DiagnosisThe diagnosis of familial Mediterranean fever (FMF) is based on a combination of clinical and molecular genetic findings.Clinical DiagnosisFeatures suggesting the diagnosis of familial Mediterranean fever (FMF) include 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 FMF in a first-degree relative At-risk ethnic group The minimal (and most current) criteria for diagnosis of FMF are the Tel Hashomer clinical criteria [Pras 1998, Livneh et al 1997]. They are:Fever plus EITHER:One or more major signs and one minor sign;
ORTwo 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: (1) Yalcinkaya 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 [Pras 1998, Livneh et al 1997]. (2) 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. Molecular Genetic TestingGene. MEFV is the only gene in which mutations are known to cause FMF. Table 1. Summary of Molecular Genetic Testing Used in Familial Mediterranean FeverView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityMEFVTargeted mutation analysis 2 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) Armenian: 90%Clinical Turkish: 90%Arab: 70%North African Jewish: 95%Iraqi Jewish: 80%Ashkenazi Jewish: 90%Sequence analysisSequence variants 3 in exon 10All groups: 90%Sequence variants 3 outside exon 10Deletion / duplication analysis 4Exonic or whole-gene deletionsUnknown; none reported 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Panel may vary by laboratory.3. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Deletion/duplication analysis refers to testing that identifies deletions/duplications not readily 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.5. van Gijn et al [2008]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (Table A and/or Pathologic allelic variants).Testing StrategyUse of molecular genetic testing to confirm/establish the diagnosis in a probandAlternative 1. Single gene testingIn most individuals with classic FMF, targeted mutation analysis of the common MEFV mutations identifies two mutations and, thus, confirms the diagnosis. If neither or only one MEFV mutation 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 mutation.
Note: Studies to try to identify a second MEFV mutation in persons with the clinical diagnosis of FMF and a single high-penetrance MEFV mutation usually have not detected a second MEFV mutation, 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 mutation. In such individuals detection of a single mutation 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 testingIf 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 causative mutation or mutations in any given individual also varies. Carrier testing for at-risk relatives with confirmed autosomal recessive inheritance of FMF requires prior identification of the disease-causing mutations in the family.Linkage analysis may be an option for carrier testing for families in which neither or only one MEFV mutation 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. Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation(s) in the family. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersIt is possible that mutations in MEFV are an additional genetic susceptibility factor in the following disorders: Behçet's disease. An increased frequency of MEFV mutations has been found in individuals with Behçet's disease [Cattan 2005, Imirzalioglu et al 2005, Rabinovich et al 2007, Ayesh et al 2008]. Rabinovich et al [2007] found that of 54 individuals with definitively proven Behçet's disease, 21 were heterozygous for an MEFV mutation (p.Met694Val [14 persons], p.Glu148Gln [6], p.Val726Ala [1]) and three were compound heterozygous for the mutations p.Met694Val/p.Glu148Gln, a frequency significantly higher than that expected for ethnically matched healthy individuals. Of note, the authors also found that heterozygotes were at an increased risk for venous thrombosis. Ayesh et al [2008] found that of 42 individuals with a clinical diagnosis of Behçet's disease, 17 had ten different MEFV mutations: 14 were heterozygous for one mutation, two were compound heterozygous, and one had three mutations. None had homozygous mutations. Inflammatory bowel disease (IBD). Pyrin, the protein encoded by MEFV, has been shown to interact with cryopyrin, the protein encoded by NLRP3, which is an important active member of the inflammasome. Although the NLRP3 region has been reported to be associated with Crohn's disease (CD) susceptibility, the results of some studies suggest that common variants in the MEFV region did not contribute to CD or inflammatory bowel disease susceptibility [Fidder et al 2005, Villani et al 2009]. In contrast, some studies did find an increased frequency of MEFV mutations in persons with ulcerative colitis (UC), especially those with episodic arthritis, which may suggest a possible modifying effect of MEFV in the disease process [Cattan 2005, Giaglis et al 2006, Yurtcu et al 2009, Uslu et al 2010]. Other studies found that CD appears to be more prevalent in FMF, presents later than in persons without FMF [Fidder et al 2002, Kuloğlu et al 2012], and is more often complicated by amyloidosis [Fidder et al 2002]. In a study from Turkey, Sari et al [2008] reported the concurrent manifestation of IBD and FMF in three infants (age <6 months) with