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Familial Mediterranean Fever

Synonym: Recurrent Polyserositis

, MD and , MB, ChB.

Author Information
, MD
Director, Raphael Recanati Genetic Institute,
Molecular Genetics / Medical Genetics
Rabin Medical Center
Petah Tikva
Professor, Pediatrics and Genetics
Sackler School of Medicine
Tel Aviv, Israel
, MB, ChB
Medical Genetics
Raphael Recanati Genetic Institute
Rabin Medical Center
Petah Tikva, Israel

Initial Posting: ; Last Update: June 19, 2014.

Summary

Disease characteristics. Familial Mediterranean fever (FMF) comprises two phenotypes: type 1 and type 2.

  • FMF type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication.
  • FMF type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual.

Diagnosis/testing. The diagnosis of FMF is suspected in individuals with recurrent episodes of fever associated with abdominal pain (peritonitis) and/or pleuritic pain and/or arthritis (ankle/knee) usually lasting two to three days. A high erythrocyte sedimentation rate (ESR), leukocytosis, and a high serum concentration of fibrinogen are characteristic. MEFV is the only gene in which pathogenic variants are currently known to cause FMF. Affected individuals may have biallelic MEFV pathogenic variants or a heterozygous MEFV pathogenic variant.

Management. Treatment of manifestations: Treatment of an acute episode is mainly supportive, including administration of intravenous saline for hydration and use of nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, or dipyrone for pain relief; treatment of febrile and inflammatory episodes with NSAIDs; routine treatment of end-stage renal disease, including live related-donor renal transplantation.

Prevention of primary manifestations: Homozygotes for the p.Met694Val pathogenic variant or compound heterozygotes for p.Met694Val and another disease-causing allele require lifelong treatment with colchicine (1-2 mg/day orally in adults and 0.5-1 mg/day in children according to age and weight). Colchicine prevents the inflammatory attacks and the deposition of amyloid. Individuals who do not have the p.Met694Val pathogenic variant and who are only mildly affected (those with infrequent inflammatory attacks) should either be treated with colchicine or monitored every six months for the presence of proteinuria.

Surveillance: Annual physical examination, urine spot test for protein, and evaluation for hematuria for all affected individuals including those treated with colchicine; consider monitoring of acute-phase reactants (ESR and fibrinogen levels) at regular intervals during attack-free periods, particularly in those with the p.Met694Val pathogenic variant.

Agents/circumstances to avoid: Possible worsening of symptoms with cisplatin; possible adverse effect on renal transplant graft survival with cyclosporin A.

Evaluation of relatives at risk: Offer molecular genetic testing to all first-degree relatives and other family members (regardless of symptoms) especially when the p.Met694Val allele is present because renal amyloidosis can be prevented with colchicine treatment.

Genetic counseling. FMF is usually inherited in an autosomal recessive manner, although recent studies have suggested that some heterozygotes manifest a spectrum of findings from classic FMF to mild FMF. For autosomal recessive FMF: In general, both parents of an affected individual with biallelic MEFV pathogenic variants are unaffected heterozygotes. However, in populations with a high carrier rate and/or a high rate of consanguineous marriages, it is possible that one or both parents have biallelic pathogenic variants and are affected. Symptomatic heterozygotes have also been reported. Thus, it is appropriate to consider molecular genetic testing of the parents of the proband to establish their genetic status. If both parents are heterozygotes, the risk to sibs of inheriting two pathogenic variants and being affected is 25%. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the MEFV pathogenic variants in the family are known.

GeneReview Scope

Familial Mediterranean Fever: Included Disorders
  • Familial Mediterranean fever type 1
  • Familial Mediterranean fever type 2

For synonyms and outdated names see Nomenclature.

Diagnosis

The diagnosis of familial Mediterranean fever (FMF) is based on a combination of clinical and molecular genetic findings.

Suggestive Findings

Diagnosis of FMF should be suspected in individuals with the following:

  • Recurrent febrile episodes accompanied by peritonitis, synovitis, or pleuritis
  • Recurrent erysipelas-like erythema
  • Repeated laparotomies for "acute abdomen" with no pathology found
  • Amyloidosis of the AA type that characteristically develops after age 15 years in untreated individuals, even in those who do not have a history of recurrent inflammatory attacks
  • Favorable response to continuous colchicine treatment
  • Membership in an at-risk ethnic group

The minimal (and most current) criteria for diagnosis of FMF are the Tel Hashomer clinical criteria [Livneh et al 1997, Pras 1998]:

  • Fever plus EITHER:
    • One or more major signs and one minor sign;
      OR
    • Two minor signs.

See also Note.

Major signs

  • Fever
  • Abdominal pain
  • Chest pain
  • Joint pain*
  • Skin eruption

* It is important to make the correct diagnosis in individuals with recurrent monoarthritis. The criteria that suggest a diagnosis of FMF in persons with monoarthritis include a high fever, favorable response to colchicine, history of FMF in sibs and other family members, and an appropriate genotype [Lidar et al 2005].

Minor signs

  • Increased erythrocyte sedimentation rate (ESR)
    Normal values:
    • Men age <50 years: <15 mm/h
    • Men age 50-85 years: <20 mm/h
    • Women age <50 years: <20 mm/h
    • Women age 50-85 years: <30 mm/h
  • Leukocytosis
    Normal values: 4.5 to 11.0 times 103µL (4.5-11.0 x 10-9L)
  • Elevated serum concentration of fibrinogen
    Normal values: 200-400 mg/dL (2.00-4.00 g/L)

Note

  • Yalçinkaya et al [2009] suggested new diagnostic criteria for children; however, Kondi et al [2010] found that in a mixed population of 100 French patients the new criteria did not make a better contribution to FMF diagnosis than the Tel Hashomer criteria [Livneh et al 1997, Pras 1998].
  • In a recent study that compared persons with FMF who first manifest the disease by age two years with those who first manifest it between ages two and 16 years, Padeh et al [2010] found that early in life FMF often begins with an atypical presentation characterized by attacks of fever alone, significantly delaying diagnosis and initiation of treatment.
  • Ozçakar et al [2011] used the new set of criteria established by Yalçinkaya et al [2009] to evaluate heterozygous Turkish individuals (only one mutant allele present) with clinical manifestations of FMF. They found that the sensitivity of the new criteria was 93% (that of the Tel Hashomer criteria was 100%), and concluded that the sensitivity of their new criteria was high in heterozygotes (individuals with one mutant allele).

Molecular Genetic Testing

Gene. MEFV is the only gene in which pathogenic variants are known to cause FMF.

