Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder:149. FMF is an autoinflammatory disease caused by mutations in MEFV, a gene which encodes a 781–amino acid protein denoted pyrin.
The disorder has been given various names including familial paroxysmal polyserositis, periodic peritonitis, recurrent polyserositis, benign paroxysmal peritonitis, periodic disease or periodic fever, Reimann periodic disease or Reimann’s syndrome, Siegal-Cattan-Mamou disease, and Wolff periodic disease. Note that “periodic fever” can also refer to any of thePeriodic fever syndromes.
FMF affects groups of people originating from around the Mediterranean Sea (hence its name). It is prominently present in the Armenian people, Sephardi Jews (and, to a much lesser extent, Ashkenazi Jews), Cypriots, Turks and Arabs.
Signs and symptoms
There are seven types of attacks. Ninety percent of all patients have their first attacks before they are 18 years old. All develop over 2–4 hours and last anywhere from 6 hours to 4 days. Most attacks involve fever.
- Abdominal attacks, featuring abdominal pain, affect the whole abdomen with all signs of peritonitis (inflammation of abdominal lining), and acute abdominal pain likeappendicitis. 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 mainly occur in large joints, especially in the legs. Usually, only one joint is affected. Seventy-five percent of all FMF patients experience joint attacks.
- Chest attacks include pleuritis (inflammation of the pleura) and pericarditis (inflammation of the pericardium). Pleuritis occurs in 40% of patients, and makes it difficult to breathe or lie flat, but pericarditis is rare.
- Scrotal attacks due to inflammation of the tunica vaginalis 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)
- Fever without any of the other symptoms listed above (25%)
AA-amyloidosis with renal failure is a complication and may develop without overt crises. AA amyloid protein is produced in very large quantities during attacks, and at a low rate between them, and accumulates mainly in the kidney, as well as the heart, spleen, gastrointestinal tract and thyroid.
There appears to be an increase in the risk for developing particular vasculitis-related diseases (e.g. Henoch-Schönlein purpura), spondylarthropathy, prolonged arthritis of certain joints and protracted myalgia.
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 to detect mutations in the MEFV gene. Sequencing of exons 2, 3, 5, and 10 of this gene detects an estimated 97% of all known mutations.
A specific and highly sensitive test for FMF is the “Metaraminol Provocative Test (MPT),” whereby a single 10 mg infusion of Metaraminol is administered to the patient. A positive diagnosis is made if the patient presents with a typical, albeit milder, FMF attack within 48 hours. As MPT is more sensitive than specific, it does not identify all cases of FMF. Although a positive MPT can be very useful.
Virtually all cases are due to a mutation in the MEFV gene on the sixteenth chromosome, which codes for a protein called pyrin or marenostrin. Various mutations of this gene lead to FMF, although some mutations cause a more severe picture than others. Mutations occur mainly 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. In other words an ineffective pyrin doesn’t inhibit inflammation normally, resulting in inflammatory episodes of membranes at differing sites. 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).
Familial Mediterranean fever has an autosomal recessive pattern of inheritance.
The MEFV gene is located on the short arm of chromosome 16 (16p13). The disorder inherits in an autosomal recessive fashion. Therefore, two asymptomatic carrier parents have a 25% chance of a child with the disorder, a 50% chance of a child who is an asymptomatic carrier and a 25% chance of a child who does not carry the disorder. FMF patients who have children with a carrier or another FMF patient have a 50% and 100% chance, respectively, of having a child with FMF.
There is one known case of an affected patient with only one parent who is a carrier. This is caused by a unique mutation on thesixteenth chromosome.
Attacks are self-limiting, and require analgesia and NSAIDs (such as diclofenac).
Colchicine, a drug otherwise mainly used in gout, decreases 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. Some advise discontinuation of colchicine before and during pregnancy, but the data are inconsistent, and others feel it is safe to take colchicine during pregnancy.
Approximately 5-10% of FMF cases are resistant to colchicine therapy alone. In these cases, adding anakinra to the daily colchicine regimen has been successful.
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”.
In 1972, colchicine was discovered to prevent attacks.
The link to the MEFV gene was discovered in 1997 by two different groups, each working independently – the French FMF Consortium, and the International FMF Consortium.
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