infantile UC and the MEFV mutation p.Met694Val. One required colectomy before the diagnosis of FMF was made; in the other two, UC was not controlled until colchicine was added to the drug regimen. The authors suggest that infants with UC should be tested for MEFV mutations so that colchicine therapy can be initiated if appropriate. Rheumatoid arthritis. Mutations in MEFV, in particular the c.442G>C (p.Glu148Gln) variant, have been found to be an independent modifier of the clinical manifestations of rheumatoid arthritis [Rabinovich et al 2005, Kalyoncu et al 2006].Juvenile idiopathic arthritisAyaz et al [2009] screened 35 children with systemic-onset juvenile idiopathic arthritis (SoJIA) for 12 MEFV mutations. They found that FMF-causing mutations (most commonly c.2080A>G) were significantly more frequent in the children with SoJIA than in the general population. Six persons with MEFV mutations were among those with the most resistant disease course, requiring biologic therapy: two were homozygous and three were heterozygous for the MEFV mutation p.Met694Val; one was compound heterozygous for p.Met680Ile/p.Val726Ala. A patient with FMF and juvenile idiopathic arthritis with osteoporosis was successfully treated with etanercept [Kaya et al 2010].Ankylosing spondylitis. A higher frequency of MEFV variants (primarily c.2080A>G) has been found in persons with ankylosing spondylitis than in healthy controls and controls with rheumatoid arthritis [Akar et al 2009, Akkoc et al 2010]. Palindromic rheumatism. One report found an unexpectedly high frequency of MEFV mutations in persons with anti-citrullinated protein antibody-negative palindromic rheumatism [Cañete et al 2007]; however, a later study found that anti-cyclic citrullinated peptide antibodies were not associated with FMF [Karatay et al 2010a]. Another paper reported that the level of anti-cyclic citrullinated peptide antibodies was higher in persons with FMF with arthritis than without arthritis [Ceri et al 2010].Systemic lupus erythematosus (SLE). There are several reports of the co-occurrence of SLE with FMF [Lidar et al 2008, Yildiz et al 2010]. While this co-occurrence could be coincidental, it may result in part from underdiagnosis of SLE because of overlapping manifestations and a milder disease phenotype associated with co-occurrence with FMF. The 'protective' association between SLE and FMF may be attributed in part to the absence of anti-serum amyloid P (SAP) antibodies in persons with FMF and in persons with both SLE and FMF [Lidar et al 2008]. Another possibility is that inflammation per se may ameliorate SLE since it is likely that increased C reactive protein in persons with FMF, during and in between attacks, protects from SLE [Ozen & Bakkaloglu 2005]. Manifestations of SLE and FMF show considerable overlap; in individuals who have both disorders, recognition of the two as separate entities is critical to avoiding over- or under-treatment of either disorder [Lidar et al 2008].}

Natural HistoryFamilial 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 is a rare occurrence – it 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 (ESRD). 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].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, Tufan & Demir 2010, Senel et al 2010]. Erysipelas-like erythema 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]. 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 patients' attacks of recurrent aseptic meningitis resolved after treatment with colchicine.Reduced fertility. Untreated individuals with FMF, especially those with multiple attacks and/or amyloidosis, have a higher chance of infertility. Colchicine treatment increases fertility, but in some instances may induce oligospermia/azoospermia [Ben-Chetrit & Levy 2003]. 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]. Chronic ascites and peritoneal malignant mesotheliomaA female with FMF who was compound heterozygous for the mutations c.2080A>G and c.2040G>C developed chronic ascites that responded to a dose adjustment of colchicine [Ureten et al 2009].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 mutation c.2080A>G [Hershcovici et al 2006]. A 56-year-old woman who was a compound heterozygote for c.2080A>G and c.2282G>A had a history of FMF since childhood. She had been on hemodialysis for four years and had experienced recurrent ascites; she did not take colchicine [Sengul et al 2008].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.Other clinical findingsA 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 sub-clinical inflammation, may be mediators of atherosclerotic disease in people 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 mutation is identified. Several studies have attempted to identify a second mutation 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 mutation 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 patients in whom a second mutation was not found than in those in whom a second mutation 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 mutation tend to have milder disease (manifest mainly by fever and abdominal symptoms) than persons with two mutations. 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 mutation seems 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].

