Non classical CAH: molecular evaluation of 287 subjects from northern and southern Italy with comparison between genetical and hormonal results.

Background Non classical congenital adrenal hyperplasia (NC-CAH) due to 21-hydroxylase deficiency (21OHD) is one of the most common inherited defects of steroidogenesis. It is caused by mutations in the CYP21A2 gene that can be grouped in three categories according to the predicted level of enzymatic activity: A (complete loss of activity), B (severe) and C (mild). Objective and hypothesis The genetic characterization of suspected NC-CAH subjects with stimulated 17OHP values ranging from 800 and 15.000 ng/dl in order to: investigate the genotype and the contribution of the 1st and 2nd allele on the 17OHP levels; review the pathologic hormonal levels. Population and/or methods 287 subjects were investigated by complete sequencing of the CYP21A2 gene and by MLPA using the MRC-Holland P050B2 kit in order to identify all 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 7% normal. Among the group C/C the 50.6 % of the subjects are homozygous for V281L mutation. Taking into account the different mutations present in the 1st allele we found that the levels of 17OHP both basally and stimulated were progressively and significantly higher than the other group when the characterizing mutations were P482S, 3’UTR 13 G>A, P453S, V281L or P30L, respectively. Also the 2nd allele showed an influence on basal and stimulated 17OHP if the 1st allele is setted (i.e. V281L mutation). The V281L mutation is more frequent in the South Italian patients, instead the 3’UTR *13 G>A and the genic deletion are more frequent in North Italian patients. Precise conclusions Among affected subjects, the 94% showed 17OHP stimulated values >2000 ng/dl and only 1% values <1000 ng/dl