Familial Mediterranean fever (FMF) is a hereditaryinflammatory disorder that affects groups of patients originating from around the Mediterranean Sea (hence its name). It is prominently present in the Armenian people (up to 1 in 7 affected), Sephardi Jews (and, to a much lesser extent, Ashkenazi Jews), people from Turkey, and the Arab countries.
There are seven types of attacks. 90% of all patients have their first attacks before they are 20 years old. All develop over 2-4 hours and last anytime between 6 hours and 4 days. Most attacks involve fever:
Abdominal attacks, featuring abdominal pain affecting the whole abdomen with all signs of acute abdomen (e.g. appendicitis). They occur in 95% of all patients and may lead to unnecessary laparotomy. Incomplete attacks, with local tenderness and normal blood tests, have been reported.
Joint attacks, occurring in large joints, mainly of the legs. Usually, only one joint is affected. 75% of all FMF patients experience Joint attacks.
Chest attacks with pleuritis (inflammation of the pleural lining) and pericarditis (inflammation of the pericardium). Pleuritis occurs in 40%, but pericarditis is rare.
Scrotal attacks due to inflammation of the tunica vaginalis. This occurs in up to 5% and may be mistaken for acute scrotum (i.e. testicular torsion)
Myalgia (rare in isolation)
Erysipeloid (a skin reaction on the legs, rare in isolation)
The diagnosis is clinically made on the basis of the history of typical attacks, especially in patients from the ethnic groups in which FMF is more highly prevalent. An acute phase response is present during attacks, with high C-reactive protein levels, an elevated white blood cell count and other markers of inflammation. In patients with a long history of attacks, monitoring the renal function is of importance in predicting chronic renal failure.
A genetic test is also available now that the disease has been linked to mutations in the MEFV gene. Sequencing of exons 2, 3, 5, and 10 of this gene detects an estimated 97% of all known mutations.
Virtually all cases are due to a mutation in the MEFV gene, which codes for a protein called pyrin or marenostenin. This was discovered in 1997 by two different groups, each working independently - the French FMF Consortium, and the International FMF Consortium Various mutations of this gene lead to FMF, although some mutations cause a more severe picture than others. Mutations occur in exons 2, 3, 5 and 10.
The function of pyrin has not been completely elucidated, but it appears to be a suppressor of the activation of caspase 1, the enzyme that stimulates production of interleukin 1β, a cytokine central to the process of inflammation. It is not conclusively known what exactly sets off the attacks, and why overproduction of IL-1 would lead to particular symptoms in particular organs (e.g. joints or the peritoneal cavity).
The MEFV gene is located on the short arm of chromosome 16 (16p13). The disease inherits in an autosomal recessive fashion. Therefore, two asymptomatic carrier parents have a 25% chance of a child with the disorder. FMF patients who marry a carrier or another FMF patient have a 50% and 100% chance, respectively, in having a child with FMF.
Attacks are self-limiting, and require analgesia and non-steroidal anti-inflammatory drugs (such as diclofenac).
Since the 1970s, colchicine, a drug otherwise mainly used in gout, has been shown to decrease attack frequency in FMF patients. The exact way in which colchicine suppresses attacks is unclear. While this agent is not without side-effects (such as abdominal pain and muscle pains), it may markedly improve quality of life in patients. The dosage is typically 1-2 mg a day. Development of amyloidosis is delayed with colchicine treatment. Interferon is being studied as a therapeutic modality.
A New York allergist, Dr Sheppard Siegal, first described the attacks of peritonitis in 1945; he termed this "benign paroxysmal peritonitis", as the disease course was essentially benign. Dr Hobart Reimann, working in the American University in Beirut, described a more complete picture which he termed "periodic disease".
^ abcdefghij Livneh A, Langevitz P (2000). "Diagnostic and treatment concerns in familial Mediterranean fever". Baillieres Best Pract Res Clin Rheumatol14 (3): 477–98. doi:10.1053/berh.2000.0089. PMID 10985982.
^ ab The French FMF Consortium (1997). "A candidate gene for familial Mediterranean fever". Nat. Genet.17 (1): 25–31. doi:10.1038/ng0997-25. PMID 9288094.
^ ab The International FMF Consortium (1997). "Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever". Cell90 (4): 797–807. doi:10.1016/S0092-8674(00)80539-5. PMID 9288758.
^ Siegal S (1945). "Benign paroxysmal peritonitis". Ann Intern Med23: 1-21.
^ Reiman HA (1948). "Periodic disease. Probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclic neutropenia and intermittent arthralgia". J Am Med Assoc136: 239-44.