Familial Mediterranean Fever (FMF)

Updated October 14, 2019

This article was scientifically reviewed by YourDNA

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What is Familial Mediterranean Fever?

Familial Mediterranean fever (FMF) is an inherited condition that results in recurring episodes of painful inflammation in the abdomen, chest, pelvis, muscles or joints.

Inflammation may also take place in other parts of the body such as the heart, the membrane surrounding the brain and spinal cord.

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About half of all attacks are preceded by a “prodrome” which are mild signs and symptoms characterized by uncomfortable sensations in those areas that will later become inflamed or an overall general discomfort.

Males may also experience inflammation in their testicles. Some episodes will also include a fever, rash or headaches.

A first episode usually takes place during childhood or as a teenager. However, in a few cases, the first episode can take place much later in life.

Attacks can last anywhere from 12 to 72 hours and will vary in severity. Attacks can happen days apart from each other or the length of time can be as much as several years.

In between attacks, those affected by Familial Mediterranean fever will have no outward signs or symptoms.

But without treatment to help prevent attacks and complications, protein deposits can build up in the body’s organs, especially in the kidneys.

This protein buildup is called amyloidosis and can lead to kidney failure.

FMF is usually inherited in an autosomal recessive manner, and is caused by mutations in the MEFV gene.

Symptoms can be controlled, often through the use of a medication called colchicine. Colchicine is also used to prevent gout which is a sudden and severe pain that takes place in one or more joints due to abnormally high levels of uric acid in the blood.

Other names for Familial Mediterranean fever include:

  • Periodic peritonitis
  • Recurrent polyserositis
  • Benign paroxysmal peritonitis
  • Familial paroxysmal polyserositis
  • MEF
  • Reimann periodic disease
  • Siegal-Cattan-Mamou disease
  • Wolff periodic disease

Henoch-schonlein purpura (HSP) is a condition closely related to FMF.

It is most common in children, especially boys, and is characterized by the inflammation of small blood vessels in the skin, joints, intestines and kidneys. This inflammation causes leaking.

HSP results in a skin rash with several small bruises that have a raised appearance over the buttocks or legs.

The condition usually ends after four to six weeks but there are no long-term consequences unless the kidneys and intestines are affected.

When this happens, additional treatment is often required along with regular monitoring to prevent more serious complications.

FMF primarily affects populations originating in the Mediterranean region.

It is especially prevalent in people who are descended from Armenian, Arab, Turkish, or Jewish ancestry. It affects 1 in 200 to 1,000 people in these populations but is less common in others.

Causes of Familial Mediterranean Fever

Familial Mediterranean fever is an inherited condition. It occurs when a mutated MEFV gene is passed from one generation to the next in an autosomal recessive manner.

To be affected, a person must have a mutation in both copies of the gene in each cell. The parents of an FMF-affected person usually each carry one mutated copy of the gene.

They are known as carriers and typically do not show signs or symptoms of FMF.

The MEFV gene gives instructions to make pyrin (sometimes referred to as marenostrin), a protein thought to assist in keeping inflammation under control.

Inflammation takes place when the immune system sends signaling molecules and white blood cells to places where an injury or disease is located in the body.

These function to repair tissues and fight microbial invaders. When these missions are accomplished, the body stops an inflammatory response to prevent damage to healthy cells and tissues.

Pyrin is produced in certain while blood cells that fight infection and control inflammation.

Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight microbial invaders and facilitate tissue repair 1.

When this has been accomplished, the body stops the inflammatory response to prevent damage to its own cells and tissues.

Pyrin is thought to direct the migration of white blood cells to inflamed sites and to stop or slow the inflammatory response when it is no longer needed.

When MEFV gene does not produce pyrin the right way or in sufficient quantities, FMF can be the result.

There are more than 300 MEFV gene mutations have been identified but only four that are clearly pathogenic.

A few delete small amounts of DNA from the MEFV gene, but most MEFV mutations change one of the amino acids used to make pyrin.

The most common mutation replaces the amino acid methionine with the amino acid valine.

