Familial Mediterranean fever

Title

Other Names:

Periodic peritonitis; Recurrent polyserositis; Benign paroxysmal peritonitis; Periodic peritonitis; Recurrent polyserositis; Benign paroxysmal peritonitis; Periodic disease; Familial paroxysmal polyserositis; Periodic fever; FMF See More

Categories:

Congenital and Genetic Diseases; Immune System Diseases; Kidney and Urinary Diseases; Congenital and Genetic Diseases; Immune System Diseases; Kidney and Urinary Diseases; Musculoskeletal Diseases See More

Summary Summary

Familial Mediterranean fever (FMF) is an inherited condition characterized by episodes of painful inflammation of the abdominal lining (peritonitis); the lining surrounding the lungs (pleurisy); and the joints (arthralgia and occasionally arthritis). These episodes are often accompanied by fever, and sometimes, a characteristic ankle rash.^[1] The first episode usually occurs during childhood or the teenage years. In some cases, the first episode occurs much later in life. Between episodes, people often do not have any symptoms. FMF usually is inherited in an autosomal recessive manner, caused by mutations in the MEFV gene.^[2] Treatment for FMF aims to control symptoms and often involves the use of a medication called colchicine. Without treatment, FMF can lead to kidney failure due to a buildup of certain protein deposits (amyloidosis).^[3]

Last updated: 12/8/2015

Symptoms Symptoms

Familial Mediterranean fever (FMF) is characterized by recurrent episodes of fever accompanied by pain in the abdomen, chest, joints, pelvis, and/or muscles. Episodes may also be associated with a skin rash or headache, and rarely, pericarditis and meningitis.^[2]^[4]^[5] Amyloidosis, which can lead to kidney failure, is the most severe complication which can occur if FMF is not treated. In some cases, amyloidosis is the first sign of the condition in a person who otherwise has no symptoms.^[5]

Episodes usually last for about one to three days, and the time between episodes can vary from days to years.^[1]^[4] The first episode usually occurs during childhood or the teenage years. In some cases, the first episode occurs much later in life.^[2] The majority of people with FMF experience their first episode by age 20.^[1] People tend to be symptom-free between episodes.^[4]

Last updated: 2/1/2017

The Human Phenotype Ontology (HPO) provides the following list of features that have been reported in people with this condition. Much of the information in the HPO comes from Orphanet, a European rare disease database. If available, the list includes a rough estimate of how common a feature is (its frequency). Frequencies are based on a specific study and may not be representative of all studies. You can use the MedlinePlus Medical Dictionary for definitions of the terms below.

Signs and Symptoms	Approximate number of patients (when available)
Arthralgia	Very frequent (present in 80%-99% of cases)
Constipation	Very frequent (present in 80%-99% of cases)
Fever	Very frequent (present in 80%-99% of cases)
Myalgia	Very frequent (present in 80%-99% of cases)
Nausea and vomiting	Very frequent (present in 80%-99% of cases)
Arthritis	Frequent (present in 30%-79% of cases)
Chest pain	Frequent (present in 30%-79% of cases)
Diarrhea	Frequent (present in 30%-79% of cases)
Erysipelas	Frequent (present in 30%-79% of cases)
Erythema	Frequent (present in 30%-79% of cases)
Oral leukoplakia	Frequent (present in 30%-79% of cases)
Pleuritis	Frequent (present in 30%-79% of cases)
Proteinuria	Frequent (present in 30%-79% of cases)
Seizures	Frequent (present in 30%-79% of cases)
Acute hepatic failure	Occasional (present in 5%-29% of cases)
Arrhythmia	Occasional (present in 5%-29% of cases)
Ascites	Occasional (present in 5%-29% of cases)
Edema of the lower limbs	Occasional (present in 5%-29% of cases)
Elevated erythrocyte sedimentation rate	Occasional (present in 5%-29% of cases)
Gastrointestinal infarctions	Occasional (present in 5%-29% of cases)
Intestinal obstruction	Occasional (present in 5%-29% of cases)
Lymphadenopathy	Occasional (present in 5%-29% of cases)
Malabsorption	Occasional (present in 5%-29% of cases)
Meningitis	Occasional (present in 5%-29% of cases)
Myocardial infarction	Occasional (present in 5%-29% of cases)
Nephrocalcinosis	Occasional (present in 5%-29% of cases)
Nephropathy	Occasional (present in 5%-29% of cases)
Nephrotic syndrome	Occasional (present in 5%-29% of cases)
Orchitis	Occasional (present in 5%-29% of cases)
Osteoarthritis	Occasional (present in 5%-29% of cases)
Pancreatitis	Occasional (present in 5%-29% of cases)
Pericarditis	Occasional (present in 5%-29% of cases)
Peritonitis	Occasional (present in 5%-29% of cases)
Skin rash	Occasional (present in 5%-29% of cases)
Splenomegaly	Occasional (present in 5%-29% of cases)
Vasculitis	Occasional (present in 5%-29% of cases)
Autosomal recessive inheritance	-
Episodic fever	-
Hepatomegaly	-
Leukocytosis	-
Renal amyloidosis	-
Renal insufficiency	-

