Familial Mediterranean Fever

Definition

Familial Mediterranean fever (FMF) is an inherited disorder of the inflammatory response characterized by recurring 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 concern if the disorder is not treated. FMF is most prevalent in people of Armenian, Sephardic-Jewish, Arabic, and Turkish ancestry.

Description

FMF could be described as a disorder of "inappropriate" inflammation. That is, an event that in a normal situation causes a mild or unnoticeable inflammation 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 also sometimes called recurrent polyserositis.

During an attack, large numbers of neutrophils, a type of white blood cell, move into the affected areas causing painful inflammation and fever. These episodes may be accompanied by a skin rash 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, the attacks of fever and pain are first noticed in childhood or adolescence. The interval between these episodes may be days or months, and is not predictable. However, during these intervals people with FMF typically lead normal lives. It is not entirely clear what brings on an attack, but people with FMF often report mild physical trauma, physical exertion, or emotional stress just prior to the onset of symptoms. Treatment for FMF involves an oral medication called colchicine, which is highly effective for the episodes of fever and pain, as well as for amyloidosis and the kidney disease that can result from it.

FMF is most common in certain ethnic groups from the eastern Mediterranean region, but cases in other ethnic groups in other parts of the world are increasingly being reported. FMF is also known by many other names. They include: recurrent hereditary polyserositis, benign paroxysmal peritonitis, familial paroxysmal polyserositis, paroxysmal polyserositis, familial recurrent polyserositis, periodic fever, periodic amyloid syndrome, periodic peritonitis syndrome, Reimann periodic disease, Reimann syndrome, Siegel-Cattan-Mamou syndrome, and Armenian syndrome.

Estimates of the incidence of FMF in specific eastern Mediterranean populations range from 1 in 2000 to 1 in 100, depending on the population studied. Specific mutations in the MEFV gene are more common in certain ethnic groups, and may cause a somewhat different course of the disease. A few mutations in the MEFV gene likely became common in a small population in the eastern Mediterranean several thousand years ago. It is postulated that carrying a single copy of a mutated gene produced a modified (but not abnormal) inflammatory response that may have been protective 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. People of Armenian, Sephardic-Jewish, Arabic, and Turkish ancestry are at greatest risk for FMF. However, a better understanding and recognition of the symptoms of FMF in recent years has resulted in more reports of the condition in other ethnic groups, such as Italians and Armenian-Americans.

Causes and symptoms

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 implies 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 in each pregnancy that the child will inherit both recessive genes, and thus have the condition.

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 co-discovered the protein named it marenostrin, after ancient Latin words that referred to the Mediterranean Sea. The movement of neutrophils into an area of the body where trauma or infection has occurred is the major cause of inflammation, which is a normal process. Research has shown that pyrin has some function in controlling neutrophils. In a situation where minor trauma or stress occurs, some initial inflammation may follow, but a functional 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 neutrophils and inflammation. Left unregulated, a normal, mild inflammation spirals out of control. Exactly what causes pyrin in FMF to lose its ability to control neutrophils in some situations is not known.

The recurrent acute attacks of FMF typically begin in childhood or adolescence. Episodes of fever and painful inflammation usually last 12-72 hours. About 90% 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 100-104 °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 done, only to have the fever and abdominal pain return.

Chest pain

Pleuritis, also called pleurisy, occurs in up to half of the affected individuals in certain ethnic groups. The pain is usually on one side of the chest. Pericarditis would also be felt as chest pain.

Joint pain

About 50% 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 becomes chronic arthritis.

Myalgia

Up to 20% of individuals 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 up to one month have been reported.

Skin rash

A rash, described as erysipelas-like erythema, accompanies attacks in a minority of people, and most often occurs on the front of the lower leg or top of the foot. The rash appears as a red, warm, swollen area about 4-6 in (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 testes, but 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 renal 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 whether they will develop 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, headaches are a common occurrence during attacks, and certain types of vasculitis (inflammation of the blood vessels) seem to be more common in FMF.

Diagnosis

Individually, the symptoms that define FMF are common. 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 delay or hinder the correct diagnosis.

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 renal 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 (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.

