Familial Mediterranean fever

Definition

Familial Mediterranean fever (FMF) is an inherited disorder characterized by an inflammatory response recurring with attacks of fever accompanied by intense pain in the abdomen, chest, or joints. Attacks usually last 12–72 hours and can occasionally involve a skin rash. Kidney disease is a serious complication that may develop if the disorder is not treated. FMF is most prevalent in people of Armenian, Sephardic-Jewish, Arabic, and Turkish ancestry. The disorder takes its name from the fact that these ethnic groups live in countries along or near the eastern coast of the Mediterranean Sea.

FMF is sometimes grouped together with other periodic fevers in a category called autoinflammatory disorders. The term was invented to describe illnesses caused by genetic defects in the human immune response. Other disorders in this group are TNF-receptor associated periodic syndrome (TRAPS), hyper-IgD syndrome (HIDS), and familial Hibernian fever.

Description

FMF has been described as a disorder of "inappropriate" inflammation or an autoinflammatory syndrome. That is, an event that causes a mild or unnoticeable inflammation in most people might cause a severe inflammatory response in someone with FMF. Certain areas of the body are at risk for FMF-related symptoms. A serosa is a serous (fluid-producing) membrane that can be found inside the abdominal cavity (peritoneum), around the lungs (pleura), around the heart (pericardium), and inside the joints (synovium). The symptoms of FMF are due to inflammation of one or more of the serosal membranes (serositis). Thus, FMF is sometimes called recurrent polyserositis. Other names for the disorder are periodic peritonitis, periodic fever, periodic disease, familial paroxysmal polyserositis, periodic amyloid syndrome, periodic peritonitis syndrome, Reimann periodic disease, Reimann syndrome, Siegel-Cattan-Mamou syndrome, and Armenian syndrome.

During an attack of FMF, large numbers of neutrophils, a type of white blood cell, move into the affected areas of the body, where they cause painful inflammation and fever. These episodes may be accompanied by a skin rash (erythema) or joint pain. In a few cases, chronic arthritis is a problem. Amyloidosis is a potentially serious condition in which proteins called amyloids are mistakenly produced and deposited in organs and tissues throughout the body. Left untreated, amyloidosis often leads to kidney failure, which is the major long-term health risk in FMF.

In most cases, patients diagnosed with FMF first notice the attacks of fever and pain in childhood or adolescence . The intervals between these episodes may extend for days or months and are unpredictable. People with FMF typically lead normal lives during these pain-free intervals. It is not entirely clear what brings on an attack, although people with FMF often report mild physical trauma, physical exertion, or emotional stress just prior to the onset of symptoms. The mainstay of treatment for FMF is an oral medication called colchicine, which is highly effective for the fever and pain that accompany the disorder, as well as for amyloidosis and the kidney disease that can result from it.

Demographics

Estimates of the incidence of FMF in specific eastern Mediterranean populations range from one in 2,000 Arabs to one in 250 Sephardic Jews, one in 500 Armenians, and one in 1,000 Turks. Specific mutations in the MEFV gene are more common in certain ethnic groups and may cause a somewhat different course of the disease. Researchers think that a few mutations in the MEFV gene likely became common in a small population in the eastern Mediterranean several thousand years ago. The mutation was transmitted to later generations because people who carried a single copy of the mutated gene had a modified (but not abnormal) inflammatory response that may have protected them against some infectious agent at that time. Those who carried a single "beneficial" mutation in the MEFV gene were more likely to survive and reproduce, which may explain the high carrier frequency (up to one in five) in some populations. A better understanding and recognition of the symptoms of FMF in the late 1990s and early 2000s has resulted in more reports of the condition in other ethnic groups such as Ashkenazic Jews, Italians, Armenian-Americans, and Japanese. About 50 percent of patients diagnosed with FMF, however, have no family history of the disease.

With regard to sex, FMF is more common in men than in women, with a gender ratio of two men for every one woman. In terms of age groups, FMF is more common in younger people. One researcher states that 50–60 percent of patients are younger than 10 years, 80–95 percent are below the age of 20, with the remainder between 20 and 40 years of age. FMF is rare in people older than 40.

