The typical symptoms of the disease are recurrent attacks severe pain (due to serositis at one or more sites) and fever that last 1 to 3 days and resolves spontaneously.

The frequency of attacks varies by patient and there are usually no triggering events. Although some patients have reported vigorous exercise, exposure to cold, emotional stress and/or menstruation as triggers.

The classic presentation of the disease is sudden onset of the following:

• Fever: Temperature rises rapidly to 100.4 to 104 F. In most cases the fever precedes the other symptoms.

• Peritoneal symptoms: Almost all (95%) of patients with FMF experience painful attacks localized to the abdomen. Pain and tenderness are initially localized and then progress to become generalized. Abdominal guarding, rebound tenderness, rigidity, and an ileus are often present. (These findings closely resemble those of an acute surgical abdomen. These patients may undergo an exploratory laparotomy, during which an uninflamed appendix is removed). Recurrent attacks of peritonitis may cause adhesions that result in bowel obstruction and reduction of fertility in females.

• Pleural and pericardial symptoms: Direct inflammation of pleura, pericardium or referred pain from the diaphragmatic inflammation may onset without any triggering event. It is similar to pleuritic pain. On imaging, a small transient effusion is often seen. These episodes usually resolve within 3 to 7 days.

• Synovitis: The joint pain, arthritic like in nature is usually monoarticular or oligoarticular; joints most often affected are the knee, ankle, hip and elbow (in order of frequency). Small synovial effusions are common during attacks. Fluid analysis reveals 200 to 1 million WBCs with a predominance of neutrophils and elevated total protein concentration. The arthritis may last for weeks to months. The synovitis usually resolves without joint destruction.

• Erysipelas-like skin lesions: They have been reported in up to 40% of FMF patients. The lesion is tender, raised and red (mimicking acute cellulitis) occurring unilaterally on the lower leg, ankle or foot. Recovery occurs in days and is spontaneous.

Other less common manifestations include – pericarditis, orchitis, recurrent aseptic meningitis, febrile bouts of myalgia that may last up to a month, increased incidence of vasculitis such as polyarthritis nodosa and Henoch-Schonlein purpura.

The clinical diagnosis of FMF is based upon both the characteristic clinical features and the exclusion of other illnesses. Major criteria for the clinical diagnosis of FMF are [2]:

• Intermittent episodes of fever with good, uncomplicated intermittent health
• Concomitant serositis with abdominal pain and tenderness
• Absence of an alternative cause
• Responsiveness to colchicine
• Monoarthritis

Laboratory tests

Acute attacks of FMF are accompanied by elevated serum markers of systemic inflammation. Leukocytosis with a predominance of neutrophils is common as is elevation of sed rate and other acute phase reactants (such as C-reactive protein, erythrocyte sedimentation rate (ESR), serum amyloid protein (SAA) and fibrinogen).

Exclusion of differential diagnosis is also helpful in the diagnosis process. Exclusion of disease processes that resemble FMF must be excluded before making the clinical diagnosis of FMF. These include: surgical emergencies (appendicitis, intussception, perforated ulcer), hereditary angioedema, acute intermittent porphyria, relapsing pancreatitis, systemic lupus erythematosus and vasculitis, hypertriglyceridemia, epilepsy and abdominal migraines.

Genetic testing is now available for FMF [3].
Symptomatic patients with at least one MEFV mutation should be considered as having FMF.

Patients who show no mutation of MEFV but are symptomatic should be offered a trial of colchicine to aid in diagnosis. Response to colchicine should indicate a diagnosis of FMF in these groups of patients.

Colchicine is used to treat FMF. It reduces or eliminates FMF attacks and prevents the development of amyloidosis. Anti-inflammatory medications may be given during an attack. 

The goals of therapy and the prognosis is dependent on prevention of symptoms. Long term complications include progressive secondary amyloidosis, with depositions in the kidney, spleen liver and gut most commonly.

With the use of colchicine for diagnosis and treatment, the incidence of amyloidosis has significantly decreased [4].

FMF is an inherited autosomal recessive disorder. The MEVF gene is located on the short arm of chromosome 16 and exhibits missense and nonsense mutations at one of three sites on exon 10 of the gene.

Some studies suggest that certain phenotypic expressions, such as of M694V/M694V homozygous, are more likely to have involvement of arthritis, renal amyloidosis, erysipelas-like skin lesions, oral lesions, higher fever, and splenomegaly.