Table 1. Summary of Molecular Genetic Testing Used in Familial Mediterranean Fever

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
MEFVTargeted mutation analysis 2, 3Armenian: 90%
Turkish: 90%
Arab: 70%
North African Jewish: 95%
Iraqi Jewish: 80%
Ashkenazi Jewish: 90%
Sequence analysis 4, 5All groups: 90%
Deletion/duplication analysis 6Unknown; none reported 7

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. Pathogenic variants detected include exon 2: c.442G>C (p.Glu148Gln); exon 3:c.1223G>A (p.Arg408Gln), c.1105C>T (p.Pro369Ser); exon 10: c.2080A>G (p.Met694Val), c.2177T>C (p.Val726Ala), c.2040G>C (p.Met680Ile), c.2082G>A (p.Met694Ile), c.2084A>G (p.Lys695Arg), c.2230G>T (p.Ala744Ser), c.2282G>A (p.Arg761His), c.2076_2078del (p.Ile692del), c.1958G>A (p.Arg653His); (see Table 3)

3. Panel may vary by laboratory.

4. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Sequence variants in exon 10 and outside exon 10

6. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. van Gijn et al [2008]

Testing Strategy

Use of molecular genetic testing to confirm/establish the diagnosis in a proband

Alternative 1. Single gene testing

  • In most individuals with classic FMF, targeted mutation analysis of the common MEFV pathogenic variants identifies two pathogenic variants, thus confirming the diagnosis.
  • If neither or only one MEFV pathogenic variant is identified, particularly in individuals with non-classic FMF or a mild clinical presentation, sequence analysis of the entire coding region may be warranted to try to identify a second pathogenic variant.

    Note: Studies to try to identify a second MEFV pathogenic variant in persons with the clinical diagnosis of FMF and a single high-penetrance MEFV pathogenic variant usually have not detected a second MEFV pathogenic variant, nor has haplotype analysis identified a common haplotype that could be associated with the transmission of a second MEFV allele. It seems that a significant subset of persons with FMF – perhaps as many as 25% – have only one MEFV pathogenic variant. In such individuals detection of a single pathogenic variant appears to be sufficient to initiate a trial of colchicine [Booty et al 2009, Marek-Yagel et al 2009, Moradian et al 2010].
  • In all instances in which the clinical picture suggests FMF but MEFV molecular genetic testing is not diagnostic, the diagnosis of FMF can be confirmed if a six-month trial of colchicine therapy results in relief of the attacks, which then recur after cessation of this treatment.

Alternative 2. Multi-gene testing

  • If available, consider using a multi-gene recurrent fever panel that includes MEFV as well as a number of genes associated with recurrent fever disorders described in Differential Diagnosis. Panels vary by methods used and genes included; thus, the ability of a panel to detect a pathogenic variant(s) in any given individual also varies.

Linkage analysis may be an option for carrier testing for families in which neither or only one MEFV pathogenic variant has been identified. Samples from multiple family members, including at least one affected individual, are necessary to perform linkage analysis. The accuracy of linkage analysis depends on (1) the informativeness of genetic markers in the individual's family and (2) the accuracy of the clinical diagnosis of FMF in the affected family member.

Clinical Description

Natural History

Familial Mediterranean fever (FMF) is divided into two phenotypes (types 1 and 2):

  • FMF type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and (rarely) pericarditis and meningitis. The symptoms vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication of FMF type 1.
  • FMF type 2 is characterized by amyloidosis as the first clinical manifestation of disease in an otherwise asymptomatic individual [Pras 1998, Langevitz et al 1999, Shohat et al 1999, Koné Paut et al 2000].

Common manifestations of FMF include the following:

  • Recurrent fever during early childhood may be the only manifestation of FMF.
  • Abdominal attacks. Experienced by 90% of affected individuals, abdominal attacks start with the sudden onset of fever and pain affecting the entire abdomen. Physical examination reveals board-like rigidity of the abdominal muscles, rebound tenderness, abdominal distension, and loss of peristaltic sounds. Radiographs reveal multiple small air-fluid levels in the small bowel. The diagnosis of "acute abdomen" usually results in laparotomy, but if not, the signs and symptoms resolve without sequelae over 24-48 hours.
  • Articular attacks. Experienced by about 75% of individuals with FMF, articular attacks occur suddenly, and may be precipitated by minor trauma or effort, such as prolonged walking. The three characteristic features are (1) a very high fever in the first 24 hours, (2) involvement of one of the large joints of the leg (knee, ankle, or hip), and (3) gradual resolution of the signs and symptoms after peaking in 24-48 hours, leaving no sequelae. Often a sterile synovial effusion is present.

    The attacks are commonly in the hip or knee, but may occur in other joints such as the ankle, shoulder, temporomandibular joint, or sternoclavicular joint. The joint remains swollen and painful, as in chronic monoarthritis. Recurrent monoarthritis can be the sole manifestation of FMF; in such cases the true diagnosis may not be established for some time and only after extensive investigations [Lidar et al 2005].

    Attacks subside spontaneously only after several weeks or months; severe damage to the joint can result, and permanent deformity may require joint replacement. Around 5% of affected individuals have protracted arthritic attacks. There is evidence that arthritis, arthralgia, myalgia, and erysipelas-like erythema occur significantly more often among individuals with disease onset before age 18 years than in those with onset after age 18 years [Sayarlioglu et al 2005, Tunca et al 2005].
  • Prodrome. A prodrome (pre-attack symptoms) is experienced by about 50% of persons with FMF. The prodrome recurs in most attacks, lasts a mean of 20 hours, and manifests with either a mildly unpleasant sensation at the site of the forthcoming spell (discomfort prodrome), or with a spectrum of physical, emotional, and neuropsychological complaints (variant prodrome) [Lidar et al 2006].
  • Pleural attacks, experienced by about 45% of those with FMF, are the sudden onset of an acute, one-sided febrile pleuritis, which resolves rapidly. The individual complains of painful breathing, and breath sounds are diminished on the affected side. Radiographs may reveal a small exudate in the costophrenic angle. Attacks resolve within 48 hours. Pleuritis can rarely present as the sole manifestation of FMF [Ten Oever & de Munck 2008, Lega et al 2010, Ruiz & Gadea 2011].
  • Pericarditis, a rare occurrence, is characterized by retrosternal pain. Electrocardiogram shows an elevated ST segment. Radiographs may reveal transient enlargement of the cardiac silhouette, and echocardiography may show evidence of pericardial effusion. Recurrent pericarditis, even though it is rare, can present as the sole manifestation of FMF [Tutar et al 2001, Okutur et al 2008].
  • Amyloidosis. Type AA amyloidosis is common in untreated individuals, especially in Jews of North African origin. It presents with persistent, heavy proteinuria leading to nephrotic syndrome and progressive nephropathy leading to end-stage renal disease. Affected individuals who are otherwise asymptomatic can develop renal amyloidosis as the first and only manifestation of FMF type 2. With increased longevity of individuals with renal failure through dialysis and/or renal transplantation, amyloid deposits are being found in other organs as well. The prevalence of amyloidosis varies by ethnicity, genotype, and gender. In untreated individuals, amyloidosis can occur in 60% of individuals of Turkish heritage and in up to 75% of North African Jews [Livneh et al 1999, Shohat et al 1999].

    The age of onset of FMF attacks appears to be earlier in persons with amyloidosis than in those without amyloidosis. FMF-related manifestations of chest pain, arthritis, and erysipelas-like erythema are more common in those with amyloidosis. Long periods between disease onset and diagnosis are associated with a high risk of developing amyloidosis [Cefle et al 2005].

