CYP11B1 MUTATIONS CAUSING NONCLASSIC ADRENAL-HYPERPLASIA DUE TO 11-BETA-HYDROXYLASE DEFICIENCY

Steroid 11 beta-hydroxylase deficiency is the second most common cause of congenital adrenal hyperplasia, the inherited inability to synthes ize cortisol. Severely affected patients carry mutations in the CYB11B 1 gene that destroy enzymatic activity. Such patients have signs of an drogen excess and usually have hypertension. Mild or non-classic 11 be ta-hydroxylase deficiency has been reported previously but not studied genetically. In this study we report analysis of the CYP11B1 genes of three patients thought to suffer from nonclassic 11 beta-hydroxylase deficiency. Mutations were detected in the CYP11B1 genes of two patien ts. One was a compound heterozygote for missense mutations N133H and T 319M, whereas the other carried a nonsense mutation (Y423X) on one all ele and a missense mutation (P42S) on the other. All three missense mu tations affected enzymatic activity when expressed in vitro. No mutati ons were detected in the coding regions or intron-exon boundaries of t he CYP11B1 genes of the other putative non-classic patient, in additio n, we were unable to detect CYP11B1 mutations in two hirsute women wit h mildly elevated levels of 11 beta-hydroxylase precursors who had pre viously been identified in a screening study of patients in a reproduc tive endocrinology clinic. We conclude that nonclassic 11 beta-hydroxy lase deficiency is a rare disorder. It is not a significant cause of h yperandrogenism in women and relatively stringent criteria should be u sed to prevent its misdiagnosis.