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.

• Splenomegaly

  Her main symptoms of FMF at this stage were swelling of her left elbow, splenomegaly, and diarrhea. [bloodjournal.org]

  Splenomegaly is a common complication of amyloidosis; other organs are rarely involved. Amyloidosis is mostly prevalent among Sephardic Jews. Symptoms of an acute attack appear suddenly and last from a few hours up to 96 hours. [accessanesthesiology.mhmedical.com]

  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. [symptoma.com]

  Febrile episodes which are accompanied by peritonitis, pleuritis, synovitis, splenomegaly, hepatomegaly, myalgia, erysipelas-like erythema, protracted febrile myalgia, and seizures are clinical features of FMF [2]. [hindawi.com]

  […] of 1-2 large joints, most commonly ankles, knees or wrists chronic destructive arthritis migratory polyarthritis Skin rashes affect 40% various presentations (see below) Scrotal pain (orchitis) affects 5% especially young children Spleen enlargement (splenomegaly [dermnetnz.org]

• Fever

  Overview Familial Mediterranean fever is a genetic autoinflammatory disorder that causes recurrent fevers and painful inflammation of your abdomen, lungs and joints. [mayoclinic.org]

  Familial Mediterranean fever is a hereditary autoinflammatory disease, mainly characterized by periodic fever and serositis. [ncbi.nlm.nih.gov]

  Familial Mediterranean fever is an inherited condition characterized by recurrent episodes of painful inflammation in the abdomen, chest, or joints. These episodes are often accompanied by fever and sometimes a rash or headache. [ghr.nlm.nih.gov]

• Amyloidosis

  However, homozygosis for SAA1 α/α polymorphism was associated with proteinuria and amyloidosis whereas carrying the β/β polymorphism was found to be protective for amyloidosis. [ncbi.nlm.nih.gov]

• Turkish

  History Meanings of "familial mediterranean fever" in Turkish English Dictionary : 1 result(s) Category English Turkish Medical 1 Medical familial mediterranean fever ailevi akdeniz ateşi Meanings of "familial mediterranean fever" with other terms in [tureng.com]

  Based on these observations, the ACE I/D variant D/D genotypes implicate a possible risk in the FMF-related amyloidosis among Turkish population. [ncbi.nlm.nih.gov]

  The mortality rate among Turkish patients was high, but this high rate may have represented selection bias. No pre–colchicine-therapy data are available from Arabic patients. [emedicine.com]

• High Fever

  Familial Mediterranean Fever (FMF) is a genetic disorder passed down from parents to children. The disease causes high fevers and bouts of inflammation. [babymed.com]

  These episodes occurred monthly along with a high fever and elevation of the C-reactive protein (CRP) level. The patient became afebrile and his CRP level decreased following the administration of a non-steroidal anti-inflammatory drug. [ncbi.nlm.nih.gov]

• Chills

  Chilliness or a shaking chill may accompany the attacks. Involvement of the peritoneum is indicated by the subjective symptom of marked abdominal soreness and the objective finding of widespread, exquisite direct and rebound tenderness. [doi.org]

  Symptoms may include repeated episodes of: Abdominal pain Chest pain that is sharp and gets worse when taking a breath Fever or alternating chills and fever Joint pain Skin sores (lesions) that are red and swollen and range from 5 to 20 cm in diameter [nlm.nih.gov]

  Symptoms may include repeated episoders of: Abdominal pain Chest pain that is sharp and gets worse when taking a breath Fever or alternating chills and fever joint pain Skin lesions that are red and swollen and range from 5 - 20 cm in diameter Signs and [web.archive.org]

  Patients may present with: High fever Joint inflammation and pain Chills Chest pain when breathing Pain in the abdomen Skin lesions It is not uncommon for the condition to go unnoticed until children reach 15 years of age. [babymed.com]

• Pleuritic Pain

  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. [symptoma.com]

  The peritoneal inflammation causes an abdominal pain that is initially localized and becomes generalized to resolve in 12 to 48 h. Pleuritis or pericarditis can cause chest pain. Pleuritic pain is unilateral, and lasts 12 to 48 h [10]. [ojrd.biomedcentral.com]

• Tachypnea

  Other symptoms include chest pain secondary to pleuritis (in 45%), fever, tachypnea, usually unilaterally decreased breath sounds, and pleural friction rub. A mono- or oligo- articular arthritis involving hip, knee or ankle is seen in 75%. [clinicaladvisor.com]