Causes and symptoms

Causes

FMF is a genetic condition inherited in an autosomal recessive fashion. Mutations in the MEFV gene (short for Mediterranean fever) on chromosome number 16 are the underlying cause of FMF. Autosomal recessive inheritance means that a person with FMF has mutations in both copies of the MEFV gene. All genes come in pairs, and one copy of each pair is inherited from each parent. If neither parent of a child with FMF has the condition, it means they carry one mutated copy of the MEFV gene, but also one normal copy, which is enough to protect them from disease. If both parents carry the same autosomal recessive gene, there is a one in four chance with each pregnancy that the child will inherit both recessive genes and develop FMF.

The MEFV gene carries the instructions for production of a protein called pyrin, named for pyrexia, a medical term for fever. The research group in France that codiscovered the protein in 1997 named it marenostrin, after mare nostra , the Latin words that the ancient Romans used for the Mediterranean Sea. Research has shown that pyrin has some function in controlling neutrophils, which are the white blood cells that move into an area of the body affected by stress or trauma. In a person with a normal immune system, some inflammation may follow stress or trauma, but the pyrin protein is responsible for shutting down the response of neutrophils once they are no longer needed. An abnormal pyrin protein associated with FMF may be partly functional but unstable. In some instances, the abnormal pyrin itself seems to be "stressed", and loses its ability to regulate the inflammatory response to trauma. Without such regulation, a normal inflammatory response spirals out of control. Exactly what causes pyrin in FMF to lose its ability to control neutrophils in some situations is not fully understood as of 2004.

Symptoms

The recurrent acute attacks of FMF typically begin in childhood or adolescence. These acute episodes of fever and painful inflammation usually last 12–72 hours. About 90 percent of people with FMF have their first attack by age 20. The group of symptoms that characterizes FMF includes the following:

• Fever: An FMF attack is nearly always accompanied by a fever, but it may not be noticed in every case. Fevers are typically 100 to 104°F (38–40°C). Some people experience chills prior to the onset of fever.
• Abdominal pain: Nearly all people with FMF experience abdominal pain at one point or another, and for most it is the most common complaint. The pain can range from mild to severe and can be diffuse or localized. It can mimic appendicitis , and many people with undiagnosed FMF have had appendectomies or exploratory surgery of the abdomen only to have the fever and abdominal pain return.
• Chest pain (pleuritis): Pleuritis, also called pleurisy, occurs in up to half of the affected individuals in certain ethnic groups. The pain is usually felt on one side of the chest. Pericarditis, an inflammation of the membrane surrounding the heart, would also be felt as chest pain.
• Joint pain: About 50 percent of people with FMF experience joint pain during attacks. The pain is usually confined to one joint at a time, and often involves the hip, knee, or ankle. For some people, however, the recurrent joint pain eventually becomes chronic arthritis.
• Muscle pain (myalgia): Up to 20 percent of individuals with FMF report muscle pain. These episodes typically last less than two days and tend to occur in the evening or after physical exertion. Rare cases of muscle pain and fever lasting as long as one month have been reported.
• Skin rash. A rash described as an erythema (skin reddening) resembling erysipelas accompanies FMF attacks in a minority of people. The rash typically occurs on the front of the lower leg or top of the foot, and appears as a red, warm, swollen area about 4–6 inches (10–15 cm) in diameter.
• Amyloidosis: FMF is associated with high levels in the blood of a protein called serum amyloid A (SAA). Over time, excess SAA tends to be deposited in tissues and organs throughout the body. The presence and deposition of excess SAA is known as amyloidosis. Amyloidosis may affect the gastrointestinal tract, liver, spleen, heart, and (in males) testes, but its effects on the kidneys are of greatest concern. The frequency of amyloidosis varies among the different ethnic groups, and its overall incidence is difficult to determine because of the use of colchicine to avert the problem. Left untreated, however, those individuals who do develop amyloidosis of the kidneys may require a kidney transplant or may even die of renal failure. The frequency and severity of a person's attacks of fever and serositis seem to have no relation to the risk of developing amyloidosis. In fact, a few people with FMF have been described who have had amyloidosis but apparently no other FMF-related symptoms.
• Other symptoms: A small percentage of boys with FMF develop painful inflammation around the testes, while girls may experience episodes of inflammation in the pelvis. In other patients, headaches are a common occurrence during attacks. Lastly, certain types of vasculitis (inflammation of the blood vessels) seem to be more common in people diagnosed with FMF.

