Clinical phenotype and genotype association in patients with 21-hydroxylase deficiency

Abstract

Introduction:Congenital adrenal hyperplasia (CAH) is an autosomalrecessively transmitted disease and 95% of CAH cases aredue to 21-hydroxylase deficiency (21-OHD). There are more than100 mutations that cause CAH due to 21-OHD and the clinical expressionof the disease is reported to correlate with mutated alleles.The aim: The aim of this study was to investigate responsiblemutations and then to evaluate genotype-phenotype relationshipin CAH patients with 21-OHD.Methods: Mutations were firstly investigated by sequenceanalysis by Sanger method; when needed Multiplex Ligation-dependentProbe Amplification (MLPA) technique was applied. Mutationswere grouped as of group 0, A, B or C and compared withthe expected clinical phenotype i.e. Group 0: Salt wasting (SW),Group A: SW, Group B: Simple virilizing (SV), Group C: Nonclassical(NC) and positive predictive value (ppv) was determined forthe different groups (1).Subjects:Genotype was investigated in 40 cases with 21-OHD(33 classical, 7 nonclassical).Results: Responsible mutations were determined in 37of the cases (n:15 SW, n:15 SV, n:7 NC). The rate of parentalconsanguinity was 43.2%. In 4 compound heterozygotes genotypeswere determined after the genotyping of parents. In 11 cases onlySanger method, in 26 cases Sanger and MLPA methods were used.Mutations were identified in 73 alleles from 37 cases (mutationonly in one allele in one case: Deletion/Not detected). The mostcommon mutation was IVS2-13A/C>G (28.3%), followed byp.I172N mutation (17.5%) and large gene deletions (14.7%). Inaddition, heterozygosity for p.Y59N mutation which has not beenpreviously reported in our region and a higher rate (10.8%) for thep.V281L mutation than that reported before was found.