Information on the following diseases can be found in the Related Disorders section of this report:

• Appendicitis
• Amyloidosis

The symptoms of familial Mediterranean fever, which may be recurring, typically include fever, severe abdominal pain, and/or chest pain. This pain occurs due to inflammation of the delicate membranes that line the abdomen and lungs (polyserositis). The abdominal pain, which usually occurs in the lower right quadrant, may be acute and severe; it is frequently confused with acute appendicitis. These attacks generally last up to 24 hours but may continue for 4 days.

Approximately 75 percent of people with Familial Mediterranean Fever have episodes of joint pain (arthralgia). The pain, which may be accompanied by swelling, may be very severe and limit the range of motion in the affected joints. Attacks of arthritis usually subside within 7 days and joint function is restored. However, in some affected individuals, these episodes can also continue for several weeks or months. Some individuals with familial Mediterranean fever have painful swollen red (erythematous) skin lesions (pyoderma) on the lower legs.

Some affected individuals may have an abnormally enlarged liver and/or spleen (hepatosplenomegaly). Individuals with familial Mediterranean fever may also experience depression and other psychological difficulties.

Some individuals with the disorder may experience a serious complication known as amyloidosis. In this condition, a fatty-like substance (amyloid) accumulates in various parts of the body. If amyloid accumulates in the kidneys (renal amyloidosis), kidney function may be impaired and life-threatening complications may occur. Some affected individuals may experience intestinal obstruction and inflammation of the membranes that line the brain (meningitis) as complications of amyloidosis associated with familial Mediterranean fever. Affected individuals from certain ethnic populations (such as those of Turkish or Sephardic Jewish descent) may have a relatively high incidence of amyloidosis when compared with those from other ethnic groups. (For more information on this disorder, see the Related Disorders section below.)
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In most cases, familial Mediterranean fever (FMF) is inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.

Two teams of researchers have identified the gene responsible for familial Mediterranean fever. The disease gene, which is located on the short arm (p) of chromosome 16 (16p13)*, encodes for a protein (named "pyrin" or "marenostrin") that is thought to play an important role in controlling inflammation. Researchers have identified four mutations of the gene during genetic analysis of affected individuals in several ethnic groups. The gene may be referred to as the MEFV (Mediterranean fever) gene.

Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered.

Some researchers suggest that different mutations of the FMF gene may be associated with different levels of disease severity. For example, the researchers stressed that a particular FMF gene mutation (known as "Met694Val") is common in certain populations with more severe disease including earlier disease onset, increased frequency of inflammation of the joints (arthritis) and the membranes that line the lungs (pleuritis), and a high occurrence of amyloidosis. These researchers believe that a different FMF gene mutation (called "Val726Ala"), is present in other populations in which the disease tends to be more mild and amyloidosis occurs less frequently. Additional studies are needed to elucidate the role specific FMF gene mutations may play in determining disease severity and potential risk of amyloidosis. Such information may be essential since ongoing preventive (prophylactic) therapy with the medication colchicine may prevent amyloidosis from developing in those at risk for this serious complication. (For more information, see the Standard Therapies section of the report below.)

According to the medical literature, there may be other FMF gene mutations that have not yet been identified. In addition, some researchers suggest that, in rare cases, there may be other factors that may be able to trigger the expression of the disease in those who have inherited only one mutated FMF gene (multifactorial inheritance). It has also been suggested that certain FMF gene mutations may be inherited as an autosomal dominant trait, meaning that only a single copy of the disease gene is needed to result in expression of the disorder. Additional research is needed to further understand the specific causes of FMF in individuals who currently appear to carry just one FMF disease gene for the disorder.
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Familial Mediterranean fever is a rare disorder that affects more males than females. The symptoms generally begin during childhood or the teen years. Episodes of symptoms typically continue throughout life. Most affected individuals have ancestors who lived in areas around the Mediterranean Sea. Sephardic and Iraqi Jews, Turks, Levantine Arabs, and Armenians are at higher risk for this disease than other populations. It is estimated that, within these populations, as many as 1 person in 200 may have the disease and 1 in 5 may be a carrier for the disease. A recent study in Italy indicated that FMF might be more common in Italians than was previously thought.

Approximately 50 percent of people with FMF have no known family history of this disease. In most cases, the onset of symptoms associated with FMF is between five and 15 years of age. Approximately 90 percent of cases occur before 20 years of age.
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Symptoms of the following disorders can be similar to those of familial Mediterranean fever. Comparisons may be useful for a differential diagnosis:

Appendicitis is a common disorder characterized by the acute inflammation of the appendix. The symptoms usually include the sudden onset of pain in the stomach and abdomen, nausea, and/or vomiting. After a few hours, the pain becomes more localized to the lower right portion of the abdomen.

Lyme disease is an infectious disease caused by the spirochete bacterium Borrelia burgdorferi. The bacterium is carried and transmitted by deer ticks (Ixodes dammini), In most cases, Lyme disease is first characterized by the appearance of a red skin lesion (erythema chronicum migrans), which begins as a small elevated round spot (papule) that expands to at least five centimeters in diameter. Symptoms may then progress to include low-grade fever, chills, muscle aches (myalgia), headaches, a general feeling of weakness and fatigue (malaise), and/or pain and stiffness of the large joints (infectious arthritis), especially in the knees. Such symptoms may tend to occur in recurrent cycles. In severe cases, heart muscle (myocardial) and/or neurological abnormalities may occur. (For more information on this disease, choose "Lyme" as your search term in the Rare Disease Database.)

