PS29. GENETICS OF CONGENITAL ADRENAL HYPERPLASIA DUE TO 21 HYDROXYLASE DEFICIENCY
MIRJANA KOCOVA Department for Endocrinology and genetics, Pediatric Clinic, Medical Faculty, Vodnjanska bb, 1000 Skopje, Republic of Macedonia e-mail: ozonunit@unet.com.mk
*Corresponding Author:
page: 31

Abstract

Congenital adrenal hyperplasia (CAH) is inherited as an autosomal recessive disease. The 21 hydroxilase deficiency (21OH) causes more than 90% of CAH cases. The incidence of CAH is between 1:10 000 and 1:15 000 in different populations Phenotype of the disease is extremely variable depending on the mutation of the CYP 21 gene located among the genes for the complement on the short arm of chromosome 6. Severe salt wasting (SW) form is life threatening and should be promptly diagnosed and treated. Simple virilizing form, on the other hand, is milder and is usually manifested by virilization and precocious puberty. Late onset form (LO) is characterized by mild symptoms usually in adolescent girls with hirsutism and oligoamenorrhea, sterility or multiple miscarriages. High levels of 17OHP in the sera confirm the diagnosis. Clinical and genetic studies of CAH have been conducted in Macedonian population since 1985. Participation in the Yugoslav study showed high prevalence of late onset form genes in Macedonian population through HLA typing. Large survey based on survey of cases from nurseries, schools and adolescent clinics confirmed incidence of salt wasting form (SW) 1:12 000 that is comparable with other European populations. Incidence of the late onset form (LO) was 1: 7000 that is comparable to other Mediterranean populations. Many different mutations of the CYP 21 gene encoding 21 OH enzyme are described, causing classical and non classical forms of the disease; however, several mutations are common. The association genotype/phenotype has been confirmed in most of the patients. The SW form has been associated with large deletions, splicing I2 mutation, 8bp deletion, and Q318X (exon 8) mutations. Both mutations are severe in 90% of cases. Simple virilizing (SV) is associated with I172N mutation in exon 4. Usually one mutation in this form is severe, the other is mild. LO forms are most frequently associated with V281L mutation. In this form both mutations are moderate or mild. Several methods for genetic diagnosis have been applied with different results. Amplification of the gene and pseudo gene with a panel of primers, followed by RFLP with different restriction enzymes provides detection of the most common mutations as well as the zigocity. In the Macedonian population based on the analysis of 59 patien ts from 48 families, the most common mutation in SW forms was I2 splicing mutation (35% of examined chromosomes) and Q318X (26%). In LO forms the most common mutation was V281L. Mutation V281L is common in the general population also. Some rare combinations of mutations have also been detected such as the combination I2+V281L on the one chromosome, and I2 on the other. Timely molecular diagnosis of CAH gives an insight into the form of the disease, and provides appropriate treatment and better therapeutic outcomes. It is a useful tool for prenatal diagnosis of the disease.




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