familial Mediterranean fever (redirected from Wolff Periodic disease)

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〉.

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fever /fe·ver/ (fe´ver)

1. pyrexia; elevation of body temperature above the normal (37°C).

2. any disease characterized by elevation of body temperature.

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blackwater fever  a dangerous complication of falciparum malaria, with passage of dark red to black urine, severe toxicity, and high mortality.

boutonneuse fever  a tickborne disease endemic in the Mediterranean area, Crimea, Africa, and India, due to infection with Rickettsia conorii, with chills, fever, primary skin lesion (tache noire), and rash appearing on the second to fourth day.

cat-scratch fever  see under disease.

central fever  sustained fever resulting from damage to the thermoregulatory centers of the hypothalamus.

childbed fever  puerperal septicemia.

Colorado tick fever  a tickborne, nonexanthematous, febrile, viral disease caused by an arenavirus and seen in the Rocky Mountain area of the United States.

continued fever  one that varies only slightly in 24 hours.

Crimean-Congo hemorrhagic fever  a hemorrhagic fever caused by the Crimean-Congo hemorrhagic fever virus, transmitted by ticks and by contact with blood, secretions, or fluids from infected animals or humans; it occurs in the Crimea, Central Asia, and regions of Africa.

drug fever  febrile reaction to a therapeutic agent, such as a vaccine, antineoplastic, or antibiotic.

elephantoid fever  a recurrent acute febrile condition occurring with filariasis; it may be associated with elephantiasis or lymphangitis.

enteric fever  any of a group of febrile illnesses associated with enteric symptoms caused by salmonellae, especially typhoid fever and paratyphoid fever.

epidemic hemorrhagic fever  an acute infectious disease characterized by fever, purpura, peripheral vascular collapse, and acute renal failure, caused by viruses of the genus Hantavirus, thought to be transmitted to humans by contact with saliva and excreta of infected rodents.

familial Mediterranean fever  a hereditary disease usually seen in Armenians and Sephardic Jews, with short recurrent attacks of fever, pain in the abdomen, chest, or joints, and erythema like that of erysipelas; it may be complicated by amyloidosis.

Haverhill fever  the bacillary form of rat-bite fever, due to Streptobacillus moniliformis, and transmitted through contaminated raw milk and its products.

hay fever  a seasonal form of allergic rhinitis, with acute conjunctivitis, lacrimation, itching, swelling of the nasal mucosa, nasal catarrh, and attacks of sneezing, an anaphylactic or allergic reaction excited by a specific allergen (such as pollen).

hemorrhagic fevers  a group of diverse, severe viral infections seen around the world but mainly in the tropics, usually transmitted to humans by arthropod bites or contact with virus-infected rodents; they all have certain common features, including fever, hemorrhagic manifestations, thrombocytopenia, shock, and neurologic disturbances.

humidifier fever  malaise, fever, cough, and myalgia caused by inhalation of air that has been passed through humidifiers, dehumidifiers, or air conditioners contaminated by fungi, amebas, or thermophilic actinomycetes.

intermittent fever  an attack of malaria or other fever, with recurring fever episodes separated by times of normal temperature.

Katayama fever  fever associated with severe schistosomal infections, accompanied by hepatosplenomegaly and by eosinophilia.

Lassa fever  a highly fatal, acute, febrile disease seen in West Africa, caused by a virulent arenavirus and characterized by increasing prostration, sore throat, ulcerations of the mouth or throat, rash, and general aching.

metal fume fever  a disease of welders and others working with volatilized metals, marked by sudden thirst, metallic taste in the mouth, high fever with chills, sweating, and leukocytosis.

mud fever  a type of leptospirosis seen in workers in flooded fields and swamps in Germany and Russia.

nonseasonal hay fever , hay fever, perennial nonseasonal allergic rhinitis.

Oroya fever  see Carrión's disease.

paratyphoid fever  paratyphoid.

parenteric fever  a disease clinically resembling typhoid fever and paratyphoid, but not caused by Salmonella.

parrot fever  psittacosis.

pharyngoconjunctival fever  an epidemic disease due to an adenovirus, seen mainly in school children, with fever, pharyngitis, conjunctivitis, rhinitis, and enlarged cervical lymph nodes.

phlebotomus fever  a febrile viral disease of short duration, transmitted by the sandfly Phlebotomus papatasi, with dengue-like symptoms, seen in Mediterranean and Middle Eastern countries.

Pontiac fever  a self-limited disease marked by fever, cough, muscle aches, chills, headache, chest pain, confusion, and pleuritis, caused by a strain of Legionella pneumophila.

pretibial fever  an infection due to a serovar of Leptospira interrogans, marked by a rash on the pretibial region, with lumbar and postorbital pain, malaise, coryza, and fever.

puerperal fever  septicemia accompanied by fever, in which the focus of infection is a lesion of the mucous membrane of the parturient canal due to trauma during childbirth; usually due to a streptococcus.