Genotype-Phenotype Correlationsc.2080A>G (p.Met694Val). Persons who are homozygous for the mutation 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 heterozygotes for other mutations [Tunca et al 2005].A significant association has been identified between the mutation c.2080A>G and the development of amyloidosis, especially in those who are homozygous for this mutation.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 mutation 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 mutation and those who were either heterozygous for this mutation or compound heterozygous for c.2080A>G and another mutation 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 mutations. Amyloidosis occurs less frequently in the presence of mutations 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 mutations 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> 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 an effect on the development of amyloidosis [Akar et al 2006].

Differential DiagnosisRecurrent 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 mutations was found to be extremely low and no affected individual had two identified MEFV mutations [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 explained by MEFV mutations, 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 autosomal dominant mutations in NLRP3 (formerly CIAS1), 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 mutations in NOD2 that affect the central nucleotide-binding NACHT domain and has 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 mutation in TNFRSF1A. This mutation 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 analogues 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 mutation in MVK, which encodes mevalonate kinase. A subgroup of HIDS is caused by mutation 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 have a 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 [Dale 2011]. Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) is an autoinflammatory disorder with autosomal dominant inheritance. It is a rare, noninfectious form of skin ulceration, typically accompanied by neutrophilic infiltration. Two mutations (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.AmyloidosisTransthyretin-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 PainAny 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. ArthralgiaConsider the following: Acute rheumatoid arthritis Rheumatic fever Septic arthritis Collagen vascular diseases Pleuritic PainConsider the following: Pleurisy Pulmonary embolism Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with familial Mediterranean fever (FMF), the following evaluations are recommended:Complete past medical history, including family history 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 consultationTreatment of ManifestationsFor information on treatment with colchicine see Prevention of Primary Manifestations.Febrile and inflammatory episodes are usually treated with nonsteroidal anti-inflammatory drugs (NSAIDs). End-stage renal disease (ESRD) 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 ManifestationsColchicineHomozygotes/compound heterozygotes. Individuals who are homozygous for the mutation 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 mutation 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 mutation 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 mutation 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 mutation are not well known, there is no recommendation of life-long 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 patients 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, 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]. 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.Interferon alpha is another therapeutic agent that has shown signs of promise for patients 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 an eight-year-old girl with a five-year history of typical FMF attacks. She was homozygous for the mutation 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 ComplicationsTreatment with colchicine 1.0 mg/day prevents renal amyloidosis even if the FMF attacks do not respond to the drug.SurveillanceAll 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 and urine spot test for protein. Agents/Circumstances to AvoidCisplatin. 