A novel mutation of the familial Mediterranean fever gene in a Greek family related to a non-classical, variably expressed FMF phenotype

Abstract

Familial Mediterranean Fever (FMF) is a hereditary autoinXammatory disorder characterized by fever, arthritis, serosal inXammation and often secondary amyloidosis. It most commonly aVects people of Armenian, Turkish, Jewish and Arab origin and its mode of inheritance is mainly recessive connected with the MEFV gene [1, 2]. The MEFV gene, codes for the 781 amino-acid protein pyrin/marenostrin that is predominantly expressed in polymorphonuclear cells as well as in cytokine activated monocytes. It seems that pyrin acts as an anti-inXammatory molecule by inhibiting interleukin-1 (IL-1) processing and permitting macrophage apoptosis [3, 4]. At least 120 mutations or polymorphisms of the MEFV gene have been identiWed, although Wve mutations account for almost 95% of the reported cases, especially in classically aVected populations. In the current report, a novel mutation of the MEFV gene in a young woman presenting with an episode of protracted polyserositis, fever, and a signiWcant family history of recurrent fevers of unknown etiology is presented. In detail, a 20-year-old Greek female was investigated for an episode of prolonged fever and pleural, pericardial and ascitic eVusions starting approximately 4 months prior to admission. System review and physical examination were unrevealing for stigmata of autoimmune disorders including Raynaud’s phenomenon, rashes, musculoskeletal complaints, oral ulcers or renal or nervous system involvement. Her past medical history was unremarkable. However, her family medical history was signiWcant for unexplained febrile episodes during summer months of 2– 3 weeks duration of her paternal grandmother. An extensive workup for an infectious etiology, including tuberculosis, was unrevealing. Laboratory evaluation revealed elevated inXammatory markers and a positive antinuclear antibody titer (1/320, diVuse pattern), while test for antibodies against extractable nuclear antigens and double stranded antibodies was negative. A preliminary diagnosis of systemic lupus erythematosus (SLE) was presumed and an oral prednisolone regimen at a dose of 1 mg/kg was started resulting in signiWcant improvement in clinical and laboratory terms (resolution of fevers and eVusions, abatement of inXammatory markers). However, given the complete lack of other concomitant features supporting the diagnosis of SLE, the Mediterranean origin of the patient and the history of recurrent unexplained fevers of the maternal grand mother, DNA analysis including tests for both FMF and tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) mutations, as well as determination of IgD levels was performed. Of interest, DNA analysis disclosed a previously unreported heterozygous mutation of the exon 2 of the MEFV gene. Testing for TRAPS mutations was unrevealing and IgD levels were within normal limits. Prednisolone was tapered and colchicine at a dose of 0.5 mg bid was instituted; no symptom recurrence was noted over 2 years of follow-up. Dimitrios Zonios and Clio P. Mavragani have equally contributed.