Last updated: 9/1/2017

Cause Cause

Familial Mediterranean fever (FMF) usually is caused by changes in both copies of a person's MEFV gene. Changes in genes that are responsible for causing disease are also called pathogenic variants, or mutations.^[1]^[2]

Pathogenic variants are usually inherited from one or both parents. There is nothing either parent can do before or during a pregnancy to cause them. Over 80 different pathogenic variants in the MEFV gene are known to cause FMF.^[1]^[2]

The MEFV gene normally provides instructions for making a protein called pyrin, which is found in white blood cells called granulocytes. It is thought that this protein plays a role in keeping inflammation under control. Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease, and pyrin may stop or slow down the inflammatory process once it is no longer needed.^[1]^[2]

When the MEFV gene is mutated and pyrin is not formed correctly or working properly, inflammation is not regulated as it should be. This is thought to result in the painful inflammation, rashes and fever that characterize FMF.^[1]^[2]

Last updated: 6/10/2016

Inheritance Inheritance

FMF is almost always inherited in an autosomal recessive manner.^[2] This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a:

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

As many as 1 in 5 people of Sephardic Jewish, Armenian, Arab and Turkish heritage is a carrier of FMF.^[1]

In rare cases, FMF appears to be inherited in an autosomal dominant manner.^[2] This means that to be affected, a person needs to have a mutation in only one copy of the responsible gene in each cell. In some cases, an affected person inherits the mutation from an affected parent. Other cases may result from new (de novo) mutations in the gene. A person with autosomal dominant FMF has a 50% chance to pass the mutated gene on to each child.

In some cases, FMF may appear to be autosomal dominant when it is actually autosomal recessive. This phenomenon is called pseudodominance.^[2]

Last updated: 12/8/2015

Diagnosis Diagnosis

In making a diagnosis of FMF, doctors take several factors into account:^[1]

whether a person has symptoms of FMF and whether the symptoms are recurrent
how a person responds to colchicine treatment
family medical history and ancestry
results of genetic testing

Testing for the following may also be helpful to make a diagnosis of FMF:^[1]

Elevated white blood cell count, which is an indication of an immune response.
Elevated erythrocyte sedimentation rate (ESR), which is an indication of an inflammatory response.
Elevated plasma fibrinogen, which helps stop bleeding. An elevated amount would indicate that something might be wrong with this mechanism.
Elevated serum haptoglobin, which would indicate that red blood cells are being destroyed, a common occurrence in rheumatic diseases, such as FMF.
Elevated C-reactive protein, which is a special type of protein produced by the liver that is 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).

Last updated: 12/8/2015

Testing Resources

The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Treatment Treatment

The goal of treatment for familial Mediterranean fever (FMF) is to control symptoms because there is no cure for the condition.^[6]

Treatment of an acute episode may include:^[5]

intravenous saline for hydration
nonsteroidal anti-inflammatory drugs (NSAIDs) for fever and inflammatory episodes
NSAIDs, paracetamol or dipyrone for pain relief
routine treatment of end-stage renal disease (kidney failure), including renal transplantation

Depending on disease severity or the presence of specific mutations, lifelong treatment with colchicine may be needed. Colchicine prevents inflammatory attacks and the deposition of amyloid. Those who are only mildly affected (with infrequent inflammatory attacks) may either be treated with colchicine or be monitored every six months for the presence of protein in the urine (proteinuria). Others may only be treated with colchicine if they develop severe inflammatory episodes and/or proteinuria as a result of amyloidosis. Those who are unresponsive to oral colchicine may respond to intravenous colchicine, or one of several other medications. Colchicine is not effective as treatment for an acute FMF attack.^[5]

Last updated: 2/1/2017

Management Guidelines

GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
Orphanet Emergency Guidelines is an article which is expert-authored and peer-reviewed that is intended to guide health care professionals in emergency situations involving this condition.

