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   MeshID        = D010505 |
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'''Familial Mediterranean fever''' (FMF) is a [[genetic disorder|hereditary]] [[inflammation|inflammatory]] disorder that affects groups of patients originating from around the Mediterranean Sea (hence its name). It is prominently present in the Armenian people (up to 1 in 7 affected), Sephardi Jews (and, to a much lesser extent, Ashkenazi Jews), people from Turkey, the Arab countries and Lebanon.<ref name=Livneh>Livneh A, Langevitz P. Diagnostic and treatment concerns in familial Mediterranean fever. ''Baillieres Best Pract Res Clin Rheumatol'' 2000;14(3):477-98. PMID 10985982.</ref>
'''Familial Mediterranean fever''' (FMF) is a [[genetic disorder|hereditary]] [[inflammation|inflammatory]] disorder that affects groups of patients originating from around the Mediterranean Sea (hence its name). It is prominently present in the Armenian people (up to 1 in 7 affected), Sephardi Jews (and, to a much lesser extent, Ashkenazi Jews), people from Turkey, the Arab countries and Lebanon.<ref name=Livneh>Livneh A, Langevitz P. Diagnostic and treatment concerns in familial Mediterranean fever. ''Baillieres Best Pract Res Clin Rheumatol'' 2000;14(3):477-98. PMID 10985982.</ref>


==Clinical symptoms==
==Historical Perspective==
===Attacks===
A New York allergist, Dr Sheppard Siegal, first described the attacks of [[peritonitis]] in 1945; he termed this "benign paroxysmal peritonitis", as the disease course was essentially benign.<ref>Siegal S. Benign paroxysmal peritonitis. ''Ann Intern Med'' 1945;23:1-21.</ref> Dr Hobart Reimann, working in the American University in Beirut, described a more complete picture which he termed "periodic disease".<ref>Reiman HA. Periodic disease. Probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclic neutropenia and intermittent arthralgia. ''[[Journal of the American Medical Association|JAMA]]'' 1948;136:239-44.</ref><ref>{{WhoNamedIt|synd|2503}}</ref>
 
==Pathophysiology==
Virtually all cases are due to a mutation in the ''MEFV'' gene, which codes for a protein called ''pyrin'' or ''marenostenin''. This was discovered in 1997 by two different groups, each working independently - the French FMF Consortium,<ref name=FConsort>The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997;17:25-31. PMID 9288094</ref> and the International FMF Consortium<ref name=IConsort>The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997;90:797-807. PMID 9288758.</ref> Various mutations of this gene lead to FMF, although some mutations cause a more severe picture than others. Mutations occur in [[exon]]s 2, 3, 5 and 10.<ref name=Livneh/>
 
The function of pyrin has not been completely elucidated, but it appears to be a suppressor of the activation of [[caspase 1]], the [[enzyme]] that stimulates production of [[IL-1|interleukin 1β]], a [[cytokine]] central to the process of [[inflammation]]. It is not conclusively known what exactly sets off the attacks, and why overproduction of IL-1 would lead to particular symptoms in particular organs (e.g. joints or the peritoneal cavity).<ref name=Livneh/>
 
===Genetics===
The ''[[MEFV]]'' gene is located on the short arm of [[chromosome 16 (human)|chromosome 16]] (16p13). The disease inherits in an [[autosomal recessive]] fashion. Therefore, two asymptomatic carrier parents have a 25% chance of a child with the disorder. FMF patients who marry a carrier or another FMF patient have a 50% and 100% chance, respectively, in having a child with FMF.<ref name=FConsort/><ref name=IConsort/>
 
==Natural History, Complications and Prognosis==
[[amyloidosis|AA-amyloidosis]] with [[renal failure]] is a complication and may develop without overt crises. AA (amyloid protein) is produced in very large quantities during attacks and at a low rate between them, and accumulates  mainly in the [[kidney]], as well as the [[heart]], [[spleen]], [[gastrointestinal tract]] and the [[thyroid]].<ref name=Livneh/>
 