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 mutation p.Met694Ile [Sasaki et al 2009].Evaluation of Relatives at RiskMolecular 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 ManagementBen-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 pregnancy197 pregnancies in women with FMF who did not take colchicine during pregnancy312 pregnancies in healthy women of similar age and ethnicityNo 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 InvestigationFurther 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 patients with FMF responding favorably to treatment with these agents [Ozgocmen & Akgul 2011]. Other IL-1β inhibitors: There are reports of patients with colchicine-resistant FMF who benefitted from canakinumab, a long-acting fully humanized anti-IL-1β monoclonal antibody [Mitroulis et al 2010, Meinzer et al 2011, Mitroulis et al 2011, Ozgocmen & Akgul 2011]. Mitroulis et al [2010] suggested that the use of canakinumab in the prevention and resolution of FMF attacks may reinforce the suggested implication of impaired inflammasome regulation in the pathogenesis of the disease, in contradistinction to the non-specific IL-1 inhibition by anakinra [Mitroulis et al 2010]. Rilonacept (IL-1 Trap/Arcalyst), another long-acting interleukin-1 blocker, is a dimeric fusion glycoprotein, consisting of the Fc portion of human IgG1 and the human IL-1 receptor (IL-1RI and IL-1 receptor accessory protein) extracellular domains [Mitroulis et al 2010]. It has recently been reported that the weekly administration of this agent leads to immediate resolution of the inflammatory symptoms in patients with familial cold autoinflammatory syndrome (FCAS) (see Differential Diagnosis) [Goldbach-Mansky et al 2008, Hoffman et al 2008]. Thus, rilonacept may also be expected to ameliorate the symptoms in FMF [Chae et al 2009, McDermott 2009]. 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 patient 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]. One study showed that a selective serotonin reuptake inhibitor (SSRI), paroxetine, significantly decreased the number of acute attacks in patients 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMEFV16p13​.3PyrinCatalogue of Somatic Mutations in Cancer (COSMIC)
The registry of MEFV sequence variants
MEFV homepage - Mendelian genesMEFVData 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) View in own window 249100FAMILIAL MEDITERRANEAN FEVER; FMF 608107FAMILIAL MEDITERRANEAN FEVER GENE; MEFVNormal allelic variants. MEFV comprises ten exons. Some consider c.442G>C to be a normal allelic variant (see following discussion).Pathologic allelic variants/variants of unknown clinical significance. To date, 222 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 pathologic or normal 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 mutation 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]. Studies that describe c.442G>C as a disease-causing mutation include those by Stoffman et al [2000], Gershoni-Baruch et al [2002], Konstantopoulos et al [2005], Topaloglu et al [2005], Solak et al [2008], and Tomiyama et al [2008], as well as The Registry of MEFV Sequence Variants (See Table A).
Other studies have not found c.442G>C to be associated with clinical disease and have, therefore, considered it a normal allelic variant [Ben-Chetrit et al 2000, Tchernitchko et al 2003, Tchernitchko et al 2006]. In one study, among 242 controls, the sequence variant c.442G>C was the most common, a finding that the authors attributed to the reduced penetrance of this pathologic variant, suggesting that the presence of this variant explained the considerable proportion of genetically affected individuals in this population who remained asymptomatic [Mattit et al 2006].Affected individuals in the ‘one or no detectable mutation’ category. Mattit et al [2006] tested for four mutations (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 mutation. Sequence analysis of the entire coding region of exon 10 in persons in whom only one or no mutation was detected identified the mutations 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 mutation’ category did in fact have mutations 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 mutation can have the clinical manifestations of classic FMF: The presence of less common mutations 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 mutations in GJB2 and GJB6 that cause hearing loss). This may explain the failure to detect in a substantial number of patients either a second mutation 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 mutation 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 InheritanceLarge 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 that not a single deletion/duplication could be detected in this large cohort. This result suggested 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 VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change Protein Amino Acid ChangeReference SequencesUncertain clinical significancec.442G>Cp.Glu148GlnNM_000243​.2
NP_000234​.1Pathologicc.1105C>Tp.Pro369Serc.1223G>Ap.Arg408Glnc.1772T>Cp.Ile591Thrc.1958G>Ap.Arg653Hisc.2040G>Cp.Met680Ilec.2076_2078delp.Ile692delc.2080A>Gp.Met694Valc.2082G>Ap.Met694Ilec.2084A>Gp.Lys695Argc.2177T>Cp.Val726Alac.2230G>Tp.Ala744Serc.2282G>Ap.Arg761HisSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 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 (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-causing mutations are situated) to regulate caspase-1 activation and consequently IL-1β production. The assumption is that mutations 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 mutations 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].