Before calling it FMF: MEFV variants of uncertain significance in autoinflammatory disease

OBJECTIVES: Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent febrile attacks and serositis, with a high prevalence and carrier frequency of MEFV variants in Eastern Mediterranean populations. In this setting, interpretation of MEFV variants of uncertain significance (VUS) is challenging, and their clinical relevance remains controversial. We aimed to describe the clinical characteristics of patients carrying mono- or biallelic MEFV VUS and to compare them with patients harboring biallelic pathogenic MEFV variants, including assessment of FMF and PFAPA classification according to Eurofever/PRINTO criteria. METHODS: This retrospective study included pediatric patients with recurrent autoinflammatory manifestations who underwent MEFV genetic analysis and were receiving colchicine. Patients were stratified by MEFV genotype, and clinical features, attack characteristics, treatment profiles, and classification status were compared. RESULTS: Patients with MEFV VUS exhibited fewer classical FMF features, such as serositis-related chest pain and arthritis, but more frequent atypical manifestations, including diarrhea, oral aphthae, and lymphadenopathy, along with longer attack duration. Measures of disease burden, including age at onset and attack frequency, were similar between groups. FMF criteria were fulfilled by approximately half of patients with VUS. CONCLUSION: Patients with autoinflammatory disease carrying MEFV variants of uncertain significance may exhibit atypical clinical features. Alternative diagnoses should be considered, and further genetic evaluation may be required.