Primarily a genetic disease due to Mendelian-recessive inheritance of Mediterranean fever gene mutations.
Occurs mainly in people of Mediterranean ancestry, especially from Arabian countries, Turkey, Israel, and Armenia.
Characterized by recurrent attacks of fever and systemic inflammation, typically lasting 24 to 72 hours and presenting in childhood.
Rare manifestations include chronic arthritis, spondyloarthropathy, myopathies, and fibromyalgia.
Clinical judgment is important in establishing the diagnosis, which is often made retrospectively.
Majority respond to colchicine, which is almost always diagnostic and distinguishes from other inherited periodic fever syndromes.
Colchicine is the only proven treatment and prevents the most serious and life-threatening complication, renal amyloidosis.
Familial Mediterranean fever (FMF; phenotype Mendelian Inheritance in Man number 249100) is part of the currently expanding family of autoinflammatory disorders. The disease originated over 2000 years ago in western Asia and spread to the Mediterranean basin and the rest of the globe with the advent of extensive global migration. First classified as a clinical disease by Siegal in 1949,  this genetic disorder of specific populations has both clinical and genetic definitions. 
The clinical definition is recurrent self-limiting attacks of fever, severe abdominal pain, arthralgias or monoarthritis, pleurisy, or an erysipeloid rash on one ankle or foot, typically lasting 24 to 72 hours. FMF mainly affects populations from the Mediterranean basin, especially people of Arabian, Turkish, Sephardic Jewish, and Armenian ancestry, in whom the disease is relatively frequent. For the majority of patients, the first clinical signs appear during childhood.
The genetic definition is disease caused by Mendelian-recessive inheritance due to mutations in the Mediterranean fever (MEFV) gene coding for a protein named marenostrin/pyrin. MEFV gene analysis is the only objective tool that confirms FMF. However, MEFV carriers sometimes present with FMF-like disease. Indeed, mutation analysis in a large series showed that up to 30% of clinical FMF patients had a single mutated allele only in the MEFV gene.   The reason FMF carriers may express symptoms is still unclear. Therefore, the diagnosis remains predominantly clinical because mutations cannot always be identified on both alleles, even after complete gene analysis.
FMF's major complication is systemic secondary amyloidosis. This can readily be prevented by colchicine prophylaxis, which explains the need for prompt and accurate diagnosis.
Professor of Paediatrics
Schulich School of Medicine & Dentistry
Department of Paediatrics
Division of Paediatric Rheumatology
University of Western Ontario
ED is an author of a number of references cited in this monograph.
Dr Erkan Demirkaya would like to gratefully acknowledge Dr Véronique Hentgen and Dr Ghaith Mitri, the previous contributors to this monograph. VH has been reimbursed by Novartis Pharmaceuticals (the manufacturer of canakinumab) for attending several conferences, has received consulting fees from Novartis Pharmaceuticals, and is an author of a number of references cited in this monograph. GM declares that he has no competing interests.
Distinguished Professor of Medicine
The Jack and Donald Chia Professor of Medicine
Division of Rheumatology, Allergy and Clinical Immunology
Genome and Biomedical Sciences Facility
University of California at Davis
MEG declares that he has no competing interests.
Medical Unit for Autoinflammatory Diseases
Arnaud de Villeneuve Hospital
IT declares that she has no competing interests.
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