Objectives: We have genotyped the patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency identified from March 1980 to December 1997 through a combined program of neonatal screening and case survey in the 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-September 1983 and March 1991-December 1997) and a 'phase B' of clinical monitoring only (October 1983-February 1991) were taken into account.
Patients: A total of 61 patients (20 salt wasting, nine simple virilizing and 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% classical, 3.3% nonclassical forms), large gene conversion (9.2% classical, 1.7% nonclassical 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 difference (chi2 = 5.101; P < 0.025) in the distribution of classical genotypes was found in Romagna (south-east; incidence 1 : 7437 newborns) compared to Emilia (north-west; incidence 1 : 25 090 newborns). Two putative new mutations were found in our population. Little discrepancy was found between genotype 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 substantial similarity in the mutational spectrum of classical forms found in our study, based on the detection of all the classical patients of a specific area, leads us to believe that the distribution of mutations is due to the inherent characteristics of the gene locus, and that regional effects play a minor role. Prompt neonatal genotyping can be of valuable diagnostic assistance in neonatal screening for the confirmation of the diagnosis in newborns with moderately elevated 17 hydroxyprogesterone levels.