Abstract

Familial Mediterranean Fever (FMF) is the first described and most prevalent monogenic autoinflammatory periodic fever syndrome worldwide. The disease is caused by pathogenic variants in the MEFV (Mediterranean fever) gene, which lead to dysregulated innate immune responses and a persistent hyperinflammatory state. Despite extensive genetic characterization, the molecular mechanisms linking MEFV mutations to aberrant inflammation remain incompletely understood. Moreover, substantial clinical heterogeneity—manifested as incomplete penetrance, variable expressivity, and modulation by additional autoinflammatory genes—indicates that FMF pathogenesis extends beyond classical Mendelian inheritance. Emerging evidence suggests that epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation, may contribute to phenotypic variability, disease severity, and therapeutic response; however, available data are limited and occasionally conflicting. This review provides a comprehensive and up-to-date overview of the genetic, molecular, and epigenetic factors implicated in FMF, highlights unresolved controversies, and proposes future research priorities aimed at elucidating disease mechanisms and improving clinical management.