CYP21 analysis and phenotype/genotype relationship in the screened population of the Italian Emilia-Romagna region

OBJECTIVES We have genotyped the patients with congenital adrenal hyperplas ia due to 21-hydroxylase deficiency identified from March 1980 to December 1997 through a combined program of neonatal screening and case survey in th e Emilia-Romagna Region (Italy). We have also analysed retrospectively the possible advantages of genotypical neonatal classification. DESIGN A 'phase A' of screening and clinical monitoring (March 1980-Septemb er 1983 and March 1991-December 1997) and a 'phase B' of clinical monitorin g only (October 1983-February 1991) were taken into account. PATIENTS A total of 61 patients (20 salt wasting, nine simple virilizing an d 32 nonclassical forms) were genotyped, HLA typed and hormonally tested to understand better the genotype/phenotype relationship and the epidemiology and geographical distribution of associated mutations. The fully genotyped patients were classified into four mutation groups according to the degree of enzymatic activity ('null' and 'A' to 'C'). RESULT The most frequent genotype alterations were deletion (24.1% classica l, 3.3% nonclassical forms), large gene conversion (9.2% classical, 1.7% no nclassical forms), In2 splice (27.7% classical, 15.0% nonclassical forms), I172N (5.5% classical, 10.0% nonclassical forms), V281L (3.7% classical, 43 .3% nonclassical forms), P453S (5.0% nonclassical forms). A significant dif ference ((chi)2 = 5.101; P< 0.025) in the distribution of classical genotyp es was found in Romagna (south-east; incidence 1 :7437 newborns) compared t o Emilia (north-west; incidence 1 :25 090 newborns). Two putative new mutat ions were found in our population. Little discrepancy was found between gen otype and phenotype. CONCLUSIONS The high frequency of genotypes 'null' or 'A' in the 'phase A' vs. 'phase B' of our study confirms the usefulness of neonatal screening in preventing the death of male patients with salt wasting forms. The substan tial similarity in the mutational spectrum of classical forms found in our study, based on the detection of all the classical patients of a specific a rea, leads us to believe that the distribution of mutations is due to the i nherent characteristics of the gene locus, and that regional effects play a minor role. prompt neonatal genotyping can be of valuable diagnostic assis tance in neonatal screening for the confirmation of the diagnosis in newbor ns with moderately elevated 17 hydroxyprogesterone levels.