There appears to be an increase in the risk for developing particular [[vasculitis]]-related diseases (e.g. [[Henoch-Schönlein purpura]]), [[spondylarthropathy]], prolonged [[arthritis]] of certain joints and protracted myalgia.<ref name=Livneh/>
 
==Diagnosis==
The diagnosis is clinically made on the basis of the history of typical attacks, especially in patients from the ethnic groups in which FMF is more highly prevalent.
===Symptoms===
There are seven types of attacks. 90% of all patients have their first attacks before they are 20 years old. All develop over 2-4 hours and last anytime between 6 hours and 4 days. Most attacks involve [[fever]]:<ref name=Livneh/>
There are seven types of attacks. 90% of all patients have their first attacks before they are 20 years old. All develop over 2-4 hours and last anytime between 6 hours and 4 days. Most attacks involve [[fever]]:<ref name=Livneh/>
# Abdominal attacks, featuring [[abdominal pain]] affecting the whole abdomen with all signs of [[acute abdomen]] (e.g. [[appendicitis]]). They occur in 95% of all patients and may lead to unnecessary [[laparotomy]]. Incomplete attacks, with local tenderness and normal blood tests, have been reported.
# Abdominal attacks, featuring [[abdominal pain]] affecting the whole abdomen with all signs of [[acute abdomen]] (e.g. [[appendicitis]]). They occur in 95% of all patients and may lead to unnecessary [[laparotomy]]. Incomplete attacks, with local tenderness and normal blood tests, have been reported.
Line 33: Line 50:
# [[Fever]] without any symptoms (25%)
# [[Fever]] without any symptoms (25%)


===Complications===
===Laboratory Studies===
[[amyloidosis|AA-amyloidosis]] with [[renal failure]] is a complication and may develop without overt crises. AA (amyloid protein) is produced in very large quantities during attacks and at a low rate between them, and accumulates  mainly in the [[kidney]], as well as the [[heart]], [[spleen]], [[gastrointestinal tract]] and the [[thyroid]].<ref name=Livneh/>
An [[acute phase response]] is present during attacks, with high [[C-reactive protein]] levels, an elevated [[white blood cell]] count and other markers of [[inflammation]]. In patients with a long history of attacks, monitoring the [[renal function]] is of importance in predicting [[chronic renal failure]].<ref name=Livneh/>
 
There appears to be an increase in the risk for developing particular [[vasculitis]]-related diseases (e.g. [[Henoch-Schönlein purpura]]), [[spondylarthropathy]], prolonged [[arthritis]] of certain joints and protracted myalgia.<ref name=Livneh/>
 
==Diagnosis==
The diagnosis is clinically made on the basis of the history of typical attacks, especially in patients from the ethnic groups in which FMF is more highly prevalent. An [[acute phase response]] is present during attacks, with high [[C-reactive protein]] levels, an elevated [[white blood cell]] count and other markers of [[inflammation]]. In patients with a long history of attacks, monitoring the [[renal function]] is of importance in predicting [[chronic renal failure]].<ref name=Livneh/>


A genetic test is also available now that the disease has been linked to mutations in the ''MEFV'' gene.  Sequencing of exons 2, 3, 5, and 10 of this gene detects an estimated 97% of all known mutations.<ref name=Livneh/>
A genetic test is also available now that the disease has been linked to mutations in the ''MEFV'' gene.  Sequencing of exons 2, 3, 5, and 10 of this gene detects an estimated 97% of all known mutations.<ref name=Livneh/>
==Disease mechanism==
===Pathophysiology===
Virtually all cases are due to a mutation in the ''MEFV'' gene, which codes for a protein called ''pyrin'' or ''marenostenin''. This was discovered in 1997 by two different groups, each working independently - the French FMF Consortium,<ref name=FConsort>The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997;17:25-31. PMID 9288094</ref> and the International FMF Consortium<ref name=IConsort>The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997;90:797-807. PMID 9288758.</ref> Various mutations of this gene lead to FMF, although some mutations cause a more severe picture than others. Mutations occur in [[exon]]s 2, 3, 5 and 10.<ref name=Livneh/>
The function of pyrin has not been completely elucidated, but it appears to be a suppressor of the activation of [[caspase 1]], the [[enzyme]] that stimulates production of [[IL-1|interleukin 1β]], a [[cytokine]] central to the process of [[inflammation]]. It is not conclusively known what exactly sets off the attacks, and why overproduction of IL-1 would lead to particular symptoms in particular organs (e.g. joints or the peritoneal cavity).<ref name=Livneh/>
===Genetics===
The ''[[MEFV]]'' gene is located on the short arm of [[chromosome 16 (human)|chromosome 16]] (16p13). The disease inherits in an [[autosomal recessive]] fashion. Therefore, two asymptomatic carrier parents have a 25% chance of a child with the disorder. FMF patients who marry a carrier or another FMF patient have a 50% and 100% chance, respectively, in having a child with FMF.<ref name=FConsort/><ref name=IConsort/>


