Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Complete analysis of the CYP21 gene was performed in 56 unrelated French wo men with symptomatic nonclassical congenital adrenal hyperplasia. The mutat ional spectrum and the phenotype-genotype correlation were examined. The ov erall predominant mutation was V281L, which was present on 51% of alleles a nd in 80% of women. Three novel mutations were found: L317M, R435C, and a 5 '-end gene conversion. Sixty-three percent of the women were carrying a sev ere mutation of the CYP21 gene, and hence risk giving birth to children wit h a classical form of the disease. In such cases, screening for heterozygos ity in the partner is crucial. Potential genotype/phenotype correlations we re examined by classifying the patients into three groups according to the CYP21 allelic combinations: A (mild/mild), B (mild/severe), and C (severe/s evere). Primary amenorrhea was more frequent, and mean basal and stimulated 17-hydroxyprogesterone levels were higher in compound heterozygotes for mi ld and severe mutations (group B) compared with women with two mild mutatio ns (group A), but there was a considerable overlap for individual values. S urprisingly, in two women, a severe mutation was found on both alleles (gro up C). Therefore, the phenotype cannot be accurately predicted from the gen otype. Variability in phenotypic expression may be conditioned by mechanism s other than genetic heterogeneity at the CYP21 locus.