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

Colchicine (Brand name: Colcrys) - Manufactured by AR Holding Company, Inc.
FDA-approved indication: Treatment of Familial Mediterranean Fever.
National Library of Medicine Drug Information Portal
Medline Plus Health Information
Canakinumab (Brand name: Ilaris) - Manufactured by Novartis Pharmaceuticals Corporation
FDA-approved indication: Treatment for Familial Mediterranean Fever (FMF) in adult and pediatric patients; for Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) in adult and pediatric patients; and for Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) in adult and pediatric patients.
National Library of Medicine Drug Information Portal

Prognosis Prognosis

People with FMF who are compliant with daily colchicine can probably expect to have a normal lifespan, if colchicine is started before proteinuria develops. Even with amyloidosis, the use of colchicine, dialysis, and kidney transplantation should extend a patient's life beyond 50 years of age.^[7]

Last updated: 12/8/2015

Do you have updated information on this condition? Let us know.

Research Research

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

ClinicalTrials.gov lists trials that are studying or have studied Familial Mediterranean fever. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.
The Research Portfolio Online Reporting Tool (RePORT) provides access to reports, data, and analyses of research activities at the National Institutes of Health (NIH), including information on NIH expenditures and the results of NIH-supported research. Although these projects may not conduct studies on humans, you may want to contact the investigators to learn more. To search for studies, enter the disease name in the "Text Search" box. Then click "Submit Query".

Patient Registry

The International Society of Systemic Auto-Inflammatory Diseases maintains patient registries for people with Familial Mediterranean fever.

Organizations Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Autoinflammatory Alliance
P.O. Box 590354
San Francisco, CA 94118
Telephone: 415-831-8782
E-mail: karen@autoinflammatory.org
Website: http://www.autoinflammatory.org/
Center for Jewish Genetics
30 South Wells St.
Chicago, IL 60606
Telephone: 312-357-4717
Fax: 312-855-3295
E-mail: jewishgeneticsctr@juf.org
Website: https://www.jewishgenetics.org/
FMF & AID Global Association
Schüracherstrasse 25a
8306 Brüttisellen
Switzerland
Telephone: +41 76 415 4010
E-mail: info@fmfandaid.org
Website: https://www.fmfandaid.org/
International Society of Systemic Auto-Inflammatory Diseases (ISSAID)
Website: http://fmf.igh.cnrs.fr/ISSAID/index.php?menu=0
Contact form: http://fmf.igh.cnrs.fr/ISSAID/contact.php

Social Networking Websites

RareConnect has an online community for patients and families with this condition so they can connect with others and share their experiences living with a rare disease. The project is a joint collaboration between EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders).

Do you know of an organization? Send us your suggestions.

Living With Living With

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Genetics Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by GeneTests, the American College of Medical Genetics, and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.

Learn More Learn More

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

The Cleveland Clinic provides an overview of the different types of periodic fever syndromes.
Genetics Home Reference (GHR) contains information on Familial Mediterranean fever. This website is maintained by the National Library of Medicine.
MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
The National Center for Biotechnology Information (NCBI) was established in 1988 as a national resource for molecular biology information. Click on the link to view information on this topic.
The National Human Genome Research Institute's (NHGRI) website has an information page on this topic. NHGRI is part of the National Institutes of Health and supports research on the structure and function of the human genome and its role in health and disease.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research, and the dissemination of information on research progress in these diseases. Click on the link to view information on this topic.
The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
PubMed is a searchable database of medical literature and lists journal articles that discuss Familial Mediterranean fever. Click on the link to view a sample search on this topic.

News & Events News & Events

News

Don’t Miss the NCATS Toolkit for Patient-Focused Therapy Development Event
August 31, 2017
Funding Opportunities Now Available for the Undiagnosed Diseases Network (UDN) Phase II
August 30, 2017
IRDiRC Goals 2017-2027: New Rare Disease Research Goals for the Next Decade
August 10, 2017
Young Investigator Initiative Career Development and Grant Mentoring Program
June 21, 2016
Bacterial Toxins Make The Body Go Boom: Familial Mediterranean Fever Study Gives Insight on Immunity
June 8, 2016

NCATS Co-Sponsored Conferences

Autoinflammation 2013: The Seventh International Congress of FMF and Autoinflammatory Diseases Wednesday, May 22, 2013 - Sunday, May 26, 2013
Location: Lausanne, Switzerland
Description: The goals of this meeting include the exchange of clinical and scientific information regarding the autoinflammatory diseases. This is likely to result in improvements in the diagnosis and treatment of these diseases. Past Congresses have resulted in new scientific collaborations, development of registries for patients with specific autoinflammatory disorders, and the initiation of multicenter clinical trials.