This particular mutation is associated with an increased risk of developing amyloidosis, a complication resulting in abnormal protein deposits that can lead to kidney failure.

When pyrin is not produced in sufficient quantities or becomes a malformed pyrin protein, pyrin cannot perform its role in controlling inflammation, leading to FMF.

The Genetic Pattern of Inheritance of Familial Mediterranean Fever

FMF is almost always inherited in an autosomal recessive pattern. To be affected, a person must have both copies of a mutated gene in each cell.

Parents of a person affected with FMF usually only carry one copy of the gene each and are referred to as carriers.

Carriers generally do not show any signs or symptoms of FMF.

Children of carriers of an autosomal recessive condition such as FMF will have the following probabilities of manifesting the disease:

  1. 25% chance to have the condition
  2. 50% chance to be a carrier like each of the parents
  3. 25% chance to not have the condition and not be a carrier

In some rare cases, FMF may be inherited in an autosomal dominant pattern. This means a person only needs to have one copy of the mutated gene in each cell.

In an autosomal dominant condition, a person may inherit the mutated gene from an affected parent.

But there are cases that may occur as a result of new mutations of the gene. This is known as a de novo mutation.

A person with autosomal dominant FMF has a 50% chance of passing the mutated gene to each of their children.

There are a few cases where FMF appears to be autosomal dominant but it is actually autosomal recessive.

This is called pseudodominance and happens when a gene mutation occurs frequently in a population.

As a result, a disorder with autosomal recessive inheritance such as FMF can appear in multiple generations in a family, a pattern that mimics autosomal dominant inheritance.

For example, pseudodominance can appear frequently in people of non-Ashkenazi Sephardic Jewish, Armenian, Greek, Italian, Arab and Turkish heritage where as many as 1 in 5 people are carriers.

Who Gets Familial Mediterranean Fever?

Anyone can be stricken with FMF, but it appears more frequently in people of Mediterranean descent.

As many as 1 in 5 people of non-Ashkenazi Sephardic Jewish, Armenian, Greek, Italian, Arab and Turkish heritage are carriers of the mutated gene.

FMF manifests in one out of 200 to 1,000 people in these populations but is less common in others.

People with a family history of FMF are also at an increased risk of the disease as well.

Signs & Symptoms of Familial Mediterranean Fever

The main signs and symptoms of FMF are recurring fever and abdominal, chest and joint pain. Severe abdominal pain may appear to be appendicitis, and some patients may undergo surgery to remove the appendix.

Chest pain may be so severe that it is difficult to breathe deeply 2. Joints are normally only affected one at a time, and most commonly in the ankle or the knee.

Joint pain may also be so intense that a patient may not be able to walk until the attack subsides.

Some patients develop a red rash on their lower extremities, usually near the ankles and feet.

Skin lesions that are red and swollen and range from 5 to 20 cm in diameter may also develop as well.

They may be warm or hot to the touch and most often occur between the ankle and the knee 3.

Joint pain and swelling is sometimes misdiagnosed as acute rheumatic fever or juvenile idiopathic arthritis 4.

In a few cases, children may have recurrent pericarditis (inflammation of the outer layer of the heart), myositis (muscle inflammation), meningitis (inflammation of the membrane surrounding the brain and spinal cord), or orchitis (testicular inflammation) 5.

Symptoms usually peak in 12 to 24 hours and attacks may vary in severity of symptoms.

There have only been limited studies as to what triggers FMF attacks. Based on available information it is believed that physical stresses such as cold exposure, tiredness and emotional stresses, menstral cycles could provoke attacks.

Studies also indicate that having the alpha version of the serum amyloid A1 protein will increase the chances of developing amyloidosis.

Studies indicate that people with the alpha version of the protein are two to seven times more likely to develop amyloidosis than are people with the beta or gamma version.

Diagnosis of Familial Mediterranean Fever

Several tests and observations are used to diagnose FMF. These include clinical evaluations, genetic testing, a detailed patient history and the identification of symptoms associated with the disease.

About 30% of all patients do not have mutations in both genes, so a diagnosis of FMF must also be combined with symptoms and an examination.