Patients with these mutations require higher doses of cholchine to prevent attacks than patients with mutations in other genes.

FMF is most prevalent in patients in persons of Mediterranean ethnicity [1]:

• Sephardic Jewish – prevalence 1 case/250-1000 population; gene frequency of 1/8-16
• Ashkenazi Jewish – prevalence: 1 case/73,000 population; gene frequency 1/5
• Armanian – prevalence: 1 case/500 population
• Arabic persons – prevalence 1 case/2600 population in children; gene frequency 1/50.

Gender: FMF is more prevalent in adult men than in adult women (male to female ratio is 1.5:2.1).

Age of onset differs: < 10 years old (50-60%), < 20 years old: (80-95%) and 20 to 40 years old ( -10%). Onset in persons older than 40 years is rare.

The MEFV gene encodes a large amino acid protein that is expressed mainly in the cytoplasm in cells of myloid lineage along with synovial fibroblasts and dendritic cells.

It is responsible for the production of a protein called pyrin, which acts as an intranuclear regulator of transcription of the peptides involved in inflammation.

Pyrin is expressed mostly in neutrophils and plays a key role in the innate immune system by defending the body against external pathogens and noxious agents. It triggers the release of IL-1 which regulates apoptosis. Mutations in this gene render it unable to perform these protective functions.

There are no guidelines for prevention of FMF.

Familial Mediterranean Fever (FMF), also called polyserositis, is in inflammatory disorder characterized by recurrent paroxysmal attacks of fever and serosal inflammation that includes peritonitis, pleuritis and arthritis that last for one to three days and then spontaneously abate.

It is an autosomal recessive disorder that is most commonly seen in persons of Mediterranean ethnicity.

Familial Mediterranean fever is an inflammatory disorder that causes recurrent bouts of fevers and painful inflammation of your abdomen, lungs and joints. It is an inherited disorder that occurs mainly in persons from the Mediterranean area (including Sephardic Jews, Arabs, Italians, Armenians and Turks).

Persons of other ethnicities may also have the disease. There is no cure for this disorder however you can do things to prevent and alleviate your symptoms.

What are the symptoms of FMF?

The symptoms usually start in childhood. The symptoms are painful attacks and usually last one to three days, and then completely stop.

• Fever
• Abdominal pain
• Chest pain
• Achy, swollen joints
• Muscle aches
• Skin lesions, redness, cellulitis

What causes this disorder?

FMF is caused by a defective gene (gene mutation) that is passed from parents to children. The gene mutation occurs in a gene called MEFV. The degree and type of symptoms you experience are based on the part of the gene that is affected. It is an autosomal recessive trait, meaning that both parents must have the mutated gene in order for their child to develop the disease.

How is it diagnosed?

Tests that are used to diagnose MFM include:

• Physical exam – your doctor will ask you about your symptoms and examine you

• Review of your family history – your doctor will ask you about any illness that your family members have had, in particular your first degree relatives (mother, father, brothers, and sisters).

• Blood tests – When you are experiencing an attack, certain inflammatory markers are elevated in your body. One such marker is the white blood cell count. During your attacks, your doctor may ask you to have lab work performed.

• Genetic testing is the definitive way to diagnose this disorder (although sometimes the test may be falsely negative). Genetic testing will allow scientists to evaluate your DNA, specifically the MEFV gene that contains the defect that causes this disease.

What are the treatments for this disease?

There is no cure for FMF at this time. However, there are treatments that can help prevent the symptoms. Medications that are commonly used to control symptoms are:

Colchicine - This drug is taken in pill form and reduces inflammation in your body and helps prevent attacks. Your doctor will determine the right dose for you based on your symptoms.

Anti-inflammatory medications may be given during an attack. There are currently some anti-inflammatory medications that are in testing now; you may be eligible to take these medications or enroll in a clinical trial. Ask your doctor about these newer medications.

Support groups may be helpful in reducing your anxiety and depression about the disease. You may also get information through others about ways to help reduce your symptoms through a support group. Even talking to a family member, friend or counselor can help.

1. Gershoni-Baruch R, Brik R, Shinawi M, Livneh A. The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever. Eur J Hum Genet. Feb 2002;10(2):145-9
2. Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever by a molecular genetics method. Ann Intern Med 1998; 129: 539.
3. Babior BM, Matzner Y. The familial Mediterranean fever gene—cloned at last. N Engl J Med 1997; 337:1548.
4. Tunca M, Akar S, Onen F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 2005; 84:1.