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 Excerpt

Clinical characteristics: Familial Mediterranean fever (FMF) is divided into two phenotypes: type 1 and type 2.

  1. 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, if untreated.

  2. 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 established in a proband with Tel Hashomer clinical criteria of major and minor features. Major features include fever, abdominal pain, chest pain, joint pain, and skin eruption. Minor features include increased erythrocyte sedimentation rate (ESR), leukocytosis, and elevated serum fibrinogen. Identification of biallelic MEFV pathogenic variants on molecular genetic testing confirms the diagnosis. Up to 25% of individuals with FMF have only one MEFV pathogenic variant identified. A six-month trial of colchicine therapy can establish the diagnosis if molecular testing is inconclusive.

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 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. Individuals who are homozygous or compound heterozygous for p.Glu148Gln should only be treated with colchicine if they develop severe inflammatory episodes and/or proteinuria as a result of amyloidosis. Symptomatic individuals with a heterozygous MEFV pathogenic variant may benefit from a trial of colchicine. Individuals who are unresponsive to colchicine may respond to intravenous colchicine or one of several other medications.

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.

Sections




Summary

Clinical characteristics.

Familial Mediterranean fever (FMF) is divided into 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, if untreated.
  • 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 established in a with Tel Hashomer clinical criteria of major and minor features. Major features include fever, abdominal pain, chest pain, joint pain, and skin eruption. Minor features include increased erythrocyte sedimentation rate (ESR), leukocytosis, and elevated serum fibrinogen. Identification of MEFV pathogenic variants on confirms the diagnosis. Up to 25% of individuals with FMF have only one MEFV identified. A six-month trial of colchicine therapy can establish the diagnosis if molecular testing is inconclusive.

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 renal transplantation.

Prevention of primary manifestations: Homozygotes for the p.Met694Val or compound heterozygotes for p.Met694Val and another disease-causing 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. Individuals who are or for p.Glu148Gln should only be treated with colchicine if they develop severe inflammatory episodes and/or proteinuria as a result of amyloidosis. Symptomatic individuals with a heterozygous MEFV pathogenic variant may benefit from a trial of colchicine. Individuals who are unresponsive to colchicine may respond to intravenous colchicine or one of several other medications.

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 .

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 to all first-degree relatives and other family members (regardless of symptoms) especially when the p.Met694Val is present because renal amyloidosis can be prevented with colchicine treatment.

Genetic counseling.

FMF is usually inherited in an 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 MEFV pathogenic variants are unaffected heterozygotes. However, in populations with a high and/or a high rate of 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 of the parents of the 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 for pregnancies at increased risk are possible if the MEFV pathogenic variants in the family are known.

GeneReview Scope

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

For synonyms and outdated names see Nomenclature.

Diagnosis

Suggestive Findings

Familial Mediterranean fever (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
  • A with FMF
  • Membership in an at-risk ethnic group

Establishing the Diagnosis

The minimal (and most current) clinical criteria used to establish the diagnosis of FMF are the Tel Hashomer clinical criteria [, ]. Identification of MEFV pathogenic variants on molecular testing confirms the diagnosis if clinical features are inconclusive. A colchicine six-month therapy trial can be used to confirm the diagnosis if MEFV molecular testing is inconclusive.

Tel Hashomer Clinical Criteria

Fever AND:

  • One additional major feature and one minor feature
    OR
  • Two minor features

Major features

  • Fever
  • Abdominal pain
  • Chest pain
  • Joint pain (see Note)
  • Skin eruption

Note: 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 [].

Minor features

  • 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 value: 4.5-11.0 x 103µL [4.5-11.0 x 109L])
  • Elevated serum fibrinogen concentration (normal value: 200-400 mg/dL [2.00-4.00 g/L])

Note: Early in life FMF often begins with an atypical presentation characterized by attacks of fever alone, significantly delaying diagnosis and initiation of treatment. Although other diagnostic criteria for children have been suggested by and , and found that the new criteria did not make a better contribution to FMF diagnosis than the Tel Hashomer criteria.

Molecular Genetic Testing

Molecular genetic testing approaches can include single- testing, use of a , and more comprehensive testing.

Single- testing. Sequence analysis of MEFV is performed first.

Note: Up to 25% of individuals with FMF have only one MEFV identified; this appears to be sufficient to initiate a trial of colchicine [, , ].