The following disorders may be associated with FMF as secondary characteristics. They are not necessary for a differential diagnosis:

Amyloidosis is a term applied to a group of metabolic disorders in which amyloid (a fibrous protein) accumulates in the tissues of the body. The excessive accumulation of amyloid causes the affected organ to malfunction. The accumulation may be localized, general, or systemic. The nephrotic (kidney) syndrome associated with amyloidosis is usually accompanied by increased levels of protein in the urine (proteinuria), which worsens as the disease progresses and may finally result in kidney failure. The kidneys become small, pale, and hard. (For more information on this disorder, choose "Amyloidosis" as your search term in the Rare Disease Database.)
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Diagnosis
Because certain gene mutations known to cause familial Mediterranean fever have been identified, precise genetic testing may be possible in some cases. However, such testing may only be available through research laboratories with a special interest in this disease. In addition, because the four mutations of the FMF gene that have been identified to date are present in only about 85 percent of individuals who have or are carriers for FMF, precise diagnosis may be difficult in some cases, such as in individuals with symptoms characteristic of FMF who appear to carry just one FMF disease gene. Further research is needed to better understand the genetic causes and to improve the diagnosis of FMF.

Therapies
For reasons that are not yet clearly understood, the medication colchicine may prevent or reduce attacks in FMF. In addition, if an attack is ongoing, colchicine therapy may often halt the symptoms. Studies have also shown that ongoing preventive (prophylactic) therapy with colchicine may prevent amyloidosis from developing in those at risk for this serious complication. Colchicine therapy may also help treat amyloidosis in affected individuals who have developed this condition.

Corticosteroid drugs have not proven effective for the treatment of this disease. Narcotic medications should not be used routinely to control pain because of the possibility of drug addiction. For more information, contact:

Dr. Deborah Zemer
Dr. Avi Livneh
Heller Institute for Medical Research
Sheba Medical Center
Tel Hashomer
Israel

When the function of the kidneys has been severely impaired by amyloidosis associated with familial Mediterranean fever, renal dialysis and kidney transplantation may become necessary.
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Researchers at the National Institutes of Health (NIH) are conducting genetic tests and provide genetic counseling. Furthermore, they are following a small number of FMF patients who are being treated with newer anti-inflammatory drugs such as Interferon-a. As a result of these small scale studies, a clinical trial may be started during the year 2000. For more information, contact:

NIH/ National Institute of Arthritis and Musculoskeletal Diseases
Ms. Jane Dean, RN
1-800-891-4437

In France, a large-scale, long-term study of a set of neuromuscular and non-neuromuscular genetic diseases is underway. Blood samples will be used to extract DNA samples for study. Among the diseases being investigated is FMF.

For more information on this study please contact:

Association Francaise Contre Les Myopathies
1 Rue De L'Internationale
BP 59 - 91002
Evry CEDEX, Nancy
France
Phone: 011 33 88 1 69 47 28 28
Fax: 011 33 88 60 77 12 16

An individual with FMF was treated with thalidomide. Extreme caution must be used in the administration of thalidomide, since this medication may interfere with normal fetal development during pregnancy (teratogen), potentially causing severe birth defects. However, more research is necessary to determine the long-term safety and effectiveness of thalidomide as a potential treatment for individuals with FMF.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 249100; Last Update: 4/15/03.

TEXTBOOKS
Thoene JG., ed. Physicians’ Guide to Rare Diseases. Montvale, NJ: Dowden Publishing Company Inc; 1995:760-61.

Wright DG. Familial mediterranean fever. In: Bennett JC, Plum F., eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:907-08.

Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse station, NJ: Merck Research Laboratories; 1999:2485-86.

Larson DE. ed. Mayo Clinic Family Health Book. New York, NY: William Morrow and Company, Inc; 1996:793.

Buyce ML., ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:733.

REVIEW ARTICLES
Ozen S. Vasculopathy, Behcet’s syndrome, and familial Mediterranean fever. Curr Opin Rheumatol. 1999;11:393-98.

Direskeneli H, et al. First International Conference on familal Mediterranean fever, Jerusalem, Israel, September 7-11, 1997. J Rheumatol. 1998;25:2236-39.

Majeed HA, et al. Recurrent episodic fever. A presenting feature of familial Mediterranean fever. J Med Leban. 1998;46:12-15.

Familial Mediterranean fever: from inflammation to amyloidosis. Nephrol Dial Transplant. 1998;13:1919-20.

JOURNAL ARTICLES
La Regina M, et al. Familial Mediterranean fever is no longer a rare disease in Italy. Eur J Hum Genet. 2003;11:50-6.

Odabas AR, et al. Familial Mediterranean fever. South Med J. 2002;95:1400-3.

Seyahi E, et al. Successful treatment of familial Mediterranean fever attacks with thalidomide in a colchicines resistant patient. Clin Exp Rheumatol. 2002;20:S43-4.

Touitou I. Genetic diagnosis of periodic diseases (familial Mediterranean fever or FMF). Pathol Biol (Paris). 2002;50:357-60.

Ozen S. New interest in an old disease: familial mediterranean fever. Clin Exp Rheumatol. 1999;17:745-49.

Tutar HE, et al. Recurrent pericarditis in familial mediterranean fever. Acta Paediatr. 1999;88:1045-46.

Guven M, et al. Colchicine toxicity. Clin Nephrol. 1999;52:197.

Livneh A, et al. Pulmonary associations in familial mediterranean fever. Curr Opin Pulm Med. 1999;5:326-31.

Thomas KT, et al. Periodic fever syndrome in children. J Pediatr. 1999;135:15-21.

Ozdogan H, et al. Prevalence of juvenile chronic arthritis and familial mediterranean fever in Turkey: a field study. J Rheumatol. 1999;26:1638-39.

Booth DR, et al. Pyrin/marenostrin mutations in familial mediterranean fever. QJM. 1998;91:603-06.