Genetic defects in the cyp21a2 gene in heterozygous girls with premature adrenarche and adolescent females with hyperandrogenemia.

UNLABELLED: Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disorder primarily caused by mutants in the CYP21A2 gene. Heterozygosity for CYP21A2 mutations in females increases their risk of clinically manifesting hyperandrogenism and the present study was designed to seek evidence on the prevalence and consequences of heterozygous CYP21A2 mutations in children with premature adrenarche and adolescents with hyperandrogenemia. The hormonal response to ACTH was evaluated in 17 girls with clinical signs of premature adrenarche and 17 adolescent females with hyperandrogenemia, along with direct DNA sequencing and MLPA analysis for mutations in the CYP21A2 gene. The suspicion of heterozygote state was based on the median plasma 17-OHP before and 60 minutes after ACTH stimulation. All 34 patients were identified as carriers of CYP21A2 mutations. The most frequent mutations among this cohort of carriers were the mild p.V281L (52.9%), followed by p.Q318stop (20.6%), p.V304M (8.9%), p.P482S (5.9%), p.P453S (5.9%), large deletion/conversion exons 1-4 (2.9%) and large deletion/conversion exons 6-8 (2.9%). Higher values of stimulated 17-OHP levels were found in the carriers of the p.V281L mutation compared with carriers of other mutations (mean=21.9 nmol/L vs 17.0 nmol/L). This finding supports the already identified notion that carriers of the mild p.V281L are at higher risk for hyperandrogenism than carriers of severe mutations. IN CONCLUSION: a. Females with premature adrenarche and hyperandrogenemia are likely to bear heterozygous CYP21A2 mutations, therefore systematic evaluation of 17-OHP values in combination with the molecular testing of CYP21A2 gene is beneficial, b. carriers of the mild p.V281L, are at higher risk of androgen excess compared to carriers of other types of mutations.