Direct analysis of the MEFV gene for FMF mutations is the only method to be certain of the diagnosis. However, it is not yet possible to detect all MEFV gene mutations that might cause FMF. 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 more rare than FMF.

Treatment

Colchicine is a chemical compound that can be used as a medication, and is frequently prescribed for gout. Some years ago, colchicine was discovered to also be effective in reducing the frequency and severity of attacks in FMF. Treatment for FMF at this point consists of taking colchicine daily. Studies have shown that about 75% of FMF patients achieve complete remission of their symptoms, and about 95% show marked improvement when taking colchicine. Lower effectiveness has been reported, but there is some question about the number of FMF patients who choose not to take their colchicine between attacks when they are feeling well, and thus lose some of the ability to prevent attacks. Compliance with taking colchicine every day may be hampered by its side effects, which include diarrhea, nausea, abdominal bloating, and gas. There is a theoretical risk that colchicine use could damage chromosomes in sperms and eggs, or in an embryo during pregnancy, or that it might reduce fertility. However, studies looking at reproduction in men and women who have used colchicine have so far not shown any increased risks. Colchicine is also effective in preventing, delaying, or reversing renal disease associated with amyloidosis.

Other medications may be used as needed to deal with the pain and fever associated with FMF attacks. Dialysis and/or renal transplant might become necessary in someone with advanced kidney disease. Given its genetic nature, there is no cure for FMF, nor is there likely to be in the near future. 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.

Prognosis

For those individuals who are diagnosed early enough and take colchicine consistently, the prognosis is excellent. Most will have very few, if any, attacks of fever and polyserositis, and will likely not develop serious complications of amyloidosis. The problem of misdiagnosing FMF continues, but education attempts directed at both the public and medical care providers should improve the situation. Future research should provide 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 diseases in which abnormal inflammation and immune response are a problem.

KEY TERMS

Acute phase reactants— Blood proteins whose concentrations increase or decrease in reaction to the inflammation process.

Amyloid— A waxy translucent substance composed mostly of protein, that forms plaques (abnormal deposits) in the brain.

Amyloidosis— Accumulation of amyloid deposits in various organs and tissues in the body such that normal functioning of an organ is compromised.

Colchicine— A compound that blocks the assembly of microtubules-protein fibers necessary for cell division and some kinds of cell movements, including neutrophil migration. Side effects may include diarrhea, abdominal bloating, and gas.

Leukocyte— A white blood cell. The neutrophils are a type of leukocyte.

Leukocytosis— An increase in the number of leukocytes in the blood.

Neutrophil— The primary type of white blood cell involved in inflammation. Neutrophils are a type of granulocyte, also known as a polymorphonuclear leukocyte.

Pericarditis— Inflammation of the pericardium, the membrane surrounding the heart.

Peritonitis— Inflammation of the peritoneum, the membrane surrounding the abdominal contents.

Pleuritis— Inflammation of the pleura, the membrane surrounding the lungs.

Pyrexia— A medical term denoting fevers.

Serositis— Inflammation of a serosal membrane. Polyserositis refers to the inflammation of two or more serosal membranes.

Synovitis— Inflammation of the synovium, a membrane found inside joints.

Resources

ORGANIZATIONS

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

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. 〈http://www.rarediseases.org〉.

National Society of Genetic Counselors. 233 Canterbury Dr., Wallingford, PA 19086-6617. (610) 872-1192. 〈http://www.nsgc.org/GeneticCounselingYou.asp〉.

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.

KEY TERMS

Acute phase reactants —Blood proteins whose concentrations increase or decrease in reaction to the inflammation process.

Amyloid —A waxy, translucent, starch-like protein that is deposited in tissues during the course of certain chronic diseases such as rheumatoid arthritis and Alzheimer's disease.

Amyloidosis —The accumulation of amyloid deposits in various organs and tissues in the body so that normal functioning is compromised. Primary amyloidosis usually occurs as a complication of multiple myeloma. Secondary amyloidosis occurs in patients suffering from chronic infections or inflammatory diseases such as tuberculosis, rheumatoid arthritis, and Crohn's disease.