    Clinically detectable pulmonary amyloidosis secondary to FMF is rare; only a few cases have been reported to date [Erdem et al 2006, Sahan & Cengiz 2006, Koksal et al 2012].

Rarer manifestations of FMF attacks include the following:

  • Protracted febrile myalgia is a severe debilitating myalgia with prolonged low-grade fever, increased erythrocyte sedimentation rate (~100), leukocytosis, and hyperglobulinemia. The symptoms may also include high fever, abdominal pain, diarrhea, arthritis/arthralgia, and transient vasculitic rashes mimicking Henoch-Schönlein purpura. Protracted febrile myalgia usually lasts six to eight weeks and responds to treatment with prednisone. Streptococci could be one of the agents triggering this syndrome [Soylu et al 2006, Senel et al 2010, Tufan & Demir 2010].
  • Erysipelas-like erythema (ELE) is characterized by fever and hot, tender, swollen, sharply bordered red lesions that are typically 10-35 cm2 in area and occur mainly on the legs, between the ankle and the knee, or on the dorsum of the foot. The lesions usually last one to two days. Isolated temperature elevation lasting a few hours can occur without any pain or inflammation [Kavukcu et al 2009]. Rarely ELE can be the first disease manifestation of FMF [Lidar et al 2013].
  • Vasculitides are rare and include Henoch-Schönlein purpura (in ~5% of individuals with FMF) and polyarteritis nodosa [Cattan 2005, Girisgen et al 2012].
  • Recurrent urticaria has been reported as a rare manifestation of FMF [Alonso et al 2002].
  • Aseptic meningitis can occur rarely in FMF [Vilaseca et al 1982, Collard et al 1991, Gedalia & Zamir 1993, Karachaliou et al 2005]. In each of the reported cases, the affected individuals’ attacks of recurrent aseptic meningitis (RAM) resolved after treatment with colchicine. However, Capron et al [2013] performed a systematic review of the literature to assess the number and validity of published case reports that purport to demonstrate a causal relationship between RAM and FMF. They concluded that the finding of RAM due to FMF was poorly supported; only one case report – in which the affected individual did not meet the current clinical diagnostic criteria of FMF – suggested a possible causal relationship between the two.

Reduced fertility. Untreated individuals with FMF, especially those with multiple attacks and/or amyloidosis, are at higher risk for infertility. Colchicine treatment increases fertility, but in some instances may induce oligospermia/azoospermia [Ben-Chetrit & Levy 2003, Mijatovic et al 2003, Dotters-Katz et al 2012].

  • Since colchicine may inhibit mitosis, concern was raised as to the effect of colchicine on sperm proliferation and motility in affected individuals receiving colchicine [Ozturk et al 2011].
    • A person with gout who was treated with colchicine developed azoospermia, which reappeared following rechallenge with the drug [Merlin 1972].
    • However, two studies found that males undergoing long-term colchicine therapy had normal sperm counts and normal levels of testosterone, follicle stimulating hormone, luteinizing hormone, and prolactin [Bremner & Paulsen 1976, Levy & Yaffe 1978].
    • In contrast, a study of 62 Turkish men with Behçet’s disease undergoing long-term colchicine treatment reported oligospermia in 23 (37%) and azoospermia in two [Sarica et al 1995].
    • Thus, while it is tempting to ascribe the azoospermia in FMF to colchicine therapy, in one male with FMF with infertility, testicular biopsy showed amyloidosis of the testes [Haimov-Kochman et al 2001].
  • Sperm motility, and hence ovum penetration, depend on microtubular function; thus, the question of whether colchicine may affect sperm motility is relevant.
    • This question was studied in an in vitro system exposing sperm to different colchicine concentrations and different durations [Ben-Chetrit et al 1993]. Significant inhibition of sperm motility occurred only after an incubation period of at least 18 hours with a minimum concentration of 10 µg/mL – a concentration approximately 3,000-fold higher than the plasma colchicine concentration with normal therapeutic doses; thus, it is unlikely that standard colchicine treatment would inhibit sperm motility in normal circumstances.

Decreased atopy. Several studies have shown that FMF may have a protective effect against development of asthma, atopic sensitization, and allergic rhinitis (7% in individuals with FMF compared to 20% in the general population) [Sackesen et al 2004, Yazici et al 2013].

Chronic ascites

  • A female with FMF who was compound heterozygous for the pathogenic variants c.2080A>G and c.2040G>C developed chronic ascites that responded to a dose adjustment of colchicine [Ureten et al 2009].
  • A woman age 56 years who was compound heterozygous for c.2080A>G and c.2282G>A had a history of FMF from childhood. She had been on hemodialysis for four years and had experienced recurrent ascites; she did not take colchicine [Sengul et al 2008].
  • Bektaş et al [2008] reported four individuals with FMF who had repetitive periods of fever and ascites from childhood. One was a homozygote for c.2080A>G/c.2080A>G (p.Met694Val/Met694Val), one was a heterozygote for c.2080A>G (p.Met694Val), and the other two were compound heterozygotes for c.2080A>G/c.2177T>C (p.Met694Val/p.Val726Ala). In all four the ascites regressed with colchicine therapy.
  • Cakir et al [2010] described a male age six years with massive ascites. Colchicine treatment was initiated, and the ascites subsided within one week without any recurrence during the next 12 months; however, testing for the common MEFV mutations was negative for FMF.
  • A woman age 47 years with ascites was found to be homozygous for c.2080A>G/c.2080A>G (p.Met694Val/p.Met694Val); after treatment with colchicine the quantity of ascites decreased [Aslan et al 2012].

Peritoneal malignant mesothelioma

  • The possibility of local inflammation leading to cancer at the same site was suggested by the occurrence of peritoneal malignant mesothelioma in two persons with FMF who had recurrent peritoneal involvement during childhood. Both were homozygous for the pathogenic variant c.2080A>G [Hershcovici et al 2006].

Psychological features. Makay et al [2010] found that depression scores of individuals with FMF were significantly higher than their healthy peers; however, no significant difference regarding anxiety scores was observed between persons with FMF and the control group. Although disease duration did not correlate significantly with the depression and anxiety scores, it did correlate with the FMF severity score. In a later study, Deger et al [2011] found that depression and anxiety were more frequent in persons with FMF than in healthy individuals.

Neurologic manifestations. Feld et al [2012] reviewed the literature on neurologic manifestations reported in individuals with FMF and found a possible association of FMF with stroke, multiple sclerosis, and other demyelinating disorders.