Contact: Daniel Kastner, M.D., Ph.D., 301-496-8364kastnerd@nih.gov

Co-funding Institute(s): National Human Genome Research Institute, Office of Rare Diseases Research
Autoinflammation 2010, the Sixth International Conference on FMF and other Autoinflammatory Diseases Thursday, September 2, 2010 - Monday, September 6, 2010
Location: Royal Tropical Institute, Amsterdam, The Netherlands
Description: Autoinflammation 2010 was the sixth conference in a series that started more than 10 years ago in Jerusalem. The first conference focused primarily on familial Mediterranean fever (FMF), but soon other hereditary periodic fever syndromes were included. These syndromes were the first to be recognized as autoinflammatory disorders. Recent years have seen an exciting development of scientific knowledge on inflammation and its regulation, and these rare disorders have played a major role in this development. Experts in the field of autoinflammatory disorders, both clinicians and basic scientists, from all over the world met in Amsterdam to exchange research results and opinions on clinical practice. The scientific program included plenary talks, meet-the-expert sessions, interactive workshops, and laptop presentations. Topics ranged from FMF and the other hereditary autoinflammatory diseases to acquired autoinflammatory disorders, such as gout, and from pathogenesis and genetics to clinical phenotype and therapy. Also included was a 1-day program for patients.

Contact: Daniel Kastner, M.D., Ph.D., 301-496-8364kastnerd@nih.gov

Co-funding Institute(s): Office of Rare Diseases Research, National Institute of Arthritis and Musculoskeletal and Skin Diseases
- Agenda ( - 82KB)

GARD Answers GARD Answers

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

I was diagnosed with familial Mediterranean fever (FMF) as a child. I have been taking daily doses of colchicine which have helped in reducing or practically eliminating the abdominal and chest attacks. One aspect of the FMF that has not been helped is the swelling of feet resulting from sitting for several hours during long flights or when walking long distances. The swelling of the feet is also usually associated with severe cramps of the calf muscles. Is this common and are there any treatments which help these symptoms? See answer
How is amyloidosis diagnosed in those with familial Mediterranean fever? How is the effectiveness of colchicine monitored? See answer
My son has been found to carry a single familial Mediterranean fever (FMF) gene mutation. Could he still have FMF? See answer
Are there any precipitating factors for Familial Mediterranean Fever attacks? See answer
I have a patient who may have Williams syndrome. His mother was previously diagnosed with familial Mediterrranean fever, but she has facial features consistent with Williams syndrome. Do Williams syndrome and familial Mediterranean fever share any signs or symptoms? See answer
We recently lost a colleague to Familial Mediterranean Fever. Are his siblings at risk to have inherited this condition? Is genetic testing available to individuals at risk? See answer
What is familial Mediterranean fever (FMF)? Is there any connection between fibromyalgia and FMF? Has any link been established between a family history of arthritis and FMF? See answer
I have had symptoms of Familial Mediterranean Fever since an early age. I was diagnosed through a gene test a few years ago. I would like to learn about the disease, including the prognosis of the condition and available support. See answer

Have a question? Contact a GARD Information Specialist.

References References

Learning about Familial Mediterranean Fever. NHGRI. November 2011; http://www.genome.gov/12510679.
Familial Mediterranean Fever. Genetics Home Reference (GHR). June 2014; http://ghr.nlm.nih.gov/condition=familialmediterraneanfever.
Familial Mediterranean Fever (FMF). Autoinflammatory Alliance. 2014; http://www.nomidalliance.org/fmf.php.
Tran M and Spencer FA. Thromboepidemiology: Identifying patients with heritable risk for thrombin-mediated thromboembolic events. American Heart Journal. 2005;
Mordechai Shohat. Familial Mediterranean fever. GeneReviews. December 15, 2016; https://www.ncbi.nlm.nih.gov/books/NBK1227/.
Jatin M. Vyas. Familial Mediterranean Fever. MedlinePlus. August 31, 2014; https://medlineplus.gov/ency/article/000363.htm.
Meyerhoff J & Diamond HS. Familial Mediterranean Fever. Medscape. March 2015; http://www.emedicine.com/med/topic1410.htm.