Substitutions in the CYP21A2 promoter explain the simple‐virilizing form of 21‐hydroxylase deficiency in patients harbouring a P30L mutation

Summary The classical and nonclassical phenotypes of 21‐hydroxylase deficiency represent a continuous spectrum of the impairment of 21‐hydroxylase activity due to mutations between the CYP21A2 gene. These mutations occur mainly by microconversion in the homologous nonfunctional CYP21A1P gene. The P30L mutation is associated with the nonclassical form, and it reduces the activity to 30–40% of the normal enzyme. We have described three female patients exhibiting a simple virilizing phenotype and bearing the P30L mutation in compound heterozygosis with a severe mutation. To identify additional mutations causing this phenotype, the promoter region was sequenced and four mutations were identified: −126C → T, −113G → A, −110T → C and −103 A → G. These substitutions are normally present in the promoter region of the pseudogene and in vitro studies demonstrated that they reduced the transcriptional activity fivefold. They might have been converted to the CYP21A2 promoter together with the P30L mutation in these patients. Therefore, these substitutions in synergism with the P30L mutation might decrease the enzyme activity resulting in a more severe phenotype, and a DNA sequence of −167 bases of the CYP21A2 gene should be performed in patients with 21‐hydroxylase deficiency in whom the phenotype is more severe than predicted by the genotype.