Other clinical findings

  • A lower bone mineral density was found in people with FMF than in a control group matched for age, sex, and body mass index [Yildirim et al 2010]. The authors suggested that this may be secondary to active inflammatory periods and subclinical inflammation resulting from the disease.
  • Serum homocysteine and lipoprotein(a) concentrations are often increased in individuals with FMF during attack-free periods [Karatay et al 2010b]. The authors suggested that these elevated levels, which are markers of subclinical inflammation, may be mediators of atherosclerotic disease in persons with FMF.
  • A study to determine the prevalence of periodontal disease among persons with FMF and to evaluate the possible relationship of periodontitis to amyloidosis in individuals with FMF found that the prevalence of moderate to severe periodontitis in people with amyloidosis was significantly greater than in those without amyloidosis and in controls. Serum levels of acute-phase reactants in people with FMF were reduced significantly following nonsurgical periodontal therapy [Cengiz et al 2009].

Clinical findings in individuals with FMF in whom only one MEFV pathogenic variant is identified. Several studies have attempted to identify a second pathogenic variant in persons diagnosed clinically as having FMF (according to the Tel Hashomer clinical criteria) in whom only one high-penetrance MEFV mutation was identified [Booty et al 2009, Koné-Paut et al 2009, Marek-Yagel et al 2009, Moradian et al 2010]. A second pathogenic variant was identified in a small number of individuals [Marek-Yagel et al 2009, Moradian et al 2010]. In each of these studies, analysis revealed that the clinical features were milder and the attacks shorter and less frequent in the symptomatic individuals in whom a second pathogenic variant was not found than in those in whom a second pathogenic variant was found. Most of the heterozygotes described by Booty et al [2009] had an incomplete abdominal attack (abdominal pain without frank peritonitis) as the major criterion of the disease; in 84% the response to colchicine therapy was either complete or partial.

Persons with one pathogenic variant tend to have milder disease (manifest mainly by fever and abdominal symptoms) than persons with two pathogenic variants. MEFV heterozygous genotypes produce a phenotype intermediate between that of homozygous affected individuals and homozygous wild-type unaffected individuals [Moradian et al 2010]. However, in these individuals, detection of a single pathogenic variant appears to be sufficient in the presence of clinical symptoms for the diagnosis of FMF and the initiation of a trial of colchicine [Booty et al 2009].

Young children (age <6 years) with a single MEFV pathogenic variant and symptoms of recurrent autoinflammatory disorder were found to have a milder disease course compared to individuals with biallelic pathogenic variants, with no major differences in presenting signs or initial response to colchicine [Hentgen et al 2013a]. However, clinical signs of FMF completely disappeared at puberty in five of 18 individuals with a single MEFV pathogenic variant, allowing them to discontinue colchicine without recurrence of symptoms. The authors concluded that young children can present with an FMF-like disease similar to that seen in individuals with biallelic pathogenic variants that is not necessarily predictive of lifelong illness.

Genotype-Phenotype Correlations

c.2080A>G (p.Met694Val). Persons who are homozygous for the pathogenic variant c.2080A>G (p.Met694Val) have an earlier age of onset and higher frequencies of arthritis and arthralgia than persons who are homozygous or compound heterozygous for other pathogenic variants [Tunca et al 2005].

A significant association has been identified between the pathogenic variant c.2080A>G and the development of amyloidosis, especially in those who are homozygous for this pathogenic variant:

  • Duşunsel et al [2008] found that c.2080A>G was not associated with increased severity of disease but was significantly associated with amyloidosis.
  • Soylemezoglu et al [2010] found that homozygosity for c.2080A>G was associated with a lower response to colchicine treatment. They suggested that such patients may therefore be at an increased risk of developing amyloidosis.

Other information on possible genotype-phenotype correlations with the pathogenic variant c.2080A>G is conflicting:

  • Delibaş et al [2005], Mattit et al [2006], and Pasa et al [2008] found that c.2080A>G (p.Met694Val) is associated with a generally more severe form of the disease; however, an earlier study by Balci et al [2002] found no such association.
  • Some recent studies did find that individuals with FMF who were homozygous for the c.2080A>G pathogenic variant and those who were either heterozygous for this pathogenic variant or compound heterozygous for c.2080A>G and another pathogenic variant experienced a more severe clinical course according to the Tel Hashomer Severity Score for FMF [Sohar et al 1997]; of note, the rates of amyloidosis in these studies were low [Inal et al 2009, Caglayan et al 2010, Ureten et al 2010].

Other pathogenic variants. Amyloidosis occurs less frequently in the presence of pathogenic variants other than c.2080A>G [Shohat et al 1999, Shinar et al 2000, Ben-Chetrit & Backenroth 2001, Ben-Chetrit 2003].

Other possible modifiers. Although disease severity, including the major clinical manifestations, amyloidosis, and other associated manifestations, are influenced by the MEFV pathogenic variants themselves, intra- and interfamilial clinical differences suggest that these parameters are also influenced by other genes (outside the MEFV locus) and/or environmental factors.

  • Studies have suggested that gender, serum amyloid A concentration, and genes involved in predisposition to arthritis may play a role as modifiers [Akar et al 2003, Gershoni-Baruch et al 2003, Yilmaz et al 2003].
  • The effects of the major histocompatibility complex class I chain-related gene A (MICA) on the course of FMF have been studied and no MICA allele was found to have any independent risk factor effect [Medlej-Hashim et al 2004]. However, one study suggested that the A5 allele had a protective effect against the development of amyloidosis in a subgroup of c.2080A>G homozygotes [Turkcapar et al 2007]. Another study found that the impact of c.2080A>G homozygosity on the age at disease onset was exacerbated if people also inherited MICA-A9, whereas the frequency of attacks was found to be dramatically reduced in individuals with MICA-A4. The authors commented that these results clarify, at least partly, the inconsistent phenotype-MEFV correlation in FMF [Touitou et al 2001].
  • Another study found that the genotype SAA1-13T has at least some effect on the development of amyloidosis [Akar et al 2006].

Nomenclature

Previously used names no longer in common use for the disease that is now generally known as familial Mediterranean fever are "familial paroxysmal polyserositis" and "periodic disease."

Prevalence

FMF predominantly affects populations living in the Mediterranean region, especially North African Jews, Armenians, Turks, and Arabs. The pathogenic variant c.2080A>G (p.Met694Val) is found in more than 90% of affected Jewish persons of North African origin.

FMF is also seen (although in much lower numbers) in many other countries, where it shows considerable variability in severity and type of manifestations [Ben-Chetrit & Touitou 2009]; the variability may be attributable to the type of mutation or to environmental factors. In some cases, individuals may have been misdiagnosed as having another disease with similar clinical features (e.g., Behçet's disease, systemic lupus erythematosus, palindromic rheumatism, rheumatic fever). The limited number of individuals diagnosed with FMF in certain areas of the world is probably attributable to lack of awareness of the disorder [Ben-Chetrit & Touitou 2009].

The FMF phenotype in Arabs appears to be distinct, and the range and distribution of MEFV pathogenic variants are different from those noted in other ethnic groups [El-Shanti et al 2006]. Among the Arab populations, the distribution of mutations varies by country.

FMF has also been reported in other parts of the world. Prevalence and mutation frequencies by country are shown in Table 2 (pdf).

