Background: Congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency (11OHD), a rare autosomal recessive disorder, is the second most common form of CAH, resulting in glucocorticoid deficiency, hyperandrogenism and hypertension.
Objective and hypotheses: To investigate the specific CAH mutations in CYP11B1 gene and to examine for genotype-phenotype correlations.
Method: 21 patients (n=9, 46, XX; n=12, 46, XY) with the classical 11OHD from 20 unrelated Turkish families were included in this study. Diagnosis of 11OHD was based on both clinical and hormonal criteria. Mutation screening of CYP11B1 gene was performed using direct Sanger sequencing analysis. Known mutations were confirmed by database and literature search. Novel mutations were analyzed by in silico prediction tools (PolyPhen-2, SIFT and Mutation Taster).
Results: The age of diagnosis at onset ranged from 6 days to 12.5 years. The rate of consanguinity was very high (75%). Four out of nine 46, XX patients received a late diagnosis (age 28.7 years) and were raised as males due to severe masculinization (Prader genital stages IV and V). Mutation analyses in 20 index patients revealed 12 different mutations in CYP11B1 gene. These mutations were homozygous (HM) p.L299P (30%, 6/20), HM p.R141X (10%, 2/20), HM c.954G>A (silence, cryptic splicing; 10%, 2/20), HM IVS8+2T>C (novel splice-donor mutation, 5%, 1/20), compound heterozygous (CHT)((p.L299P)+(IVS8+2T>C); 5%, 1/20), HM p.W116C (5%, 1/20), HM p.R384Q (5%, 1/20), HM p.R448C (5%, 1/20), HM c.1449_1451delGGT (5%, 1/20), CHT ((G393+AG)+(p.L299P)); 5%, 1/20), HM c.1179_1180dupGA (novel; 5%, 1/20) and HM p.R143P (novel missense; 5%, 1/20). One patient had mutation in only one allele (p.T318M). There was no definitive correlation between genotype and phenotype.
Conclusion: In this study, three different novel mutations were detected and the p.L299P was found to be the most common mutation. The results of the study might contribute to the establishment of molecular screening strategies. Identification of the disease causing mutations provides reliable information for genetic counseling for the families.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology