Familial Mediterranean fever

Familial Mediterranean Fever (FMF), also known as the Armenian disease^[1][2] is a hereditary inflammatory disorder^[3]:149 that 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), Greeks, and people from Turkey and the Arab countries.^[4]

Signs and symptoms

Attacks

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:^[4]

1. 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.
2. Joint attacks mainly occurring in large joints, mainly in the legs. Usually, only one joint is affected. Seventy-five percent of all FMF patients experience joint attacks.
3. Chest attacks with pleuritis (inflammation of the pleural lining) and pericarditis (inflammation of the pericardium). Pleuritis occurs in 40%, but pericarditis is rare.
4. 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)
5. Myalgia (rare in isolation)
6. Erysipeloid (a skin reaction on the legs, rare in isolation)
7. Fever without any symptoms (25%)

Complications

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.^[4]

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.^[4]

Diagnosis

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.^[4] A genetic test is also available that detects mutations in the MEFV gene. Sequencing of exons 2, 3, 5, and 10 of this gene detects an estimated 97% of all known mutations.^[4]

Pathophysiology

Virtually all cases are due to a mutation in the MEFV gene on the sixteenth chromosome, which codes for a protein called pyrin or marenostenin. 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.^[4]

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).^[4]

Genetics

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.^[5][6]

Treatment

Attacks are self-limiting, and require analgesia and non-steroidal anti-inflammatory drugs (such as diclofenac).^[4]

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.^[4] Some advise discontinuation of colchicine before and during pregnancy, but the data is inconsistent and others feel that it is safe to take colchicine during pregnancy.^[7]

History

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.^[8] Dr Hobart Reimann, working in the American University in Beirut, described a more complete picture which he termed "periodic disease".^[9][10]

Colchicine has been used as a treatment since the 1970s.

The link to the MEFV gene was discovered in 1997 by two different groups, each working independently - the French FMF Consortium,^[5] and the International FMF Consortium^[6]

See also

• Urticarial syndromes

References

External Links

• GeneReview/NIH/UW entry on Familial Mediterranean Fever