• Abdominal Pain

  Chronic abdominal pain sometimes constitute a major challenge, specially when a patient has two diseases with dominant features of abdominal pain in both. [ncbi.nlm.nih.gov]

  A 49-year-old man of Turkish origin came to our outpatient clinic with isolated, persistent abdominal pain. He had a 10-year history of abdominal pain in the form of continuous shooting pain in left upper quadrant. [reumatologiaclinica.org]

• Diarrhea

  A 30-year-old Japanese man presented to us with a few years' history of recurrent episodes of fever, abdominal pain and diarrhea. [ncbi.nlm.nih.gov]

  On admission, there was no fever, and the abdominal pain and diarrhea had resolved. [bmcresnotes.biomedcentral.com]

• Vomiting

  After this period, she was hospitalized 3 times during a 4-month period with fever, nausea, vomiting, and atypical abdominal pain. [ncbi.nlm.nih.gov]

  Case A 3-month-old girl was brought to the pediatric rheumatology unit for the complaints of recurrent fever and episodes of vomiting. [hindawi.com]

  The eyes often appear as bulging and children often have episodes of vomiting. The skull is slightly increased in size. [my.clevelandclinic.org]

  Overuse of the drug can result in severe toxicity with symptoms of nausea, vomiting, diarrhea, and abdominal pain. Colcrys cannot be used in persons with kidney dysfunction. [verywellhealth.com]

  Questioning of the patient's caregiver revealed that with the swelling and discomfort, the patient developed a flulike illness consisting of fever, diaphoresis, abdominal pain, and frequent vomiting. [jamanetwork.com]

• Nausea

  After this period, she was hospitalized 3 times during a 4-month period with fever, nausea, vomiting, and atypical abdominal pain. [ncbi.nlm.nih.gov]

  Overuse of the drug can result in severe toxicity with symptoms of nausea, vomiting, diarrhea, and abdominal pain. Colcrys cannot be used in persons with kidney dysfunction. [verywellhealth.com]

  Mild symptoms (myalgia, headache, nausea, dyspnea, arthralgia, low back pain, asthenia and anxiety) precede attacks and last about 17 hours. [orpha.net]

  Case Report In October 2013, a 54-year-old Japanese man was admitted to our hospital for evaluation of periodic fever, nausea, vomiting, abdominal pain, watery diarrhea, and renal dysfunction. [karger.com]

• Acute Abdomen

  Pregnant patients with acute abdomen should be evaluated with open mind. To the best of our knowledge, this is the first published report of the coexistence of 2 different causes of acute abdomen during pregnancy. [ncbi.nlm.nih.gov]

  Treatment and prognosis Colchicine is the primary therapy and in the pre-colchicine era, the prognosis was very poor familial Mediterranean fever is in the differential for an acute abdomen, and occasionally surgery is erroneously performed because of [radiopaedia.org]

  The severe abdominal pain in FMF may be confused with an acute abdomen due to appendicitis or other acute surgical pathologies. [rheumatologyadvisor.com]

  Attacks manifest as fever (38°C-40°C lasting 12-72 hours and not responding to antibiotics), diffuse or localized abdominal pain (often mimicking acute abdomen), constipation (diarrhea in children), arthralgias (in large joints), arthritis (in upper/lower [orpha.net]

• Chest Pain

  Patients with P369S have higher abdominal pain, chest pain and fever than expected. Arthritis was high in K695R heterozygous genotype. One hundred and eighteen patients were carrying more than one polymorphic allele. [ncbi.nlm.nih.gov]

  Less common symptoms include Chest pain: About 30% of affected people have chest pain. [merckmanuals.com]

• Arthritis

  Both FMF and rheumatoid arthritis (RA) involve arthritis; however, their coexistence is rare. We describe two RA patients with an MEFV mutation in exon 2, who were diagnosed with FMF at an age of over 50 years. [ncbi.nlm.nih.gov]

  Chronic arthritis: Approximately 5% of patients with FMF develop chronic arthritis that sometimes leads to destructive arthritis of hips or knees and may necessitate joint replacements. [emedicine.com]

• Arthralgia

  He had frequent and severe arthralgias, despite colchicine, then etanercept and adalimumab, impairing his quality of life. [ncbi.nlm.nih.gov]

