Primarily a genetic disease due to Mendelian-recessive inheritance of Mediterranean fever gene mutations.
Occurs mainly in people of Mediterranean ancestry, especially from Arab countries, Turkey, Israel, and Armenia.
Characterized by recurrent attacks of fever and systemic inflammation, typically lasting 24-72 hours and presenting in childhood.
Rare manifestations include chronic arthritis, spondyloarthropathy, myopathies, and protracted febrile myalgia.
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 24-72 hours. FMF mainly affects populations from the Mediterranean basin, especially people of Arab, 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.
History and exam
Key diagnostic factors
- periodic fever
- abdominal pain
- altered bowel habit
- acute joint pain/swelling
- response to colchicine
- erysipelas-like skin lesions
Other diagnostic factors
- pleuritic chest pain
- acute myalgia
- history of appendectomy
- abdominal scars
- chronic joint pain
- pleural rub
- chronic myalgia/fibromyalgia
- neck stiffness
- acute scrotal pain + swelling
- visual disturbances
- Mediterranean ancestry
- age <20 years old
- male sex
- positive family history
- genetic mutation
- country of origin: Armenia, Turkey, or the Mediterranean basin
- psychological stress
- viral illness
- physical exertion
- extreme exhaustion
- use of vasoconstrictor sympathomimetics
1st investigations to order
- erythrocyte sedimentation rate
- serum fibrinogen
- serum amyloid A
- urine analysis
Investigations to consider
- chest x-ray
- joint x-ray
- abdominal CT
- chest CT
- joint MRI
- genetic testing
Erkan Demirkaya, MD, MSc
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 topic.
Dr Erkan Demirkaya would like to gratefully acknowledge Dr Véronique Hentgen and Dr Ghaith Mitri, the previous contributors to this topic.
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 references cited in this topic. GM declares that he has no competing interests.
M. Eric Gershwin, MD
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.
Isabelle Touitou, MD, PhD
Medical Unit for Autoinflammatory Diseases
Arnaud de Villeneuve Hospital
IT declares that she has no competing interests.
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