New Diseases Linked to MEFV Variants or Pyrinopathies

Autoinflammatory diseases (AIDs) are characterized by dysregulation of innate immunity, leading to systemic inflammation. Familial Mediterranean fever (FMF) is the most common AID, associated with variants in exon 10 of MEFV. This gene codes for pyrin, a key protein in the inflammasome of the same name, involved in the innate immune response. Since the discovery of FMF, many other pathogenic variants of MEFV have been identified. These variants, apart from exon 10, are responsible for a variety of AIDs known as pyrin-associated AIDs or pyrinopathies. Variants in exon 10, 8, 5, and 3 are associated with dominant forms of FMF. Other inflammatory clinical pictures not resembling typical FMF are possible: pyrin-associated autoinflammation with neutrophilic dermatosis is characterized by febrile attacks and severe neutrophilic dermatosis associated with variants in exon 2; pyrin-associated autoinflammation with hypereosinophilia was described among patients displaying severe inflammation and hypereosinophilia-associated variants in exon 2, different from pyrin-associated autoinflammation with neutrophilic dermatosis; and pyrin-associated autoinflammation associated with neuroinflammation manifests with systemic inflammation, serositis, and neuroinflammation associated with variants in exon 9. Somatic forms of FMF have also been described. We present here a review of the literature on the various AIDs associated with pathogenic MEFV variants and propose a practical approach to the genetic diagnosis of MEFV-associated AIDs.