Non-classical CAH: molecular evaluatlon of 287 subjects from Northern and Southern Italy with comparison between genetic and hormonal results

Background: Non classical congenital adrenal hyperplasia (NC-CAH) due lO 21-hydroxylase defieieney (210HD) is olle ofthe most common inherited defects of steroidogenesis. It is caused by mutations in the CYP21A2 gene that can be grouped in three categories according lO the predicted leve l of enzymatic aetivity: A (complete loss ofactivity), B (severe) and C (mild). Objective and hypotheses: The genetic characterization of suspected NCCAH subjects with stimulated 170HP values ranging from 800 and 15.000 ng/dl in order to: investigate thc genotype and thc contribution of the l'' and 200! allele 011 the 170HP levels; review the pathologic hormonallevels. Methods: 287 subjects were illvestigated by complete sequellcing of thc CYP21A2 gene and by MLPA using the MRC-Holland P050B2 kit in order lo identitY ali possible mutations including variation of the copy number. Results: The 71.8% of the subjects showed both the alleles affected (37.4 % are compound heterozygous C/C, the 15.5 % are C!B and the 43.7 % are C/A), the 21.2 % resulted heterozygous and 70/0 normal. Among the group C/C the 50.6 % of the subjects are homozygous for V281 L mutation. Taking into account thc different mutations present in the I ~ allele we found that the levels of 170HP both basally and stimulated were progressively and signifieantIy higher than the other group when tbe characterizing mutations were P482S, 3'UTR 13 G>A, P453S, V281L or P30L, respectively. Aiso tbe 2"" allele showed an influence on basai and stimulated 170HP if the l" allele is setted (i.e. V281L mutation). The V281L mutation is more frequent in the South ltalian patients, instcad tbe 3 'UTR ., 13 G>A and the genie deletion are more frequellt in North ltalian patients. Conclusions: Among affected subjects, the 94% showed 170HP stimulated values >2000 ng/dl and ollly 1% values < 1000 ng/dl.