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

objectivesFamilial 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 harbouring biallelic pathogenic MEFV variants, including assessment of FMF and PFAPA classification according to Eurofever/PRINTO criteria.

methodsThis retrospective study included paediatric 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.

resultsPatients with MEFV VUS exhibited fewer classical FMF features, such as serositis-related chest pain and arthritis, but more frequent atypical manifestations, including diarrhoea, 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.

conclusionPatients 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.