Genotype-Phenotype Associations of Children With Familial Mediterranean Fever in a Cohort Consisting of M694V Mutation and Implications for Colchicine-Resistant Disease

Abstract

ObjectivesThe aim of this study was to investigate the clinical associations of the second allele mutations and the effect of genotype and presenting features on colchicine resistance in children with familial Mediterranean fever (FMF), carrying at least one M694V variant.MethodsThe medical records of the patients diagnosed with FMF, in whom at least one allele M694V mutation was detected, were reviewed. Patients were grouped according to the genotype as M694V homozygotes, compound heterozygote M694V with an exon 10 mutation, compound heterozygote M694V with a variant of unknown significance (VUS), and M694V heterozygotes. Disease severity was assessed with the International Severity Scoring System for FMF.ResultsAmong the 141 patients included, homozygote M694V (43.3%) was the most frequent MEFV genotype. Clinical manifestations of FMF at diagnosis were not significantly different according to genotypic alterations except homozygote M694V. Besides, homozygous M694V was associated with a more severe disease, with more frequent comorbidities and colchicine-resistant disease. A lower disease severity score was observed in compound heterozygotes with VUS than in M694V heterozygotes (median 1 vs 2, p = 0.006). Regression analysis revealed that homozygous M694V, arthritis, and frequency of attacks were associated with an increased risk of colchicine-resistant disease.ConclusionsClinical manifestations of FMF at diagnosis with a M694V allele were predominantly influenced by the M694V rather than the second allele mutations. Although homozygous M694V was associated with the most severe form, the presence of compound heterozygosity with a VUS did not affect disease severity or clinical features. Homozygous M694V confers the highest risk of colchicine-resistant disease.

Not easy-peasy to diagnose: familial Mediterranean fever unaccompanied by fever

“…showed that clinical features such as fever, abdominal pain, chest pain, arthritis and erysipelas-like erythema did not differ according to the homozygous or heterozygous M694V mutation [27]. However, in an adult study published by Balta et al, FMF patients revealed genotype-phenotype correlation, and fever was most prevalent in patients with homozygous exon 10 mutations [28].…”