Q fever  a febrile rickettsial infection, usually respiratory, first described in Australia, caused by Coxiella burnetii.

rat-bite fever  either of two clinically similar acute infectious diseases, usually transmitted through a rat bite, one form (bacillary) of which is caused by Streptobacillus moniliformis and the other form (spirillary) by Spirillum minor.

recurrent fever 

1. relapsing f.

2. recurrent paroxysmal fever occurring in various diseases, such as malaria.

relapsing fever  any of a group of infectious diseases due to various species of Borrelia, marked by alternating periods of fever and apyrexia, each lasting from five to seven days.

remittent fever  one that shows significant variations in 24 hours but without return to normal temperature.

rheumatic fever  a febrile disease occurring as a sequela to Group A hemolytic streptococcal infections, characterized by multiple focal inflammatory lesions of connective tissue structures, especially of the heart, blood vessels, and joints, and by Aschoff bodies in the myocardium and skin.

Rift Valley fever  a zoonotic febrile disease with dengue-like symptoms, due to an arbovirus, transmitted to humans by mosquitoes or by contact with diseased animals; first observed in the Rift Valley, Kenya.

Rocky Mountain spotted fever  infection with Rickettsia rickettsii, transmitted by ticks, marked by fever, muscle pain, and weakness followed by a macular petechial eruption that begins on the hands and feet and spreads to the trunk and face, with other symptoms in the central nervous system and elsewhere.

rose fever  a form of hay fever caused by grass pollens released while roses or other flowers are blooming.

scarlet fever  an acute disease caused by Group A β-hemolytic streptococci, marked by pharyngotonsillitis and a skin rash caused by an erythrogenic toxin produced by the organism; the rash is a diffuse, bright red erythema, and desquamation of the skin begins as fine scaling with eventual peeling of the palms and soles.

Sennetsu fever  a febrile disease seen in Japan and Malaysia and caused by Ehrlichia sennetsu, characterized by headache, nausea, lymphocytosis, and lymphadenopathy.

septic fever  fever due to septicemia.

South African tickbite fever  boutonneuse f.

trench fever  a louse-borne rickettsial disease due to Bartonella quintana, transmitted by the body louse, Pediculus humanus corporis, and characterized by intermittent fever, generalized aches and pains, particularly severe in the shins, chills, sweating, vertigo, malaise, typhus-like rash, and multiple relapses.

typhoid fever  infection by Salmonella typhi chiefly involving the lymphoid follicles of the ileum, with chills, fever, headache, cough, prostration, abdominal distention, splenomegaly, and a maculopapular rash; perforation of the bowel may occur in untreated cases.

fever of unknown origin  (FUO) a febrile illness of at least three weeks' duration (some authorities permit a shorter duration), with a temperature of at least 38.3°C on at least three occasions and failure to establish a diagnosis in spite of intensive inpatient or outpatient evaluation (three outpatient visits or three days' hospitalization).

West Nile fever  see under encephalitis.

yellow fever  an acute, infectious, mosquito-borne viral disease, endemic primarily in tropical South America and Africa, marked by fever, jaundice due to necrosis of the liver, and albuminuria.

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familial Mediterranean fever

n.

See familial paroxysmal polyserositis.

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familial Mediterranean fever,

an autosomal-recessive intestinal disorder usually occurring in people of Mediterranean descent, characterized by short recurrent attacks of fever with pain in the abdomen, chest, or joints and erythema resembling that seen in erysipelas. It is sometimes complicated by secondary amyloidosis. The age of onset is usually between 5 and 15 years. Also called benign paroxysmal peritonitis, familial recurrent polyserositis, periodic peritonitis, periodic polyserositis, recurrent polyserositis.

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familial Mediterranean fever

Familial paroxysmal polyserositis An AR disease affecting eastern Mediterranean rim Jews, Armenian and Sephardic–the latter comprise¹⁄₂ of cases–and Arabs, Greeks, Turks, and other 'rim' inhabitants, causing episodic serosal–especially peritoneal–inflammation, more common in ♂ Clinical Onset by adolescence–recurring peritonitis, arthritis, pleuritis, diffuse abdominal pain due to serositis, episodic fever, amyloidosis, muscle 'guarding', leukocytosis, malabsorption that resolve within 24 hrs Prognosis Good in absence of renal amyloidosis, which causes terminal nephropathy, an event prevented by colchicine. Cf MEFV.

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Patient discussion about Wolff Periodic disease.

Q. Can Familial Mediterranean Fever (FMF) cause a heart enlargement? A friend of mine is suffering from FMF. its usually doesn't bother him that much and when it dose the symptoms are stomach ache and fever. he has no heart symptoms and takes no medications. his physician told him that because of the FMF he might suffer from a heart enlargement, and that he should take some oral medications daily to prevent it. how can it be?

A. This question can't be answered with a strict yes or no.
although FMF on its own can't cause heart enlargement, FMF can cause amyloidosis because of the recurrent inflammation. this may lead to enlargement of the heart which is a severe disease.
the good side is that taking medication can decrease the chance of the cardiac enlargement.