Genetic defects of the CYP21A2 gene in girls with premature adrenarche.

OBJECTIVES: To seek evidence on the prevalence of CYP21A2 genetic defects and consequences in girls with premature adrenarche (PA). METHODS: The study included 59 girls diagnosed with PA. Direct DNA sequencing and MLPA analysis were performed to identify mutations in CYP21A2 gene. RESULTS: Twelve girls were diagnosed with non-classic congenital adrenal hyperplasia (NC-CAH) based on stimulated 17-hydroxyprogesterone (17-OHP) levels and the presence of two mutations in CYP21A2, 19 were heterozygotes. The most frequent mutations detected were the mild p.Val281Leu and p.Pro453Ser. Higher levels of mean stimulated 17-OHP were found in the carriers of the p.Val281Leu mutation. The detection rate for two CYP21A2 mutations was higher in girls with PA than in adult females with hyperandrogenemia in our studied population. A notable increased allelic frequency for the known p.Asn493Ser polymorphism was observed in the pool of the 28 girls with PA in whom no mutation was identified. CONCLUSIONS: In girls with PA, the frequency of the underlying CYP21A2 genetic defects is similar to that observed in other populations. The carrier status is likely a contributing factor in the genotype-phenotype correlation in NC-CAH. However, polymorphisms and other genes may be implicated in the clinical manifestation of the disease.

High carrier frequency of 21-hydroxylase deficiency in Cyprus.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is a common autosomal recessive disorder caused by mutations in the CYP21A2 gene. The carrier frequency of CYP21A2 mutations has been estimated to be 1:25 to 1:10 on the basis of newborn screening. The main objective of this study was to determine the carrier frequency in the Cypriot population of mutations in the CYP21A2 gene. Three hundred unrelated subjects (150 males and 150 females) from the general population of Cyprus were screened for mutations in the CYP21A2 gene and its promoter. The CYP21A2 genotype analysis identified six different mutants and revealed a carrier frequency of 9.83% with the mild p.Val281Leu being the most frequent (4.3%), followed by p.Qln318stop (2.5%), p.Pro453Ser (1.33%), p.Val304Met (0.83%), p.Pro482Ser (0.67%) and p.Met283Val (0.17%). The notable high CYP21A2 carrier frequency of the Cypriot population is one of the highest reported so far by genotype analysis. Knowledge of the mutational spectrum of CYP21A2 will enable to optimize mutation detection strategy for genetic diagnosis of 21-OHD not only in Cyprus, but also the greater Mediterranean region.