What is familial Mediterranean fever?

Risk Factors

The greatest risk factor for FMF is having genetic origins from the Mediterranean basin. Sephardic Jews, North African Arabs, Armenians, Turks, Greeks, and Italians are at higher risk. With the advent of genetic testing, FMF has also been increasingly identified in Ashkenazi Jews. Occasional cases are confirmed in people without known Mediterranean ancestry. Up to 50 percent of people with FMF have a family history of the disorder.

Etiology and Genetics

FMF is caused by mutations in the MEFV
gene on the short arm of chromosome 16. More than fifty mutations in the gene have been identified. The MEFV gene is responsible for encoding a protein called pyrin (or marenostrin), which consists of 781 amino acids. Pyrin is expressed in circulating neutrophils and is believed to be responsible for blunting the inflammatory response. The FMF gene mutation may alter the pyrin molecule in such a way that it fails to suppress unknown triggers in the inflammatory response, resulting in spontaneous episodes of neutrophil-predominant inflammation.

FMF is almost always inherited in an autosomal recessive pattern. DNA testing reveals that carrier frequencies in affected populations may be as high as 1 in 3. In addition to the MEFV gene mutation, normal variations in the SAA1 gene, which encodes the serum amyloid A1 protein, may influence the course of FMF. A version of the SAA1 gene called the alpha variant may increase the risk of developing amyloidosis in some people with FMF.

Symptoms

The first signs and symptoms of FMF usually appear between the ages of five and fifteen, although initial attacks have been documented in infancy. Ninety percent of people with FMF have their first attack before the age of twenty. The attacks commonly last from twenty-four to seventy-two hours. The frequency of attacks is unpredictable and can be as high as two attacks per week or as low as one attack per year. Spontaneous remissions of several years may occur. Physical exertion, emotional stress, and menses have been noted as contributing factors; pregnancy has been cited as a remitting factor.

Fever and abdominal pain are the most common manifestations. Fever is nearly always present and may range from 100 degrees Fahrenheit (37.8 degrees Celsius) to 104 degrees Fahrenheit (40 degrees Celsius). Acute abdominal pain typically starts in one quadrant and then spreads to the whole abdomen. Rebound tenderness, guarding, and decreased bowel sounds may lead to an exploratory laparotomy that shows only a small amount of sterile peritoneal exudate.

Pleurisy occurs in about 30 percent of cases and may cause unilateral, stabbing chest pain. Arthritis, which may be seen in 25 percent of attacks, is manifested by single joint pain in the knee, ankle, or hip. The skin rash of FMF is a raised, erythematous rash that appears on the foot, ankle, or lower leg. Less common manifestations include muscle aches, scrotal inflammation, pericarditis, and vasculitis. Although the acute manifestations can be severe, most patients recover completely and are asymptomatic between attacks.

Screening and Diagnosis

FMF is usually diagnosed by its clinical presentation. Genetic testing is available and is useful for atypical cases. Genetic testing may also have some prognostic value. Certain types of MEFV mutations have been correlated with earlier age of onset, higher frequency of rash, and greater likelihood of developing amyloidosis. Because of the possibility of nonpenetrance and the potential impact on insurability, genetic screening of unaffected individuals is not recommended.

Nonspecific findings that may help lead to a diagnosis of FMF include elevation of white blood cells with neutrophil predominance, elevated ESR, C-reactive protein, and fibrinogen. Renal amyloidosis may be indicated by proteinuria. The incidence of FMF in Mediterranean populations ranges from 1 in 250 to 1 in 1,000 people, and the disorder is slightly more common in men than in women.

Treatment and Therapy

Although there is no cure for FMF, the drug colchicine decreases the frequency and intensity of attacks in about 85 percent of people diagnosed with FMF. Colchicine taken as a daily oral medication provides complete remission from attacks in most people. For those who have infrequent attacks, colchicine may be used to abort an attack if there are prodromal symptoms, but once an attack is well under way, it is no longer effective. Colchicine also prevents the development of amyloidosis and can safely be taken during pregnancy.

Prevention and Outcomes

There is no way to prevent FMF. Widespread use of prophylactic colchicine has led to a dramatic reduction in attacks and complications. In most cases FMF patients can lead normal and productive lives. The most common complication from untreated FMF is amyloidosis, which can lead to nephrotic syndrome and renal failure. Inflammation caused by FMF can also lead to infertility due to involvement of reproductive organs.

Bibliography

Dogan, Hasan, et al. "A Novel Insertion Mutation Identified in Exon 10 of the MEFV Gene Associated with Familial Mediterranean Fever." BMC Medical Genetics 15.1 (2014): 1–12. Web. 22 July 2014.

Kastner, Daniel L. "Familial Mediterranean Fever and Other Hereditary Recurrent Fevers." Harrison's Principles of Internal Medicine. Ed. Dan L. Longo et al. 18th ed. New York: McGraw, 2012. 2814–17. Print.

Ochs, Hans D., C. I. Edvard Smith, and Jennifer M. Puck, eds. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. 3rd ed. New York: Oxford UP, 2014. Print.

Lachmann, Helen J., and Philip N. Hawkins. "Hereditary Periodic Fever Syndromes." Oxford Textbook of Medicine. Ed. David A. Warrel, Timothy M. Cox, and John D. Firth. 5th ed. Vol. 1. New York: Oxford UP, 2010. 1760–65. Print.

Shohat, Mordechai, and Gabrielle J. Halpern. "Familial Mediterranean Fever." GeneReviews. Ed. Roberta A. Pagon et al. Seattle: U of Washington, Seattle, 1993–2014. NCBI Bookshelf. Natl. Center for Biotechnology Information, 19 June 2014. Web. 22 July 2014.