Differential Diagnosis

Recurrent fever. Recurrent fever syndromes are reviewed by Padeh [2005]. Testing using multi-gene panels for recurrent fever may be available. Note: The genes involved and methods used in multi-gene panels vary.

In individuals of western European heritage with a clinical diagnosis of FMF, the frequency of common MEFV pathogenic variants was found to be extremely low and no affected individual had two identified MEFV pathogenic variants [Tchernitchko et al 2005]. One of 21 affected individuals was heterozygous for c.1772T>C (p.Ile591Thr); this is a nucleotide variation of exon 9, a sequence that is not explored by the usual testing methods. Therefore, it was concluded that persons with FMF-like syndromes from these populations in fact do not have FMF but rather have another condition with a similar clinical picture that cannot be accounted for by mutation of MEFV, and thus, a search should be made for other causes in these individuals [Tchernitchko et al 2005].

The other autoinflammatory diseases for which the associated gene(s) have been identified include the following:

  • Cryopyrin-associated periodic syndromes (CAPS) are associated with pathogenic variants in NLRP3 (formerly CIAS1) inherited in an autosomal dominant manner, which encodes the protein cryopyrin [Hoffman et al 2001, Dodé et al 2002]:
    • Chronic infantile neurologic cutaneous and articular (CINCA) syndrome (also called neonatal-onset multisystem inflammatory disease [NOMID])
    • Familial cold autoinflammatory syndrome (FCAS, also known as familial cold urticaria), characterized by cold-induced attacks of fever, rash, and arthralgia but no deafness or amyloidosis
    • Muckle-Wells syndrome (MWS), characterized by urticaria, deafness, and renal amyloidosis
      Note: The genes MEFV and NLRP3 (CIAS1) belong to the pyrin gene family based on their nucleotide sequences and predicted protein structures.
  • Blau syndrome is a rare autosomal dominant disease characterized by arthritis, uveitis, skin rash, and granulomatous inflammation. It is caused by pathogenic variants in NOD2 that affect the central nucleotide-binding NACHT domain and is characterized by variable expressivity, usually affecting children younger than age four years [van Duist et al 2005].
  • Crohn disease. A strong association has been found between Crohn disease (CD) and relatively rare variants of NOD2 [Cooney et al 2010, Stappenbeck et al 2011]. The autophagy genes ATG16L1 (autophagy-related 16-like 1 gene, located on 2q37.1) and IRGM (immunity-related guanosine triphosphatase M, located on 5q33.1) have also been found to be strongly associated with CD [Massey & Parkes 2007].
  • TRAPS (TNF receptor-associated periodic syndrome) (TNF = tumor necrosis factor) is an autosomal dominant disorder caused by a pathogenic variant in TNFRSF1A. This pathogenic variant results in decreased serum levels of soluble TNF receptor leading to inflammation as a result of unopposed TNF-alpha action. Also called familial Hibernian fever, TRAPS is characterized by attacks of fever, sterile peritonitis, arthralgia, myalgia, skin rash, and conjunctivitis. Some individuals develop amyloidosis. Treatment with recombinant TNF-receptor analogs is promising. The clinical picture in TRAPS may be similar to that in FMF; the mode of inheritance and the results of molecular testing distinguish the two conditions [Aksentijevich et al 2001].
  • HIDS (hyperimmunoglobulinemia D and periodic fever syndrome) is an autosomal recessive disorder characterized by recurrent attacks of fever, abdominal pain, and arthralgia. HIDS is caused by a pathogenic variant in MVK, which encodes mevalonate kinase. A subgroup of HIDS is caused by pathogenic variant in another as-yet unknown gene. The recurrent episodes of fever and abdominal pains in HIDS are frequently indistinguishable from those in FMF, and correct diagnosis may depend on ascertainment of the effectiveness of colchicine as a treatment and on molecular testing [Simon et al 2001].
  • ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia, which are autosomal dominant disorders characterized by recurrent fever, skin and oropharyngeal inflammation, and cervical adenopathy. In congenital neutropenia, diarrhea, pneumonia, and deep abscesses in the liver, lung, and subcutaneous tissues are common in the first year of life. Individuals with congenital neutropenia are at significant risk of developing myelodysplasia (MDS) and acute myelogenous leukemia (AML). In cyclic neutropenia, cellulitis, especially perianal cellulitis, is common during the neutropenic periods. Between neutropenic periods, individuals are generally healthy, and symptoms improve in adulthood. Mutation of ELANE, which encodes leukocyte elastase, is causative.
  • PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome) is an autoinflammatory disorder with autosomal dominant inheritance. It is a rare, noninfectious form of skin ulceration, typically accompanied by neutrophilic infiltration. Two pathogenic variants (p.Ala230Thr and p.Glu250Gln) in CD2BP1/PSTPIP1, encoding proline-serine-threonine phosphatase-interacting protein (PSTPIP) 1, have been identified in patients with this condition [Nesterovitch et al 2011].
  • PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome). The episodes of periodic fever in PFAPA are frequently indistinguishable from those in FMF; molecular testing of MEFV and/or close follow up (with and without treatment) may be needed to make the correct diagnosis. To date, no genetic basis for PFAPA syndrome has been discovered [Gattorno et al 2009]. Treatment with steroids in the early stages of an attack is effective.

Amyloidosis. Transthyretin-related amyloidosis needs to be considered. This autosomal dominant disorder is characterized by a slowly progressive peripheral sensorimotor neuropathy and autonomic neuropathy as well as non-neuropathic changes of nephropathy, cardiomyopathy, vitreous opacities, and CNS amyloidosis [Ferlini et al 1992, Rapezzi et al 2006]. The disease usually begins in the third or fourth decade with paresthesia and hypesthesia of the feet, and is followed by motor neuropathy within a few years. Autonomic neuropathy includes orthostatic hypotension, constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, sexual impotence, anhidrosis, and urinary retention or incontinence. Cardiac amyloidosis causes progressive cardiomyopathy. CNS effects can include dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage. Mutation of TTR is causative.

Abdominal pain. Any cause of acute abdominal pain needs to be considered, including: acute appendicitis, perforated ulcer, intestinal obstruction, acute pyelitis, acute pancreatitis, cholecystitis, diverticulitis, and in females, gynecologic conditions such as ectopic pregnancy, acute or chronic salpingitis, torsion of ovarian cyst, bilateral pyosalpinx, and endometriosis.

Arthralgia. Consider the following:

  • Acute rheumatoid arthritis
  • Rheumatic fever
  • Septic arthritis
  • Collagen vascular diseases

Pleuritic pain. Consider the following:

  • Pleurisy
  • Pulmonary embolism

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with familial Mediterranean fever (FMF), the following evaluations are recommended:

  • Physical examination to assess joint problems
  • Urinalysis for the presence of protein. If proteinuria is found, further evaluation is required, including 24-hour urinary protein assay and renal function tests, and also, if indicated, rectal biopsy for the presence of amyloid.
  • Medical genetics consultation

Treatment of Manifestations

For information on treatment with colchicine see Prevention of Primary Manifestations.