Targeted analysis for pathogenic variants can be performed first in individuals of Armenian, Turkish, Arab, North African Jewish, Iraqi Jewish, or ancestry. Targeted analysis may include:

  • Exon 2. c.442G>C (p.Glu148Gln)
  • Exon 3
    • c.1105C>T (p.Pro369Ser)
    • c.1223G>A (p.Arg408Gln)
    Note: These two variants in 3 have been shown to be in linkage disequilibrium [].
  • Exon 10
    • c.1958G>A (p.Arg653His)
    • c.2040G>C (p.Met680Ile)
    • c.2076_2078del (p.Ile692del)
    • c.2080A>G (p.Met694Val)
    • c.2082G>A (p.Met694Ile)
    • c.2084A>G (p.Lys695Arg)
    • c.2177T>C (p.Val726Ala)
    • c.2230G>T (p.Ala744Ser)
    • c.2282G>A (p.Arg761His)
    Note: (1) Other variants with exons 2, 3, and 10 are also among the most common. (2) The exons included and pathogenic variants detected may vary by laboratory and over time.

In individuals with suspected inheritance, in addition to the above pathogenic variants, targeted testing for a few additional pathogenic variants may be considered:

  • Exon 10
    • c.1730C>A (p.Thr577Asn)
    • c.2064C>G (p.Tyr688Ter)
    • c.2076_2078delAAT (p.Ile692del)
    • c.2081_2083delTGA (p.Met694del)

A that includes MEFV and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic of the testing used for each vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of and pathogenic variants in genes that do not explain the underlying . (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused analysis that includes genes specified by the clinician. (4) Methods used in a panel may include , , and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive testing (when available) including and may be considered if single- testing (and/or use of a that includes MEFV) fails to confirm a diagnosis in an individual with features of FMF. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Familial Mediterranean Fever

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
MEFV Sequence analysis 375%-90% 4
Gene-targeted  5None reported 6, 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this .

3.

Sequence analysis detects variants that are benign, likely benign, of , likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and , , and variants; typically, or whole- deletions/duplications are not detected. For issues to consider in interpretation of results, click here.

4.

Up to 25% of individuals with FMF have only one MEFV identified [, , ].

5.

Gene-targeted detects intragenic deletions or duplications. Methods used may include , long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a -targeted microarray designed to detect single- deletions or duplications.

6.
7.

Given the proposed mechanism for FMF and the lack of observed large intragenic deletions or duplications, testing for intragenic deletions or is unlikely to identify a disease-causing variant.

Colchicine Trial

In all instances in which the clinical picture suggests FMF but MEFV 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.

Clinical Characteristics

Clinical Description

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 untreated FMF type 1.
  • FMF type 2 is characterized by amyloidosis as the first clinical manifestation of disease in an otherwise asymptomatic individual.

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 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, and (3) gradual resolution of the signs and symptoms after peaking in 24-48 hours. Often a sterile synovial effusion is present.
    The attacks are commonly in the hip or knee, but may occur in 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 individuals with monoarthritis the true diagnosis may not be established for some time and only after extensive investigations.
    Attacks subside spontaneously only after several weeks or months; severe damage to the joint can result, and permanent deformity may require joint replacement. Approximately 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.
  • Prodrome (pre-attack symptoms) are 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) [].
  • Pleural attacks, experienced by about 45% of those with FMF, are the sudden onset of an acute, febrile, unilateral pleuritis. 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 be the sole manifestation of FMF [, ].
  • 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. Rare though it is, recurrent pericarditis can be the sole manifestation of FMF [].
  • 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, , and gender. In untreated individuals, amyloidosis can occur in 60% of individuals of Turkish heritage and in up to 75% of North African Jews [, ].
    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.
    Clinically detectable pulmonary amyloidosis secondary to FMF is rare; only a few cases have been reported to date [].

Less common manifestations of FMF include the following:

  • Protracted febrile myalgia is a severe debilitating myalgia with prolonged low-grade fever, increased erythrocyte sedimentation rate (~100 mm/h), 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 [, ].
  • 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 []. Rarely ELE can be the first disease manifestation of FMF [].
  • Vasculitides are rare and include Henoch-Schönlein purpura (in ~5% of individuals with FMF) and polyarteritis nodosa [, ].
  • Recurrent urticaria has been reported as a rare manifestation of FMF [].
  • Aseptic meningitis was considered to occur rarely in FMF []. performed a systematic review of the literature and concluded that the finding of recurrent aseptic meningitis resulting from 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 [, , ]. 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 [, ]. It is important to continue colchicine treatment even when planning a pregnancy.

