Clinical and diagnostic value of genetic testing in 216 Israeli children with familial Mediterranean fever

Objective. Familial Mediterranean fever (FMF) is an autosomal recessive disease with diverse clinical presentation. The FMF gene (MEFV) has recently been cloned and 30 point mutations causing the disease have been identified. We appraised the value of mutation analysis as a diagnostic test for FMF in symptomatic pediatric patients, and explored the possible correlations between MEFV genotypes and the diverse phenotypic expression of the disease. Methods. Two hundred sixteen children who met the clinical criteria for FMF underwent molecular genetic studies to detect the 3 most common mutations in the Israeli FMF patient population (M694V, V726A, E148Q). The mutations found were related to clinical presentation and disease severity, using the Tel-Hashomer severity score. Results. Of the 216 children who fulfilled the diagnostic criteria for FMF, 82 (38.0%) had 2 of the tested mutations, 73 (33.8%) had only one mutation, and 61 (28.2%) had none of the mutations studied. The M694V was the most frequent mutation, detected in 174 of 432 MEFV alleles (40.0%). The V726A mutation was found in 39 alleles (9.0%) and the E148Q mutation in 25 (5.8%). The severity score correlated with the number of mutations. Children with no mutations presented at an older age compared to children with one of 2 mutations. Children homozygous for the M694V mutation presented at a younger age, had a higher severity score, and more commonly had arthritis. Conclusion. Limited genetic molecular testing for MEFV mutations may explain some of the FMF clinical variability, but is diagnostically ineffective. The use of clinical criteria remains essential in establishing the diagnosis of FMF.