Colchicine is not effective as treatment for an acute FMF attack. During an acute episode, the therapeutic approach should be mainly supportive, including administration of intravenous saline for hydration and use of nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol or dipyrone for pain relief [Ozturk et al 2011].

Febrile and inflammatory episodes are usually treated with NSAIDs.

End-stage renal disease caused by renal amyloidosis should be treated as for other causes of renal failure. The long-term outcome of live related-donor renal transplantation in individuals with FMF-amyloidosis is similar to that in the general transplant population [Sherif et al 2003].

Prevention of Primary Manifestations

Colchicine

  • Homozygotes/compound heterozygotes. Individuals who are homozygous for the pathogenic variant p.Met694Val or compound heterozygous for p.Met694Val and another disease-causing allele should be treated with colchicine as soon as the diagnosis is confirmed, as this drug prevents both the inflammatory attacks and the deposition of amyloid. Colchicine is given orally, 1.0-2.0 mg/day in adults. Children may need 0.5-1.0 mg/day according to age and weight. Affected individuals should receive colchicine for life.

    Individuals who do not have the p.Met694Val pathogenic variant and who are only mildly affected (those with infrequent inflammatory attacks) should either be treated with colchicine or monitored every six months for the presence of proteinuria.

    Continuous treatment with colchicine appears to be less indicated for individuals who are homozygous or compound heterozygous for the pathogenic variant p.Glu148Gln. Colchicine should only be given to these individuals if they develop severe inflammatory episodes and/or proteinuria as a result of amyloidosis.
  • Heterozygotes. The presence of a single MEFV pathogenic variant together with clinical symptoms is sufficient to warrant the initiation of a trial of colchicine; therefore, manifesting heterozygotes should be treated [Booty et al 2009]. However, since the natural history and outcome (i.e., the risk for secondary amyloidosis) for persons with FMF who are heterozygous for a single MEFV pathogenic variant are not well known, there is no recommendation of lifelong treatment with colchicine for this group [Koné-Paut et al 2009].

    Complications of colchicine use occasionally include myopathy and toxic epidermal necrolysis-like reaction.

Treatment of affected individuals who are unresponsive to colchicine. Some individuals appear to be unresponsive to colchicine treatment. In one study this was associated with inadequate colchicine concentration in mononuclear cells, possibly resulting from a genetic defect underlying FMF [Lidar et al 2004] or from poor compliance.

  • Weekly intravenous colchicine (1.0 mg) to supplement oral colchicine resulted in a 50% reduction (except joint attacks) in attack frequency in one study of 13 individuals [Lidar et al 2003].
  • Thalidomide has been used successfully [Seyahi et al 2002, Seyahi et al 2006]
  • Etanercept has been used successfully [Sakallioglu et al 2006, Seyahi et al 2006, Mor et al 2007].
  • Anakinra, an IL-1-receptor inhibitor with a short half-life, has been shown to have a therapeutic advantage in persons with FMF who are resistant to colchicine. Several reports indicate that this offers a relatively safe and effective treatment (100 mg daily or every other day) for persons who do not respond to colchicine [Belkhir et al 2007, Bhat et al 2007, Gattringer et al 2007, Kuijk et al 2007, Calligaris et al 2008, Roldan et al 2008, Moser et al 2009, Petropoulou et al 2010, Meinzer et al 2011, Ozen et al 2011, Ozturk et al 2011, Hentgen et al 2013b]. Anakinra is expensive and has mild side effects, such as painful local reactions at the site of injections and possibly bronchopulmonary infection complications, especially in persons with other risk factors for pulmonary infections. Further studies are needed to investigate the long-term effects and side effects of this drug if it is to be taken continuously as required in severely affected individuals with FMF.
  • Infliximab, a chimeric monoclonal antibody against tumour necrosis factor alpha (TNF-α), was found to be effective in the treatment of one individuals with FMF who was resistant to colchicine, resulting in the complete remission of febrile abdominal episodes [Ozgocmen et al 2006].
  • Interferon alpha is another therapeutic agent that has shown signs of promise for affected individuals who are unresponsive to colchicine. Although an early report did not demonstrate a definitive effect [Tunca et al 2004], a later study did show that early intervention with this agent was associated with reduced length or severity of FMF attacks [Tweezer-Zaks et al 2008]. A more recent paper reported a case of colchicine-resistant FMF in which a durable disease remission and regression of renal amyloidosis was induced by prolonged treatment with pegylated interferon-alpha-2a [Vandecasteele et al 2011].
  • Sulphasalazine. The use of sulphasalazine has been reported in a girl age eight years with a five-year history of typical FMF attacks. She was homozygous for the pathogenic variant p.Met694Val and had had arthritis of one knee for several months which was unresponsive to NSAIDs or colchicine. Resolution was achieved after the addition of sulphasalazine at a dose of 50 mg/kg/day [Bakkaloglu et al 2009].

Prevention of Secondary Complications

Treatment with colchicine 1.0 mg/day prevents renal amyloidosis even if the FMF attacks do not respond to the drug.

Surveillance

All individuals with FMF including those not currently being treated, those being treated with colchicine, and those receiving medication other than colchicine should undergo an annual physical examination, a urine spot test for protein, and an evaluation for hematuria [Twig et al 2014]. Kosan et al [2013] additionally recommended monitoring acute-phase reactants (ESR and fibrinogen levels) at regular intervals during attack-free periods, particularly in those with the p.Met694Val pathogenic variant.

Agents/Circumstances to Avoid

Cisplatin. One report suggests that cisplatin worsens symptoms of FMF [Toubi et al 2003].

Cyclosporin A appears to adversely affect renal transplant graft survival in individuals with FMF [Shabtai et al 2002]. It has also been reported to trigger FMF attacks, which responded well to colchicine in a previously asymptomatic individual with myelodysplastic syndrome who was heterozygous for the MEFV pathogenic variant p.Met694Ile [Sasaki et al 2009].

Evaluation of Relatives at Risk

Molecular genetic testing should be offered to all first-degree relatives and other at-risk family members whether or not they have symptoms. This is especially important when the p.Met694Val allele is present because other affected family members may not have inflammatory attacks, but nevertheless remain at risk for amyloidosis (FMF type 2) and thus need to be treated with colchicine (1.0 mg/day) to prevent the development of renal amyloidosis.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Ben-Chetrit et al [2010] conducted a survey to evaluate the outcome of pregnancies of women taking colchicine to treat FMF. Three cohorts were studied:

  • 179 pregnancies in women with FMF taking colchicine during pregnancy
  • 197 pregnancies in women with FMF who did not take colchicine during pregnancy
  • 312 pregnancies in healthy women of similar age and ethnicity

No difference was found between the three groups regarding early abortions, late abortions, or congenital malformations. Although a mild trend towards a better outcome for the colchicine-treated group was observed, the results did not reach statistical significance. The authors concluded that treatment of women with FMF with colchicine during pregnancy controls the disease and does not affect the outcome of the pregnancy; therefore, no evidence supports the recommendation for use of amniocentesis for cytogenetic studies in women taking colchicine to treat FMF solely because of this treatment.