• Calf Pain

  Non-canonical manifestations of FMF are increasingly recognized in recent years, such as calf pain, vasculitides and neurological disease. Herein, we describe unifocal osteitis in an FMF patient who responded well to anakinra. [academic.oup.com]

• Knee Pain

  Specific respiratory and neurologic signs or symptoms were not noted, but the patient complained of right hip and right knee pain, which could not be explained with objective findings. [jamanetwork.com]

• Ankle Arthritis

  […] children Typical ankle arthritis and rash in an FMF attack The pain may be so severe that the first attack is thought to be appendicitis. [amyloidosis.org.uk]

• Skin Rash

  A 54-year-old SLE patient with recurrent attacks of fever, arthritis, and skin rashes was referred to our hospital. She had been diagnosed with lupus nephritis at 19 years old. [ncbi.nlm.nih.gov]

  Skin rash that can cover most of the body. Behçet’s Disease can cause the following symptoms: Mouth or genital sores. Redness and swelling in the eyes. Arthritis. Skin problems. Swelling of the digestive system, brain, and spinal cord. [niams.nih.gov]

  These episodes may be accompanied by a skin rash or joint pain. In a few cases, chronic arthritis is a problem. [medical-dictionary.thefreedictionary.com]

  Other symptoms include arthritis, chest pain from inflammation of the lung cavity, and skin rashes. Between attacks, the patient seems healthy. [medicinenet.com]

• Purpura

  Although various skin lesions such as "erysipelas-like erythema", urticaria, nonspecific purpura, and subcutaneous nodules have been described, cutaneous vasculitis is rare. [ncbi.nlm.nih.gov]

  Vasculitis - the following are more common in those with FMF: Henoch-Schönlein purpura [ 9 ] Polyarteritis nodosa [ 10 ] Behçet's disease Not all of the above features may be present during an attack. [patient.info]

  Leukocytoclastic vasculitis is seen on biopsies from Henoch-Schönlein purpura or polyarteritis nodosa-like lesions. Investigations for myalgia (muscle pain) reveal normal muscle enzymes, electromyography (EMG) and muscle biopsy. [dermnetnz.org]

• Skin Lesion

  It may present with bilateral hilar lymphadenopathy, skin lesions, the involvement of eye and symptoms on the locomotor system. [ncbi.nlm.nih.gov]

  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. [symptoma.com]

  Symptoms may include repeated episoders of: Abdominal pain Chest pain that is sharp and gets worse when taking a breath Fever or alternating chills and fever joint pain Skin lesions that are red and swollen and range from 5 - 20 cm in diameter Signs and [web.archive.org]

• Urticaria

  Although various skin lesions such as "erysipelas-like erythema", urticaria, nonspecific purpura, and subcutaneous nodules have been described, cutaneous vasculitis is rare. [ncbi.nlm.nih.gov]

  [Crossref] Lipsker D (2013) Neutrophilic urticaria with systemic inflammation identical to neutrophilic urticarial dermatosis. JAMA Dermatol 149: 1244-1245. [oatext.com]

  There are also other reports of urticaria, purpura, angioneurotic edema, Raynaud’s phenomenon, pyoderma gangrenosum, and subcutaneous nodules. [dermatologyadvisor.com]

  The rash resembles urticaria (hives), but is not itchy. The rash increases in intensity with fever. Patients have neurologic problems from chronic meningitis (inflammation of the membranes surrounding the brain). [my.clevelandclinic.org]

• Kidney Failure

  Regarding the presence of back pain, anemia, hypercalcemia, and kidney failure, a diagnosis of MM was suspected. A skeletal survey showed punched-out lesions in the skull. [ncbi.nlm.nih.gov]

  In amyloidosis, an unusually shaped protein called amyloid is deposited in the kidneys and in many organs and tissues, impairing their function. Amyloid deposits may damage the kidneys, eventually resulting in kidney failure. [merckmanuals.com]

• Hematuria

  Bladder amyloidosis should be considered in patients with macroscopic hematuria, particularly in the kidney transplant recipients with idiopathic chronic renal disease. [ncbi.nlm.nih.gov]

  He denied complaints of dysuria, polyuria, hematuria, or any discoloration of his urine. The remainder of the review of systems was unremarkable. [bmcnephrol.biomedcentral.com]

  The presence of the protein albumin in the urine can be a symptom of kidney disease, along with microscopic hematuria (very small - microscopic - amounts of blood or blood cells in the urine), during attacks. [genome.gov]

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.