When to call the doctor

Parents should consult a doctor for their child if they have Mediterranean ancestry and their child develops recurrent attacks of fever and pain consistent with the symptoms of FMF as described above.

In general, symptoms involving one or more of the following broad groups should lead to suspicion of FMF. Unexplained recurrent fevers, polyserositis, skin rash, and/or joint pain; abnormal blood studies (see below); and kidney or other disease associated with amyloidosis. A family history of FMF or its symptoms would obviously be an important clue, but the recessive nature of FMF means there usually is no family history. The diagnosis may be confirmed when a person with unexplained fever and pain responds to treatment with colchicine, since colchicine is not known to have a beneficial effect on any other condition similar to FMF. Abnormal results on a blood test typically include leukocytosis (elevated number of neutrophils in the blood); an increased erythrocyte sedimentation rate (the rate at which red blood cells form a sediment in a blood sample); and increased levels of proteins associated with inflammation (called acute phase reactants) such as SAA.

Diagnosis

The diagnosis of FMF is often delayed because the symptoms that define the condition are common to many other disorders. Fevers occur for many reasons, and nonspecific pains in the abdomen, chest, and joints are also frequent ailments. Several infections can result in symptoms similar to FMF (Mallaret meningitis , for instance), and many people with FMF undergo exploratory abdominal surgery and ineffective treatments before they are finally diagnosed. Membership in a less commonly affected ethnic group may also delay or hinder the correct diagnosis. In many cases the doctor is able to diagnose the disorder only by a slow process of eliminating other diagnostic possibilities. He or she may order x rays or other imaging studies in order to rule out certain types of arthritis.

Direct analysis of the MEFV gene for FMF mutations is the only method to be certain of the diagnosis. While it was as of 2004 not yet possible to detect all MEFV gene mutations that might cause FMF, successful cloning of the MEFV gene has led to a rapid test that can identify the most common mutations of the gene. Thus, if DNA analysis is negative, clinical methods must be relied upon. If both members of a couple were proven to be FMF carriers through genetic testing, highly accurate prenatal diagnosis would be available in any subsequent pregnancy.

Similar syndromes of periodic fever and inflammation include familial Hibernian fever and hyperimmunoglobulinemia D syndrome, but both are much less common than FMF.

Treatment

Colchicine is an anti-inflammatory chemical compound that can be used as a medication and is frequently prescribed for gout. In the late twentieth century, colchicine was discovered to also be effective in reducing the frequency and severity of attacks in FMF. Treatment for FMF in the early 2000s consists of taking colchicine daily. Studies have shown that about 75 percent of FMF patients achieve complete remission of their symptoms, and about 95 percent show marked improvement when taking colchicine. Compliance with taking colchicine every day may be hampered by its side effects, which include diarrhea , nausea , abdominal bloating, and gas. Colchicine is also effective in preventing, delaying, or reversing kidney disease associated with amyloidosis.

Other medications may be used as needed to treat the pain and fever associated with FMF attacks. The most common drugs used are narcotics for severe pain and nonsteroidal anti-inflammatory drugs (NSAIDs) for arthritis and muscle pain. Dialysis and/or a kidney transplant might become necessary in someone with advanced kidney disease.