==Treatment==
==Treatment==
Line 56: Line 59:


Since the 1970s, [[colchicine]], a drug otherwise mainly used in [[gout]], has been shown to decrease attack frequency in FMF patients. The exact way in which colchicine suppresses attacks is unclear. While this agent is not without side-effects (such as [[abdominal pain]] and [[myalgia|muscle pains]]), it may markedly improve quality of life in patients. The dosage is typically 1-2 mg a day. Development of amyloidosis is delayed with colchicine treatment. [[Interferon]] is being studied as a therapeutic modality.<ref name=Livneh/>
Since the 1970s, [[colchicine]], a drug otherwise mainly used in [[gout]], has been shown to decrease attack frequency in FMF patients. The exact way in which colchicine suppresses attacks is unclear. While this agent is not without side-effects (such as [[abdominal pain]] and [[myalgia|muscle pains]]), it may markedly improve quality of life in patients. The dosage is typically 1-2 mg a day. Development of amyloidosis is delayed with colchicine treatment. [[Interferon]] is being studied as a therapeutic modality.<ref name=Livneh/>
==History==
A New York allergist, Dr Sheppard Siegal, first described the attacks of [[peritonitis]] in 1945; he termed this "benign paroxysmal peritonitis", as the disease course was essentially benign.<ref>Siegal S. Benign paroxysmal peritonitis. ''Ann Intern Med'' 1945;23:1-21.</ref> Dr Hobart Reimann, working in the American University in Beirut, described a more complete picture which he termed "periodic disease".<ref>Reiman HA. Periodic disease. Probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclic neutropenia and intermittent arthralgia. ''[[Journal of the American Medical Association|JAMA]]'' 1948;136:239-44.</ref><ref>{{WhoNamedIt|synd|2503}}</ref>


==References==
==References==
<div class="references-small">
{{Reflist|2}}
<references />
</div>


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[[tr:Ailevi akdeniz ateşi]]


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Revision as of 16:24, 16 July 2011

Familial mediterranean fever
ICD-10 E85.0
ICD-9 277.3
OMIM 249100 608107
DiseasesDB 9836
eMedicine med/1410 
MeSH D010505

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.

Overview

Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder that affects groups of patients originating from around the Mediterranean Sea (hence its name). It is prominently present in the Armenian people (up to 1 in 7 affected), Sephardi Jews (and, to a much lesser extent, Ashkenazi Jews), people from Turkey, the Arab countries and Lebanon.[1]

Historical Perspective

A New York allergist, Dr Sheppard Siegal, first described the attacks of peritonitis in 1945; he termed this "benign paroxysmal peritonitis", as the disease course was essentially benign.[2] Dr Hobart Reimann, working in the American University in Beirut, described a more complete picture which he termed "periodic disease".[3][4]

Pathophysiology

Virtually all cases are due to a mutation in the MEFV gene, which codes for a protein called pyrin or marenostenin. This was discovered in 1997 by two different groups, each working independently - the French FMF Consortium,[5] and the International FMF Consortium[6] Various mutations of this gene lead to FMF, although some mutations cause a more severe picture than others. Mutations occur in exons 2, 3, 5 and 10.[1]

