Pseudo-dominant mode of inheritance for familial Mediterranean fever and clinical relevance of MEFV heterozygotes in the pediatric age

Familial Mediterranean fever (FMF) is the most frequent hereditary autoinflammatory disease, inherited with an autosomal recessive pattern, characterized by self-limited episodes of fever and serositis, and caused by mutations in the MEFV gene, with most sequence variations corresponding to missense changes. The FMF gene encodes the pyrin protein, which is mainly expressed in myelomonocytic cells: its genotyping has greatly contributed to our actual knowledge of FMF, but final diagnosis remains predominantly clinical, since the couple of MEFV mutations cannot always be identified, as required by Mendel’s genetic laws. Even if the autosomal recessive transmission of FMF was established more than 15 years ago by familial studies, linkage analysis, and haplotype comparisons, a substantial number of patients from Mediterranean ancestry remains genetically unexplained, as they do not carry two mutated MEFV alleles. The description of disease manifestations among patients carrying a single mutated MEFV allele, even responding well to colchicine, are becoming more frequent, suggesting that other genes might be involved in the phenotypic expression of FMF.