Colchicine —A drug used to treat painful flare-ups of gout. It is also effective in reducing the frequency and severity of attacks in familial Mediterranean fever.

Erythema —A diffuse red and inflamed area of the skin.

Leukocyte —A white blood cell that defends the body against invading viruses, bacteria, and cancer cells. There are five types of leukocytes–neutrophils, basophils, eosinophils, lymphocytes, and monocytes.

Leukocytosis —An increased level of white cells in the blood. Leukocytosis is a common reaction to infections.

Neutrophil —The primary type of white blood cell involved in inflammation. Neutrophils are a type of granulocyte, also known as a polymorphonuclear leukocyte. They increase in response to bacterial infection and remove and kill bacteria by phagocytosis.

Pericarditis —Inflammation of the pericardium, the sac that surrounds the heart and the roots of the great blood vessels.

Peritonitis —Inflammation of the peritoneum. It is most often due to bacterial infection, but can also be caused by a chemical irritant (such as spillage of acid from the stomach or bile from the gall bladder).

Pleuritis —Inflammation of the pleura, the membrane surrounding the lungs. Also called pleurisy.

Pyrexia —A medical term meaning fever.

Pyrin —A protein that regulates the body's inflammatory response to stress or trauma. The MEFV gene involved in FMF produces an unstable form of pyrin that fails to adequately control the inflammatory response.

Serositis —Inflammation of a serosal membrane (any membrane that lines a body cavity that does not open to the outside of the body). Polyserositis refers to the inflammation of two or more serosal membranes.

Synovitis —Inflammation of the synovial membrane, the membrane that lines the inside of the articular capsule of a joint.

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: <www.nih.gov/niams>.

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

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

WEB SITES

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

Scott J. Polzin, MS

Familial Mediterranean fever

Definition

Familial Mediterranean fever (FMF) is an inherited disorder of the inflammatory response characterized by recurring 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 concern if the disorder is not treated. FMF is most prevalent in people of Armenian, Sephardic-Jewish, Arabic, and Turkish ancestry.

Description

FMF could be described as a disorder of "inappropriate" inflammation. That is, an event that in a normal situation causes a mild or unnoticeable inflammation 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 also sometimes called recurrent polyserositis.

During an attack, large numbers of neutrophils, a type of white blood cell, move into the affected areas causing painful inflammation and fever. These episodes may be accompanied by a skin rash 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, the attacks of fever and pain are first noticed in childhood or adolescence. The interval between these episodes may be days or months, and is not predictable. However, during these intervals people with FMF typically lead normal lives. It is not entirely clear what brings on an attack, but people with FMF often report mild physical trauma, physical exertion, or emotional stress just prior to the onset of symptoms. Treatment for FMF involves an oral medication called colchicine, which is highly effective for the episodes of fever and pain, as well as for amyloidosis and the kidney disease that can result from it.

FMF is most common in certain ethnic groups from the eastern Mediterranean region, but cases in other ethnic groups in other parts of the world are increasingly being reported. FMF is also known by many other names. They include: recurrent hereditary polyserositis, benign paroxysmal peritonitis, familial paroxysmal polyserositis, paroxysmal polyserositis, familial recurrent polyserositis, periodic fever, periodic amyloid syndrome, periodic peritonitis syndrome, Reimann periodic disease, Reimann syndrome, Siegel-Cattan-Mamou syndrome, and Armenian syndrome.

Genetic profile

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 implies 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 in each pregnancy that the child will inherit both recessive genes, and thus have the condition.

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 co-discovered the protein named it marenostrin, after ancient Latin words that referred to the Mediterranean Sea. The movement of neutrophils into an area of the body where trauma or infection has occurred is the major cause of inflammation, which is a normal process. Research has shown that pyrin has some function in controlling neutrophils. In a situation where minor trauma or stress occurs, some initial inflammation may follow, but a functional 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 neutrophils and inflammation. Left unregulated, a normal, mild inflammation spirals out of control. Exactly what causes pyrin in FMF to lose its ability to control neutrophils in some situations is not known.