The function of pyrin has not been completely elucidated, but it appears to be a suppressor of the activation of caspase 1, the enzyme that stimulates production of interleukin 1β, a cytokine central to the process of inflammation. It is not conclusively known what exactly sets off the attacks, and why overproduction of IL-1 would lead to particular symptoms in particular organs (e.g. joints or the peritoneal cavity).[1]

Genetics

The MEFV gene is located on the short arm of chromosome 16 (16p13). The disease inherits in an autosomal recessive fashion. Therefore, two asymptomatic carrier parents have a 25% chance of a child with the disorder. FMF patients who marry a carrier or another FMF patient have a 50% and 100% chance, respectively, in having a child with FMF.[5][6]

Natural History, Complications and Prognosis

AA-amyloidosis with renal failure is a complication and may develop without overt crises. AA (amyloid protein) is produced in very large quantities during attacks and at a low rate between them, and accumulates mainly in the kidney, as well as the heart, spleen, gastrointestinal tract and the thyroid.[1]

There appears to be an increase in the risk for developing particular vasculitis-related diseases (e.g. Henoch-Schönlein purpura), spondylarthropathy, prolonged arthritis of certain joints and protracted myalgia.[1]

Diagnosis

The diagnosis is clinically made on the basis of the history of typical attacks, especially in patients from the ethnic groups in which FMF is more highly prevalent.

Symptoms

There are seven types of attacks. 90% of all patients have their first attacks before they are 20 years old. All develop over 2-4 hours and last anytime between 6 hours and 4 days. Most attacks involve fever:[1]

  1. Abdominal attacks, featuring abdominal pain affecting the whole abdomen with all signs of acute abdomen (e.g. appendicitis). They occur in 95% of all patients and may lead to unnecessary laparotomy. Incomplete attacks, with local tenderness and normal blood tests, have been reported.
  2. Joint attacks, occurring in large joints, mainly of the legs. Usually, only one joint is affected. 75% of all FMF patients experience Joint attacks.
  3. Chest attacks with pleuritis (inflammation of the pleural lining) and pericarditis (inflammation of the pericardium). Pleuritis occurs in 40%, but pericarditis is rare.
  4. Scrotal attacks due to inflammation of the tunica vaginalis. This occurs in up to 5% and may be mistaken for acute scrotum (i.e. testicular torsion)
  5. Myalgia (rare in isolation)
  6. Erysipeloid (a skin reaction on the legs, rare in isolation)
  7. Fever without any symptoms (25%)

Laboratory Studies

An acute phase response is present during attacks, with high C-reactive protein levels, an elevated white blood cell count and other markers of inflammation. In patients with a long history of attacks, monitoring the renal function is of importance in predicting chronic renal failure.[1]

A genetic test is also available now that the disease has been linked to mutations in the MEFV gene. Sequencing of exons 2, 3, 5, and 10 of this gene detects an estimated 97% of all known mutations.[1]

Treatment

Attacks are self-limiting, and require analgesia and non-steroidal anti-inflammatory drugs (such as diclofenac).[1]

Since the 1970s, colchicine, a drug otherwise mainly used in gout, has been shown to decrease attack frequency in FMF patients. The exact way in which colchicine suppresses attacks is unclear. While this agent is not without side-effects (such as abdominal pain and muscle pains), it may markedly improve quality of life in patients. The dosage is typically 1-2 mg a day. Development of amyloidosis is delayed with colchicine treatment. Interferon is being studied as a therapeutic modality.[1]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 Livneh A, Langevitz P. Diagnostic and treatment concerns in familial Mediterranean fever. Baillieres Best Pract Res Clin Rheumatol 2000;14(3):477-98. PMID 10985982.
  2. Siegal S. Benign paroxysmal peritonitis. Ann Intern Med 1945;23:1-21.
  3. Reiman HA. Periodic disease. Probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclic neutropenia and intermittent arthralgia. JAMA 1948;136:239-44.
  4. Template:WhoNamedIt
  5. 5.0 5.1 The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997;17:25-31. PMID 9288094
  6. 6.0 6.1 The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997;90:797-807. PMID 9288758.

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de:Mittelmeerfieber he:קדחת ים תיכונית משפחתית no:Familiær middelhavsfeber nn:Familiær middelhavsfeber


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