heterozygotic carriers of 21-hydroxylase deficiency, 400-10 00 ng/dl. The significant difference in heterozygote frequency between symptomatic patients and healthy controls suggests that heterozygosit y for 21-hydroxylase deficiency may be associated with premature adren arche and functional adolescent hyperandrogenism, Longitudinal studies are necessary to determine if heterozygosity for 21-hydroxylase defic iency predicts risk for PCOS. (C) 1997 Academic Press.