ESPE Abstracts (2019) 92 P2-5

Clinical Phenotype and Genotype Association in Patients with 21-hydroxylase Deficiency

Asmar Aghayeva1, Hande Turan2, Guven Toksoy3, Aydilek Dagdeviren Cakir2, Ezgi Berkay3, Nilay Gunes4, Olcay Evliyaoglu2, Zehra Oya Uyguner3, Munis Dundar5, Beyhan Tuysuz4, Oya Ercan2


1Istanbul University –Cerrahpasa, Pediatrics department, Istanbul, Turkey. 2Istanbul University –Cerrahpasa, Pediatric Endocrinology division, Istanbul, Turkey. 3Istanbul University, Medical Genetics department, Istanbul, Turkey. 4Istanbul University –Cerrahpasa, Pediatric Genetic division, Istanbul, Turkey. 5Erciyes University, Medical Genetics department, Kayseri, Turkey


Introduction: Congenital adrenal hyperplasia (CAH) is an autosomal recessively transmitted disease and 95% of CAH cases are due to 21-hydroxylase deficiency (21-OHD). There are more than 100 mutations that cause CAH due to 21-OHD and the clinical expression of the disease is reported to correlate with mutated alleles.

The aim: The aim of this study was to investigate responsible mutations and then to evaluate genotype-phenotype relationship in CAH patients with 21-OHD.

Methods: Mutations were firstly investigated by sequence analysis by Sanger method; when needed Multiplex Ligation-dependent Probe Amplification (MLPA) technique was applied. Mutations were grouped as of group 0, A, B or C and compared with the 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 for the different groups (1).

Subjects: Genotype was investigated in 40 cases with 21-OHD (33 classical, 7 nonclassical).

Results: Responsible mutations were determined in 37 of the cases (n:15 SW, n:15 SV, n:7 NC). The rate of parental consanguinity was 43.2%. In 4 compound heterozygotes genotypes were determined after the genotyping of parents. In 11 cases only Sanger method, in 26 cases Sanger and MLPA methods were used. Mutations were identified in 73 alleles from 37 cases (mutation only in one allele in one case: Deletion/Not detected). The most common mutation was IVS2-13A/C>G (28.3%), followed by p.I172N mutation (17.5%) and large gene deletions (14.7%). In addition, heterozygosity for p.Y59N mutation which has not been previously reported in our region and a higher rate (10.8%) for the p.V281L mutation than that reported before was found.

In group 0, ppv was 72% (8 SW, 3SV); in group A, ppv was 50% (6 SW,6 SV); in group B, ppv was 85% (6 SV,1NC); in group C, ppv was 100% (6/6 NC). Deletion/Not detected was not included.

Conclusion: In our study group, genotype-phenotype correlation was found to be less in simple virilizing CAH than salt wasting and non-classical types of CAH.

Reference: 1. Hannah-Shmouni F, Chen W, Merke D.P. Genetics of Congenital Adrenal Hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009 April; 23(2): 181–192