A prospective study of the fetal safety of colchicine evaluated 238 pregnancies exposed to the drug; the study concluded that colchicine is not a major human teratogen and found no evidence for an increased risk of chromosomal abnormalities in the offspring [Diav-Citrin et al 2010].

Based on one study, FMF appears to be an independent risk factor for preterm delivery, although perinatal outcome is comparable to the general population [Ofir et al 2008].

Therapies Under Investigation

The decrease of blood nitric oxide (NO) levels in individulas with FMF may trigger fever by initiating the production of IL-6. Plasma NO levels in those with FMF were significantly increased during attack-free periods following treatment with ImmunoGuard®, which has a normalizing effect both on NO and IL-6 blood levels in persons with FMF during attacks [Panossian et al 2003]. However, further studies are needed to confirm a single report of successful treatment of FMF with ImmunoGuard® (Andrographis paniculata Nees) [Amaryan et al 2003].

The role of biologics such as anti-tumor necrosis factor (TNF) agents (infliximab, etanercept, adalimumab, golimumab) in the treatment of FMF has recently been investigated [Ozgocmen & Akgul 2011]. Anti-TNF agents have shown efficacy in rheumatic diseases, and there are many reports of persons with FMF responding favorably to treatment with these agents [Ozgocmen & Akgul 2011].

Other IL-1β inhibitors:

Hentgen et al [2013b] recommended that rilonacept and canakinumab, which are medium or long half-life molecules, should be considered only if anakinra, a short half-life molecule, has been proven to be effective. However, Meinzer et al [2011] commented that whether long-lasting drugs should be used as a first-line treatment, or only after having confirmed the clinical benefit of silencing the IL-1 pathway with short-acting drugs, or when compliance problems are encountered, needs to be discussed. They also pointed out that although long-acting molecules are appealing because of their convenience of use and thus higher likelihood of compliance, data on safety and tolerance of these drugs are currently very limited; and once taken, it is impossible to interrupt the course of their effects, some of which may be adverse [Meinzer et al 2011].

Anakinra may also be effective in the treatment of acute FMF attacks; clinical trials are planned and if these are successful it could prove to be a useful drug for this indication [Ozturk et al 2011].

One study showed that a selective serotonin reuptake inhibitor (SSRI) paroxetine significantly decreased the number of acute attacks in individuals with colchicine-resistant FMF, several of whom also suffered from depression. The authors suggested that the depression may have triggered the attacks, and that treatment of the depression had the effect of suppressing the attacks [Onat et al 2007].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Familial Mediterranean fever (FMF) is generally inherited in an autosomal recessive manner, although some recent studies have suggested that some heterozygotes manifest FMF within a phenotypic spectrum from mild to classic findings.

Many models to explain manifesting heterozygotes are under investigation including: autosomal dominant inheritance with incomplete penetrance and variable expression [Marek-Yagel et al 2009, Moradian et al 2010], digenic inheritance with a pathogenic variant in another recurrent fever-related gene, and the presence of modifying alleles in related genes or in the presence of certain environmental factors [Ozen 2009].

Other possibilities include the presence of less common pathogenic variants missed by routine testing, the presence of mutations in introns, or the presence of pathogenic variants in a neighboring gene. Ozen [2009] also suggests the possible coexistence of another autoinflammatory disease.

Risk to Family Members

Parents of a proband

  • The parents of an individual with biallelic MEFV pathogenic variants are obligate heterozygotes and therefore carry a single copy of an MEFV pathogenic variant.
  • Heterozygotes are usually asymptomatic.
  • In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that affected children may be born to an affected individual and a carrier, or even to two affected individuals. Thus, it is appropriate to consider molecular genetic testing of the parents of the proband.

Sibs of a proband. If both parents are heterozygous for an MEFV pathogenic variant:

  • At conception, each sib of an affected individual has a 25% chance of inheriting two MEFV pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes are usually asymptomatic.

If one parent has two MEFV pathogenic variants and one parent is heterozygous:

  • At conception, each sib of an individual with two pathogenic variants has a 50% chance of inheriting two pathogenic variants and being affected and a 50% chance of being heterozygous.
  • Heterozygotes are usually asymptomatic.

Offspring of a proband

  • All of the offspring inherit one MEFV pathogenic variant from a parent with two MEFV pathogenic variants.
  • In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may have two MEFV pathogenic variants or be heterozygous. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner.

Other family members of a proband. Each sib of an obligate heterozygote is at a 50% risk of being a carrier of an MEFV pathogenic variant.

Carrier Detection

Carrier testing is possible once the MEFV pathogenic variants in the family are known.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic family members. Given the ready availability of effective treatment for FMF, it is appropriate to test asymptomatic at-risk family members (particularly sibs of an affected individual). See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the MEFV pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Other issues to consider. Prenatal diagnosis of FMF, a treatable condition associated with a good prognosis with early treatment, may be controversial if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider this to be the choice of the parents, discussion and examination of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the MEFV pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Familial Mediterranean Fever: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Familial Mediterranean Fever (View All in OMIM)

134610FAMILIAL MEDITERRANEAN FEVER, AUTOSOMAL DOMINANT
249100FAMILIAL MEDITERRANEAN FEVER; FMF
608107FAMILIAL MEDITERRANEAN FEVER GENE; MEFV

Gene structure. MEFV comprises ten exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Some consider c.442G>C to be a benign allelic variant (see following discussion).

Pathogenic allelic variants/variants of unknown clinical significance. To date, 296 sequence variants have been identified, only some of which are regarded as having an associated phenotype and resulting in disease-related symptoms (For more information, see Table A, The registry of MEFV sequence variants.)

  • c.442G>C (p.Glu148Gln). Disagreement exists as to whether the c.442G>C substitution is a pathogenic or a benign allelic variant; c.442G>C is predominant in Ashkenazi and Iraqi Jews, Armenians, and Turks, and has been associated with a generally mild form of FMF. Indeed, many individuals who are either homozygous for c.442G>C or compound heterozygous for this variant and a pathogenic variant other than c.2080A>G (p.Met694Val) are asymptomatic. Such individuals are also at a low risk (if any) of developing amyloidosis. The possible exception is those who are compound heterozygous for the alleles c.[442G>C];[ 2080A>G]; such individuals may be clinically affected and also at risk of developing amyloidosis [Aksentijevich et al 1999, Tchernitchko et al 2003].
  • Affected individuals in the ‘one or no detectable pathogenic variant’ category. Mattit et al [2006] tested for four pathogenic variants (c.2080A>G [p.Met694Val], c.2082G>A [p.Met694Ile], c.2040G>C [p.Met680Ile], c.2177T>C [p.Val726Ala]) and the variant c.442G>C (p.Glu148Gln) in 83 unrelated individuals who fulfilled the international FMF criteria and 242 unrelated apparently healthy controls.