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) [, ].

Chronic ascites. A few reports have suggested that individuals with molecularly confirmed FMF have developed chronic ascites that responded to a dose adjustment of colchicine [, , , , ]. This may be a rare manifestation of FMF; However, investigation for other causes of ascites is always recommended.

Psychological features. Depression is more common in individuals with FMF [, ]. Anxiety is more frequent in persons with FMF than in healthy individuals [].

Clinical findings in individuals with FMF in whom only one MEFV is identified. The majority of MEFV heterozygotes are asymptomatic throughout life. Most of the reported families with FMF have pseudodominant transmission (i.e., the children of an individual with two pathogenic variants in MEFV and a partner are at 50% risk of having FMF). In geographic regions where FMF is common, pseudodominant transmission is frequently seen and some families have been described through five generations.

However, heterozygotes with a severe can be symptomatic, and transmission can occur. Three severe variants in 10 (2 deletions and 1 variant) have been identified: p.Met694del (common in northern European, Iranian, and Azari Turkish populations [, ]), p.Ile692del, and p.Tyr688Ter. Autosomal dominant transmission has also been described in a few families with variants including p.Met694Val (the most common Mediterranean variant) and p.Thr577Asn [].

Heterozygotes typically have a later age of onset (mean age 18 years) and milder disease (manifest mainly by fever and abdominal symptoms) than persons with pathogenic variants. Most of the heterozygotes described by had an incomplete abdominal attack (abdominal pain without frank peritonitis) as the major criterion of the disease; in most individuals the response to colchicine therapy was either complete or partial. have shown that the clinical signs of FMF completely disappeared at puberty in five of 18 individuals with a MEFV , allowing them to discontinue colchicine without recurrence of symptoms.

characterized the in 21 individuals for the p.Met694del variant. These individuals shared an identical disease haplotype that appeared to have arisen about 550 years ago. The SAA1.1 was found in four affected individuals, including two with AA amyloidosis. The median age at onset was 18 years. Three individuals presented with AA amyloidosis, two of whom had a history of unrecognized symptoms of FMF. Fifteen individuals received colchicine treatment, all with excellent responses. The 14% incidence of AA amyloidosis may reflect delay in diagnosis associated with extreme rarity of FMF in this population.

Rarely reported associations that are not considered part of the FMF

  • Peritoneal malignant mesothelioma was reported in two persons with FMF who had recurrent peritoneal involvement during childhood. Both were for the p.Met694Val [].
  • Possible association with stroke, multiple sclerosis, and other demyelinating disorders was reported by .
  • Lower bone mineral density was reported by .
  • Increased serum homocysteine and lipoprotein(a) concentrations have been reported during attack-free periods [].
  • Moderate to severe periodontitis was more common in individuals with amyloidosis. Serum levels of acute-phase reactants in people with FMF were reduced significantly following nonsurgical periodontal therapy [].

Genotype-Phenotype Correlations

c.2080A>G(p.Met694Val). Persons who are for the p.Met694Val have an earlier age of onset and higher frequencies of arthritis and arthralgia than persons who are homozygous or for other pathogenic variants []. Individuals with the p.Met694Val pathogenic variant, particularly homozygous individuals, are at increased risk for amyloidosis [] and have a decreased response to colchicine [].

Other pathogenic variants. Amyloidosis occurs less frequently in the presence of pathogenic variants other than p.Met694Val [, , , ].

Other possible modifiers. Intra- and interfamilial clinical differences independent of MEFV suggest genetic and/or environmental modifiers. Suggested modifiers:

Nomenclature

Previously used names no longer in common use for the disease that is now generally known as 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 p.Met694Val is found in more than 90% of affected Jewish persons of North African origin.

FMF occurs less frequently in many other countries, where it shows considerable clinical variability []; the variability may be attributable to the type of variant or to environmental factors. The limited number of individuals diagnosed with FMF in certain areas of the world is probably attributable to lack of awareness of the disorder [].

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