Under these circumstances, an accurate diagnosis can be difficult to make.

Making an accurate diagnosis as quickly as possible is critical to avoid unnecessary surgery which sometimes happens when children are misdiagnosed with appendicitis.

Patients already experiencing episodic fever and who have an ethnic background with a higher incidence of FMF may be given colchicine for three to six months to see if the episodes of fever and pain are less frequent or severe.

This may help substantiate a diagnosis of FMF.

A suspected diagnosis of FMF can be confirmed by genetic testing. This will identify MEFV gene mutations that cause the disease.

The following specific tests can also be helpful to make a diagnosis of FMF:

  • Elevated white blood cell count, an indication of an immune response.
  • Elevated erythrocyte sedimentation rate (ESR), an indication of an inflammatory response.
  • Elevated plasma fibrinogen, which helps stop bleeding.
  • Elevated serum haptoglobin, indicating that red blood cells are being destroyed, a common occurrence in rheumatic diseases, such as FMF.
  • Elevated C-reactive protein, a special type of protein produced by the liver only present during episodes of acute inflammation.
  • Elevated albumin in the urine, which can be a symptom of kidney disease, along with microscopic hematuria (microscopic amounts of blood in the urine).

These tests are only effective during an episode of FMF. Levels return to normal or near normal when an episode ends.

If genetic testing shows the MEFV gene mutation is present and symptoms match the typical pattern, the diagnosis of FMF is nearly certain.

Laboratory tests or x-rays can rule out other possible differential diseases to help make the diagnosis.

Treatments and Care Options for Familial Mediterranean Fever

There is no cure for FMF, but medications can be used to control symptoms. The most common of these is colchicine.

It reduces inflammation, may ease length of an attack, and also help to prevent future attacks.

Colchicine also helps to prevent the serious complication of amyloidosis.

When an FMF attack takes place, the body can produce an abnormal protein called amyloid A. It builds up in the body and can lead to organ damage which is called amyloidosis.

Colchicine can prevent the development of renal amyloidosis. Early stage renal amyloidosis is reversible.

Some individuals with FMF and amyloidosis eventually develop end stage renal disease (ESRD), ultimately requiring a kidney transplant 6.

To be effective, colchicine must be taken orally one or two times daily. FMF episodes may return even after missing only one dose.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and pain medications (analgesics) may be used to treat fever and pain.

NSAIDs can also be used to treat joint and muscle pain when colchicine is not effective.

Some investigational treatment therapies are also being investigated for those who do not respond well to colchicine.

For information about trials being conducted at the NIH Clinical Center in Bethesda, MD, the Recruitment Office at (800) 411-1222 or by email at [email protected]

Complications Associated with Familial Mediterranean Fever

There are several possible complications that can arise with FMF if it is not treated. These complications can include:

A build-up of protein in the blood. During an FMF attack, the body may produce an abnormal protein called amyloid A.

It can accumulate in your body and cause organ damage called amyloidosis.

Kidney damage. Amyloidosis damages the kidneys. This, in turn, cause nephrotic syndrome, a condition that occurs when the kidneys’ filtering systems are damaged.

Nephrotic syndrome cause people to lose large amount of protein in their urine, leading to blood clots in kidneys (renal vein thrombosis) or kidney failure.

Periodic fever.  This usually occurs along with canker sores in the mouth (aphthous stomatitis), a sore, reddened throat (pharyngitis) and inflammation of glands in the neck (cervical adenitis).

Female infertility. FMF causes inflammation that can affect the female reproductive organs.

Joint pain. Arthritis is common for people with FMF. It tends to affect knees, ankles, hips and elbows with the most frequency.

Chronic inflammation disorders. Chronic inflammation from FMF can also produce associated disorders, including:

  1. cryopyrin-associated periodic syndromes (familial cold autoinflammatory syndrome, Muckle-Wells syndrome and NOMID/CINCA)
  2. mevalonate kinase deficiency (MKD)
  3. TNF receptor-associated periodic syndrome (TRAPS)
  4. Inflammation of the blood vessels (vasculitides), including Bechet’s disease and polyarteritis nodosa.