Demographics

Estimates of the incidence of FMF in specific eastern Mediterranean populations range from one in 2,000 to one in 100, depending on the population studied. Specific mutations in the MEFV gene are more common in certain ethnic groups, and may cause a somewhat different course of the disease. A few mutations in the MEFV gene likely became common in a small population in the eastern Mediterranean several thousand years ago. It is postulated that carrying a single copy of a mutated gene produced a modified (but not abnormal) inflammatory response that may have been protective 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. People of Armenian, Sephardic-Jewish, Arabic, and Turkish ancestry are at greatest risk for FMF. However, a better understanding and recognition of the symptoms of FMF in recent years has resulted in more reports of the condition in other ethnic groups, such as Italians and Armenian-Americans.

Signs and symptoms

The recurrent acute attacks of FMF typically begin in childhood or adolescence. Episodes of fever and painful inflammation usually last 12–72 hours. About 90% 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 100–104°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 done, only to have the fever and abdominal pain return.

Chest pain

Pleuritis, also called pleurisy, occurs in up to half of the affected individuals in certain ethnic groups. The pain is usually on one side of the chest. Pericarditis would also be felt as chest pain.

Joint pain

About 50% 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 becomes chronic arthritis.

Myalgia

Up to 20% of individuals 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 up to one month have been reported.

Skin rash

A rash, described as erysipelas-like erythema, accompanies attacks in a minority of people, and most often occurs on the front of the lower leg or top of the foot. The rash appears as a red, warm, swollen area about 4–6 in (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 testes, but 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 renal 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 whether they will develop 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. Headaches are a common occurrence during attacks, and certain types of vasculitis (inflammation of the blood vessels) seem to be more common in FMF.

Diagnosis

Individually, the symptoms that define FMF are common. 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 delay or hinder the correct diagnosis.

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 renal 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 (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.

Direct analysis of the MEFV gene for FMF mutations is the only method to be certain of the diagnosis. However, it is not yet possible to detect all MEFV gene mutations that might cause FMF. 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 more rare than FMF.

Treatment and management

Colchicine is a chemical compound that can be used as a medication, and is frequently prescribed for gout. Some years ago, colchicine was discovered to also be effective in reducing the frequency and severity of attacks in FMF. Treatment for FMF at this point consists of taking colchicine daily. Studies have shown that about 75% of FMF patients achieve complete remission of their symptoms, and about 95% show marked improvement when taking colchicine. Lower effectiveness has been reported, but there is some question about the number of FMF patients who choose not to take their colchicine between attacks when they are feeling well, and thus lose some of the ability to prevent attacks. Compliance with taking colchicine every day may be hampered by its side effects, which include diarrhea, nausea, abdominal bloating, and gas. There is a theoretical risk that colchicine use could damage chromosomes in sperms and eggs, or in an embryo during pregnancy, or that it might reduce fertility. However, studies looking at reproduction in men and women who have used colchicine have so far not shown any increased risks. Colchicine is also effective in preventing, delaying, or reversing renal disease associated with amyloidosis.

Other medications may be used as needed to deal with the pain and fever associated with FMF attacks. Dialysis and/or renal transplant might become necessary in someone with advanced kidney disease. Given its genetic nature, there is no cure for FMF, nor is there likely to be in the near future. 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.

Prognosis

For those individuals who are diagnosed early enough and take colchicine consistently, the prognosis is excellent. Most will have very few, if any, attacks of fever and polyserositis, and will likely not develop serious complications of amyloidosis. The problem of misdiagnosing FMF continues, but education attempts directed at both the public and medical care providers should improve the situation. Future research should provide 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 diseases in which abnormal inflammation and immune response are a problem.

Resources

BOOKS

Kastner, Daniel L. "Intermittent and Periodic Arthritic Syndromes." Arthritis and Allied Conditions: A Textbook of Rheumatology, edited by William J. Koopman. 13th ed. Baltimore: Williams & Wilkins, 1996.

Sha'ar, Khuzama H., and Haroutone K. Armenian. "Familial Paroxysmal Polyserositis (Familial Mediterranean Fever)." In Genetic Disorders Among Arab Populations, edited by Ahmad S. Teebi, and Talaat I. Faraq. New York: Oxford University Press, 1997.