Alternative treatment

Some researchers have reported on herbal compounds that appear to be useful in managing patients with FMF. One Japanese case report concerned a patient who was helped by Kampo formulations, which are the traditional herbal medicines of Japan. A larger study of 24 Armenian patients diagnosed with FMF reported that the 14 patients who were given ImmunoGuard, a herbal preparation containing licorice root and schisandra along with several other herbs, had fewer and milder attacks of FMF than the 10 patients who were given a placebo.

Prognosis

Children who are diagnosed early enough and take colchicine consistently have an excellent prognosis. Most will have very few, if any, attacks of fever and polyserositis and will likely not develop serious complications of amyloidosis. Future research should provide doctors with a better understanding of the inflammation process, focusing on how neutrophils are genetically regulated. That information could then be used to develop treatments for FMF with fewer side effects and might also assist in developing therapies for other autoinflammatory diseases.

With regard to long-term effects of FMF, about 5 percent of patients will develop severe arthritis in adult life. Girls with FMF are likely to have fertility problems as adults; about 30 percent will be unable to have children at all, and those who can conceive have a 20 to 30 percent chance of miscarriage.

Prevention

Given the genetic nature of FMF, there is as of 2004 no cure for the disorder. Any couple that has a child diagnosed with FMF or anyone with a family history of the condition (especially those in high-risk ethnic groups) should be offered genetic counseling to obtain the most up-to-date information on FMF and testing options.

Parental concerns

Parental concerns about a child with FMF depend to some extent on the frequency and severity of attacks, as the frequency can range from two episodes per week to one per year. Families whose children have relatively infrequent attacks will be much less affected by the disorder than those whose plans are frequently disrupted by a child's acute attack. In most cases, however, children diagnosed with FMF have excellent health between attacks, can keep up with their schoolwork, participate in sports , and enjoy a normal social life. They do not require special diets, educational programs, isolation from other children, or other modifications of the family's routine. One concern that parents may wish to discuss with the doctor, however, is the narcotic medications that are often prescribed to ease the pain that accompanies acute attacks of FMF. Some of these drugs are potentially addictive, and their use should be carefully supervised.

Resources

BOOKS

"Familial Mediterranean Fever." Section 21, Chapter 289 in The Merck Manual of Diagnosis and Therapy , edited by Mark H. Beers and Robert Berkow. Whitehouse Station, NJ: Merck Research Laboratories, 2002.

PERIODICALS

Amaryan, G., et al. "Double-Blind, Placebo-Controlled, Randomized, Pilot Clinical Trial of ImmunoGuard: A Standardized Fixed Combination of Andrographus paniculata Nees , with Eleutherococcus senticosus Maxim , Schizandra chinensis Bail. , and Glycyrrhiza glabra L. Extracts in Patients with Familial Mediterranean Fever." Phytomedicine 10 (May 2003): 271–85.

Komatsu, M., et al. "Familial Mediterranean Fever Medicated with an Herbal Medicine in Japan." Pediatrics International 46 (February 2004): 81–4.

Kotone-Miyahara, Y., et al. "E148Q/M6941 Mutation in 3 Japanese Patients with Familial Mediterranean Fever." International Journal of Hematology 79 (April 2004): 235–37.

Toitou, I., et al. "Infevers: An Evolving Mutation Database for Auto-Inflammatory Syndromes." Human Mutation 24 (September 2004): 194–98.

ORGANIZATIONS

National Institute of Arthritis and Musculoskeletal and Skin Diseases. National Institutes of Health, One AMS Circle, Bethesda, MD 20892. Web site: http://www.nih.gov/niams.

National Organization for Rare Disorders Inc. (NORD). 55 Kenosia Avenue, Danbury, CT 06813–1968. Web site: http://www.rarediseases.org.

National Society of Genetic Counselors. 233 Canterbury Dr., Wallingford, PA 19086–6617. Web site: http://www.nsgc.org/GeneticCounselingYou.asp.

WEB SITES

Meyerhoff, John. "Mediterranean Fever, Familial." eMedicine , April 29, 2004. http://www.emedicine.com/med/topic1410.htm (accessed November 27, 2004).

Scott J. Polzin, MS