Colchicine reactions. People who take colchicine can also suffer from the common side effects of abdominal pain and diarrhea.

When this happens, dosing is decreased and slowly increased back to a desired level as the body learns to tolerate the drug.

Reducing milk and dairy product intake or switching to lactose-free milk may also help alleviate discomfort.

In rare cases, colchicine may cause muscle weakness, especially when taking antibiotics from the erythromycin family or statins (cholesterol medications).

Female patients who are pregnant or breast feeding do not need to stop taking colchicine. Children treated with colchicine should have bi-annual blood and urine tests.

Affected individuals are also at greater risk of developing ulcerative colitis, Crohn’s disease and rheumatoid arthritis.

About ten percent of patients do not respond well to colchicine. Medications such as rilonacept (Arcalyst), anakinra (Kineret), and canakinumab (Ilaris) can be used to block interleukin-1.

This is an important protein involved in the inflammatory process, is effective for the majority of these patients.

The Prognosis of Familial Mediterranean Fever

If left untreated FMF can be fatal. However, patients who are compliant with a regimen of colchicine and other treatments as prescribed by their doctors can expect to have a normal lifespan.

Even if a patient develops amyloidosis, using colchicine, and combining it with kidney dialysis and a kidney transplant can extend a person’s life to 50 years or more.

What to do Next: Living with Familial Mediterranean Fever

Children faced with recurring episodes of FMF and the need to take medications for the entire lives may need psychological support to help them cope with the disease.

Frequent episodes can have a dramatic impact on all members of the affected family and can spill over into all parts of a family’s life.

This can include school, athletics, and other extracurricular activities in a child’s life.

As a result, the active involvement of teachers, medical professionals, tutors, social workers, siblings and parents is part of a comprehensive support system.

When FMF is well controlled, the impacts on those who suffer from the disease can be minimal and allow for a normal and productive life to move forward.

Research into FMF continues, and it is important to stay abreast of developments and advancements of this condition.

For more information on research and patient advocacy, consider contacting these resources for assistance:

Autoinflammatory Alliance
P.O. Box 590354
San Francisco, CA 94118
Phone: (415) 831-8782
Email: [email protected]
Website: http://autoinflammatory.org

Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Phone: (301) 251-4925
Toll-free: (888) 205-2311
Website: http://rarediseases.info.nih.gov/GARD/

NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases
Information Clearinghouse
One AMS Circle
Bethesda, MD 20892-3675 USA
Phone: (301) 495-4484
Toll-free: (877) 226-4267
Email: [email protected]
Website: http://www.niams.nih.gov/

International Society for Systemic Auto-Inflammatory Diseases
Website: http://fmf.igh.cnrs.fr/ISSAID/

Orphanet: Familial Mediterranean fever

The Norton & Elaine Sarnoff Center for Jewish Genetics

National Human Genome Research Institute

National Institute of Diabetes and Digestive and Kidney Diseases: Amyloidosis and Kidney Disease

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Referenced Sources

  1. NLRP3 gene.
    Genetics Home Reference. Reviewed: September 2008, Published: September 10, 2019.
  2. Familial Mediterranean Fever.
    American College of Rheumatology. Jonathoan Hausmann, MD. Reviewed by the American College of Rheumatology Committee on Communications and Marketing. Updated May 2019.
  3. Familial Mediterranean Fever.
    National Organization for Rare Disorders. Retrieved online, September 2019.
  4. Familial Mediterranean Fever.
    American College of Rheumatology. Jonathoan Hausmann, MD. Reviewed by the American College of Rheumatology Committee on Communications and Marketing. Updated May 2019.
  5. Familial Mediterranean Fever.
    American College of Rheumatology. Jonathoan Hausmann, MD. Reviewed by the American College of Rheumatology Committee on Communications and Marketing. Updated May 2019.
  6. Familial Mediterranean Fever.
    National Organization for Rare Disorders. Retrieved online, September 2019.