PERIODICALS

Ben-Chetrit, Eldad, and Micha Levy. "Familial Mediterranean Fever." The Lancet 351 (February 28, 1998): 659-64.

Kastner, Daniel L. "Familial Mediterranean Fever: The Genetics of Inflammation." Hospital Practice 33 (April 15, 1998):131-146.

Samuels, Jonathan, et al. "Familial Mediterranean Fever at the Millennium: Clinical Spectrum, Ancient Mutations, and a Survey of 100 American referrals to the National Institutes of Health." Medicine 77 (July 1998):268-97.

ORGANIZATIONS

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

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

National Society of Genetic Counselors. 233 Canterbury Dr., Wallingford, PA 19086-6617. (610) 872-1192. <http://www.nsgc.org/GeneticCounselingYou.asp>.

Scott J. Polzin, MS, CGC

Familial Mediterranean fever

Definition

Familial Mediterranean fever (FMF) is an inherited disorder of the inflammatory response characterized by recurring 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 concern if the disorder is not treated. FMF is most prevalent in people of Armenian, Sephardic-Jewish, Arabic, and Turkish ancestry.

Description

FMF could be described as a disorder of "inappropriate" inflammation. That is, an event that in a normal situation causes a mild or unnoticeable inflammation 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 also sometimes called recurrent polyserositis.

During an attack, large numbers of neutrophils, a type of white blood cell, move into the affected areas causing painful inflammation and fever. These episodes may be accompanied by a skin rash 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, the attacks of fever and pain are first noticed in childhood or adolescence. The interval between these episodes may be days or months, and is not predictable. However, during these intervals people with FMF typically lead normal lives. It is not entirely clear what brings on an attack, but people with FMF often report mild physical trauma, physical exertion, or emotional stress just prior to the onset of symptoms. Treatment for FMF involves an oral medication called colchicine, which is highly effective for the episodes of fever and pain, as well as for amyloidosis and the kidney disease that can result from it.

FMF is most common in certain ethnic groups from the eastern Mediterranean region, but cases in other ethnic groups in other parts of the world are increasingly being reported. FMF is also known by many other names. They include: recurrent hereditary polyserositis, benign paroxysmal peritonitis, familial paroxysmal polyserositis, paroxysmal polyserositis, familial recurrent polyserositis, periodic fever, periodic amyloid syndrome, periodic peritonitis syndrome, Reimann periodic disease, Reimann syndrome, Siegel-Cattan-Mamou syndrome, and Armenian syndrome.

Genetic profile

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 implies 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 in each pregnancy that the child will inherit both recessive genes, and thus have the condition.

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 named it marenostrin, after ancient Latin words that referred to the Mediterranean Sea. The movement of neutrophils into an area of the body where trauma or infection has occurred is the major cause of inflammation, which is a normal process. Research has shown that pyrin has some function in controlling neutrophils. In a situation where minor trauma or stress occurs, some initial inflammation may follow, but a functional 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 neutrophils and inflammation. Left unregulated, a normal, mild inflammation spirals out of control. Exactly what causes pyrin in FMF to lose its ability to control neutrophils in some situations is not known.

Demographics

Estimates of the incidence of FMF in specific eastern Mediterranean populations range from one in 2,000 to one in 100, depending on the population studied. Specific mutations in the MEFV gene are more common in certain ethnic groups, and may cause a somewhat different course of the disease. A few mutations in the MEFV gene likely became common in a small population in the eastern Mediterranean several thousand years ago. It is postulated that carrying a single copy of a mutated gene produced a modified (but not abnormal) inflammatory response that may have been protective 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. People of Armenian, Sephardic-Jewish, Arabic, and Turkish ancestry are at greatest risk for FMF. However, a better understanding and recognition of the symptoms of FMF in recent years has resulted in more reports of the condition in other ethnic groups, such as Italians and Armenian-Americans.

Signs and symptoms

The recurrent acute attacks of FMF typically begin in childhood or adolescence. Episodes of fever and painful inflammation usually last 12–72 hours. About 90% 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 100–104°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 done, only to have the fever and abdominal pain return.