    Among the 83 affected individuals, 30.1% were homozygotes, 39.8% compound heterozygotes, 19.3% heterozygotes, and 10.8% had no identifiable pathogenic variant. Sequence analysis of the entire coding region of exon 10 in persons in whom only one or no pathogenic variant was detected identified the pathogenic variants c.2230G>T (p.Ala744Ser) and c.2282G>A (p.Arg761His) in a few cases. It is, therefore, possible that a significant number of affected individuals in the ‘one or no pathogenic variant’ category did in fact have pathogenic variants that were undetectable by the methods employed in this study.

    Note that the possibility of manifesting heterozygotes was raised as far back as 2001 [Livneh et al 2001]. Ozen [2009] discussed possible explanations as to how a person heterozygous for only one MEFV pathogenic variant can have the clinical manifestations of classic FMF:
    • The presence of less common pathogenic variants missed by routine testing (i.e., the easiest explanation). The second undetected mutation may be in an intron, or situated some distance from the gene itself, or possibly even in a neighboring gene (as with pathogenic variants in GJB2 and GJB6 that cause hearing loss). This may explain the failure to detect in a substantial number of patients either a second pathogenic variant when the gene and promoter region were fully sequenced or a common haplotype in their families [Booty et al 2009, Marek-Yagel et al 2009].
    • The effect of environment. Ozen [2009] postulates that a plausible explanation could be that if a person with one MEFV pathogenic variant who also carries a combination of polymorphisms that would favor more inflammation is exposed to the wrong environmental factors, he or she may cross the threshold of manifesting an FMF phenotype. See also Mode of Inheritance.
  • Large genomic alterations. van Gijn et al [2008] addressed the question of whether larger genomic alterations are involved in the pathophysiology of FMF. They used multiplex ligation-dependent probe amplification (MLPA) on a total of 216 patients with FMF symptoms and found that not a single deletion/duplication could be detected in this large cohort, suggesting that single or multiexon MEFV copy number changes do not contribute substantially (if at all) to the MEFV mutation spectrum [van Gijn et al 2008].

Table 3. Selected MEFV Allelic Variants

Variant ClassificationDNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
Uncertain clinical significancec.442G>Cp.Glu148GlnNM_000243​.2
NP_000234​.1
Pathogenicc.1105C>Tp.Pro369Ser
c.1223G>Ap.Arg408Gln
c.1772T>Cp.Ile591Thr
c.1958G>Ap.Arg653His
c.2040G>Cp.Met680Ile
c.2076_2078delp.Ile692del
c.2080A>Gp.Met694Val
c.2082G>Ap.Met694Ile
c.2084A>Gp.Lys695Arg
c.2177T>Cp.Val726Ala
c.2230G>Tp.Ala744Ser
c.2282G>Ap.Arg761His

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The normal gene is a member of a family of nuclear factors homologous to the Ro52 autoantigen. It encodes a 3.7-kb transcript that is expressed exclusively in granulocytes, white blood cells important in the immune response. The protein encoded by MEFV has been called pyrin by the International FMF Consortium, and marenostrin by the International FMF Consortium [IFMFC 1997]. The protein contains 781 amino acids and its normal function is probably to assist in controlling inflammation by deactivating the immune response.

The pyrin protein exists in several isoforms of unknown function. The recombinant full-length isoform (pyrin.fl) is cytoplasmic, whereas an alternatively spliced isoform lacking exon 2 (pyrin.DeltaEx2) concentrates in the nucleus. Native pyrin, mainly consisting of pyrin.fl, is also cytoplasmic in monocytes but is predominantly nuclear in other cell types [Jéru et al 2005].

Abnormal gene product. Normal pyrin protein interacts directly at the C-terminal B30.2 domain (where most of the FMF- pathogenic variants are situated) to regulate caspase-1 activation and consequently IL-1β production. The assumption is that pathogenic variants in persons with FMF result in less IL-1β activation and as a consequence heighten interleukin-1 (IL-1) responsiveness, resulting in increased inflammatory attacks. A new suggestion is that the MEFV pathogenic variants that cause FMF may be gain-of-function pyrin mutations. It was shown in mice that the insertion of three different mutant human B30.2 domains induced inflammatory phenotypes similar to or more severe than those seen in persons with FMF, whereas deleting mouse pyrin produced no overt inflammatory phenotype [Chae et al 2011].

References

Literature Cited

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Suggested Reading

  1. Ben-Chetrit E, Ben-Chetrit E. The rise and fall of FMF research - fifty years of publications. Clin Exp Rheumatol. 2005;23:S3–7. [PubMed: 16273758]
  2. Benson MD. Amyloidosis. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 209. New York, NY: McGraw-Hill. Available online. 2014. Accessed 6-13-14.
  3. Lidar M, Kedem R, Berkun Y, Langevitz P, Livneh A. Familial Mediterranean fever in Ashkenazi Jews: the mild end of the clinical spectrum. J Rheumatol. 2010;37:422–5. [PubMed: 20008924]
  4. Ozen S, Hoffman HM, Frenkel J, Kastner D. Familial Mediterranean fever (FMF) and beyond: a new horizon. Fourth International Congress on the Systemic Autoinflammatory Diseases held in Bethesda, USA, 6-10 November 2005. Ann Rheum Dis. 2006;65:961–4. [PMC free article: PMC1798229] [PubMed: 16606647]
  5. Samuels J, Ozen S. Familial Mediterranean fever and the other autoinflammatory syndromes: evaluation of the patient with recurrent fever. Curr Opin Rheumatol. 2006;18:108–17. [PubMed: 16344627]
  6. Schaner PE, Gumucio DL. Familial Mediterranean fever in the post-genomic era: how an ancient disease is providing new insights into inflammatory pathways. Curr Drug Targets Inflamm Allergy. 2005;4:67–76. [PubMed: 15720238]
  7. Tunca M, Ozdogan H. Molecular and genetic characteristics of hereditary autoinflammatory diseases. Curr Drug Targets Inflamm Allergy. 2005;4:77–80. [PubMed: 15720239]

Chapter Notes

Author Notes

Professor Mordechai Shohat, MD has been involved with research into familial Mediterranean fever, including the molecular analysis of MEFV and phenotype-genotype correlation studies, for over eighteen years.

For further information about familial Mediterranean fever, contact Professor Shohat:

Phone: +972-3-937-7659
Fax: +972-3-937-7660
Email: li.ca.uat.tsop@tahohsm

Revision History

  • 19 June 2014 (me) Comprehensive update posted live
  • 26 April 2012 (me) Comprehensive update posted live
  • 30 April 2009 (me) Comprehensive update posted live
  • 25 February 2008 (ms) Revision: clarification of PFAPA in Differential Diagnosis
  • 2 January 2008 (ms) Revision: Molecular Genetics, Pathologic allelic variants
  • 28 February 2007 (me) Comprehensive update posted to live Web site
  • 5 November 2004 (me) Comprehensive update posted to live Web site
  • 13 November 2002 (me) Comprehensive update posted to live Web site
  • 8 August 2000 (me) Review posted to live Web site
  • 4 April 2000 (ms) Original submission
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