EXHAUSTIVE SCREENING OF THE 21-HYDROXYLASE GENE IN A POPULATION OF HYPERANDROGENIC WOMEN

21-hydroxylase (21-OH) deficiency accounts for the vast majority of no nclassic (NC) forms of congenital adrenal hyperplasia (CAH), and is as sociated with symptoms detectable either in childhood (precocious pube rty) or sometimes only later in adulthood (hirsutism, acne, amenorrhea ). While the severe forms of the disease responsible for salt wasting or simple virilization have been extensively studied, the NC 21-OH def iciency is less well characterized, especially in adults. We studied t he 21-OH gene (CYP21) in a population of 69 unrelated hyperandrogenic subjects suspected to be homozygous or heterozygous for NC 21-OH defic iency, based on basal and adrenocorticotrophin (ACTH)-stimulated plasm a 17-hydroxyprogesterone (17-OHP, 17-OHPSI) and 21-desoxycortisol (21- DOF, 21-DOFSI) levels. To identify all mutations involved, determinati on of the whole gene sequence, including exons, exon-intron junctions, and promoter region, was performed, followed by a study of large rear rangements and identification of compound heterozygotes. Alterations w ere identified in at least one allele of 55 hyperandrogenic subjects. Two NC alterations, Val282Leu and Pro454Ser, were detected in 68% and 7% of the affected alleles, respectively, whereas mutations involved i n severe forms were identified in 21% of them. These results document the utility of a molecular diagnosis in hyperandrogenic women suspecte d of being either heterozygous or homozygous for NC 21-OH deficiency a nd clearly indicate the importance of genetic counseling in such a pop ulation.