Chest pain

Pleuritis, also called pleurisy, occurs in up to half of the affected individuals in certain ethnic groups. The pain is usually on one side of the chest. Pericarditis would also be felt as chest pain.

Joint pain

About 50% 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 becomes chronic arthritis.

Myalgia

Up to 20% of individuals 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 up to one month have been reported.

Skin rash

A rash, described as erysipelas-like erythema, accompanies attacks in a minority of people, and most often occurs on the front of the lower leg or top of the foot. The rash appears as a red, warm, swollen area about 4–6 in (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 testes, but 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 renal 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 whether they will develop 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. Headaches are a common occurrence during attacks, and certain types of vasculitis (inflammation of the blood vessels) seem to be more common in FMF.

Diagnosis

Individually, the symptoms that define FMF are common. 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 delay or hinder the correct diagnosis.

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 renal 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 (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.

Direct analysis of the MEFV gene for FMF mutations is the only method to be certain of the diagnosis. However, it is not yet possible to detect all MEFV gene mutations that might cause FMF. 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 more rare than FMF.

Treatment and management

Colchicine is a chemical compound that can be used as a medication, and is frequently prescribed for gout. Some years ago, colchicine was discovered to also be effective in reducing the frequency and severity of attacks in FMF. Treatment for FMF at this point consists of taking colchicine daily. Studies have shown that about 75% of FMF patients achieve complete remission of their symptoms, and about 95% show marked improvement when taking colchicine. Lower effectiveness has been reported, but there is some question about the number of FMF patients who choose not to take their colchicine between attacks when they are feeling well, and thus lose some of the ability to prevent attacks. Compliance with taking colchicine every day may be hampered by its side effects, which include diarrhea, nausea, abdominal bloating, and gas. There is a theoretical risk that colchicine use could damage chromosomes in sperms and eggs, or in an embryo during pregnancy, or that it might reduce fertility. However, studies looking at reproduction in men and women who have used colchicine have so far not shown any increased risks. Colchicine is also effective in preventing, delaying, or reversing renal disease associated with amyloidosis.

Other medications may be used as needed to deal with the pain and fever associated with FMF attacks. Dialysis and/or renal transplant might become necessary in someone with advanced kidney disease. Given its genetic nature, there is no cure for FMF, nor is there likely to be in the near future. 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.

Prognosis

For those individuals who are diagnosed early enough and take colchicine consistently, the prognosis is excellent. Most will have very few, if any, attacks of fever and polyserositis, and will likely not develop serious complications of amyloidosis. The problem of misdiagnosing FMF continues, but education attempts directed at both the public and medical care providers should improve the situation. Future research should provide 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 diseases in which abnormal inflammation and immune response are a problem.

Resources

BOOKS

Kastner, Daniel L. "Intermittent and Periodic Arthritic Syndromes." In Arthritis and Allied Conditions: ATextbook of Rheumatology, edited by William J. Koopman. 13th ed. Baltimore: Williams & Wilkins, 1996.

Sha'ar, Khuzama H., and Haroutone K. Armenian. "Familial Paroxysmal Polyserositis (Familial Mediterranean Fever)." In Genetic Disorders Among Arab Populations, edited by Ahmad S. Teebi, and Talaat I. Faraq. New York: Oxford University Press, 1997.

PERIODICALS

Ben-Chetrit, Eldad, and Micha Levy. "Familial Mediterranean Fever." The Lancet 351 (February 28, 1998): 659-64.

Kastner, Daniel L. "Familial Mediterranean Fever: The Genetics of Inflammation." Hospital Practice 33 (April 15, 1998):131-146.

Samuels, Jonathan, et al. "Familial Mediterranean fever at the millennium: clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health." Medicine 77, (July 1998):268-97.

ORGANIZATIONS

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

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

National Society of Genetic Counselors. 233 Canterbury Dr., Wallingford, PA 19086-6617. (610) 872-1192. <http://www.nsgc.org/GeneticCounselingYou.asp>.

Scott J. Polzin, MS, CGC

Mediterranean fever (med-it-er-ay-ni-ăn) n.
1. see brucellosis.

2. see polyserositis.