Elsevier

Autoimmunity Reviews

Volume 12, Issue 1, November 2012, Pages 31-37
Autoimmunity Reviews

Review
Familial Mediterranean fever: New phenotypes

https://doi.org/10.1016/j.autrev.2012.07.019Get rights and content

Abstract

Familial Mediterranean fever (FMF) is an inherited autosomal recessive disorder, ethnically restricted and commonly found among individuals of Mediterranean descent, caused by MEditerranean FeVer gene (MEFV) mutations on chromosome 16. It is the most frequent periodic febrile syndrome among the autoinflammatory syndromes. Clinically, FMF can be distinguished into three phenotypes: type 1, which is commonly associated with recurrent short episodes of inflammation and serositis, including fever, peritonitis, synovitis, pleuritis, but also pericarditis, orchitis or meningitis episodes; type 2, characterized by the evidence of reactive amyloid-associated (AA) amyloidosis, the most severe complication of FMF, as the first clinical manifestation of the disease in an otherwise asymptomatic individual; type 3, referred to the ‘silent’ homozygous or compound heterozygote state, in which two MEFV mutations are detected without signs or symptoms of FMF nor of AA amyloidosis. In the recent years it has been observed that also heterozygous mutation carriers can suffer from a mild or incomplete form of FMF, named ‘FMF-like’ disease. The influence of other modifiers genes and/or environmental factors can contribute to the variable penetrance and to the phenotypic variability of FMF. The insight into complex clinical and genetic cases will provide adjunctive details for the comprehension of the mechanisms of this kaleidoscopic disease.

Section snippets

Familial Mediterranean fever (FMF): definition and diagnostic criteria

Familial Mediterranean fever (FMF, OMIM ID: 249100) is an autosomal recessive disease characterized by recurring self-limited short episodes of fever and serositis resulting in pain in the abdomen, chest, joints and muscles; it is the most common of the periodic hereditary fevers.

FMF mainly affects Middle Eastern populations and other ethnic groups living around the Mediterranean basin, such as Jews, Armenians, Turks, Arabs, with high prevalence (1/200–1/1000); also, it is not considered rare

The FMF phenotypes

Clinically, FMF can be distinguished into three phenotypes: type 1, which is commonly associated with recurrent short episodes of inflammation and serositis, including fever, peritonitis, synovitis, pleuritis, but also pericarditis, orchitis or meningitis episodes; type 2, characterized by the evidence of amyloidosis as the first clinical manifestation of the disease in an otherwise asymptomatic individual; type 3, referred to the ‘silent’ homozygous or compound heterozygote state, in which two

Our experience

Since 1990s the Periodic Fevers Research Centre of Catholic University of Sacred Heart of Rome had dedicated its attention to the diagnosis and treatment of patients with periodic autoinflammatory syndromes, accruing a patients experience of more than 1100 individuals and providing us an extensive clinical familiarity with these conditions.

Since 1998 to 2011, among all patients evaluated in our Centre for fever of unknown origin (FUO), 311 (163 M: 148 F) received certain diagnosis of FMF,

Conclusions

As diagnosis of FMF is clinical, an accurate clinical history, together with the monitoring of disease activity through the parameters of inflammation (CRP, SAA, ESR, fibrinogen, white blood cell count), is pivotal for the clinician to determine a correct diagnosis in suspected cases of FMF.

The awareness of FMF prevalence in the population as well as the presence of referee Centers with expert-field clinicians, have a major role to achieve an early diagnosis and thus, to shorten the diagnostic

Take-home messages

  • FMF is an autosomal recessive disease caused by MEFV gene mutations on chromosome 16

  • The identification of MEFV mutations contribute to the different FMF phenotype diagnosis.

  • MEFV mutation may aggravate the autoimmune disease course and influence the therapy.

  • There are variable penetrance and expression of FMF, also in heterozygous subjects.

Conflict of interest statement

The authors deny any financial and personal relationships with other people or organizations that could inappropriately influence the content of this article.

References (79)

  • E. Ben-Chetrit et al.

    Familial Mediterranean fever

    Lancet

    (1998)
  • K. Konstantopoulos et al.

    Familial Mediterranean fever associated pyrin mutations in Greece

    Ann Rheum Dis

    (2003)
  • M. La Regina et al.

    Familial Mediterranean fever is no longer a rare disease in Italy

    Eur J Hum Genet

    (2004)
  • The French FMF Consortium

    A candidate gene for familial Mediterranean fever

    Nat Genet

    (1997)
  • The International FMF Consortium

    Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever

    Cell

    (1997)
  • M. Centola et al.

    The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators

    Blood

    (2000)
  • A. Diaz et al.

    Lipopolysaccharide-induced expression of multiple alternatively spliced MEFV transcripts in human synovial fibroblasts: a prominent splice isoform lacks the C-terminal domain that is highly mutated in familial Mediterranean fever

    Arthritis Rheum

    (2004)
  • F. Milhavet et al.

    The infevers autoinflammatory mutation online registry: update with new genes and functions

    Hum Mutat

    (2008)
  • R. Brik et al.

    Familial Mediterranean fever: clinical and genetic characterization in a mixed pediatric population of Jewish and Arab patients

    Pediatrics

    (1999)
  • I. Touitou

    The spectrum of familial Mediterranean fever (FMF) mutations

    Eur J Hum Genet

    (2001)
  • E. Yilmaz et al.

    Mutation frequency of Familial Mediterranean fever and evidence for a high carrier rate in the Turkish population

    Eur J Hum Genet

    (2001)
  • H.A. Majeed et al.

    Genotype\phenotype correlations in Arab patients with familial Mediterranean fever

    Semin Arthritis Rheum

    (2002)
  • R. Gershoni-Baruch et al.

    The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever

    Eur J Hum Genet

    (2002)
  • A. Livneh et al.

    Criteria for the diagnosis of familial Mediterranean fever

    Arthritis Rheum

    (1997)
  • E. Tunçbilek et al.

    Consanguineous marriage in Turkey and its impact on fertility and mortality

    Ann Hum Genet

    (1994)
  • F. Yalçinkaya et al.

    A new set of criteria for the diagnosis of familial Mediterranean fever in childhood

    Rheumatology (Oxford)

    (2009)
  • A. Kondi et al.

    Validation of the new pediatric criteria for the diagnosis of familial Mediterranean fever: data from a mixed population of 100 children from the French reference centre for auto-inflammatory disorders

    Rheumatology (Oxford)

    (2010)
  • Z.B. Ozçakar et al.

    Application of the new pediatric criteria and Tel Hashomer criteria in heterozygous patients with clinical features of FMF

    Eur J Pediatr

    (2011)
  • A. Balbir-Gurman et al.

    Vasculitis in siblings with familial Mediterranean fever: a report of three cases and review of the literature

    Clin Rheumatol

    (2007)
  • H. Ozdogan et al.

    Vasculitis in familial Mediterranean fever

    J Rheumatol

    (1997)
  • I. Ben-Zvi et al.

    Chronic inflammation in FMF: markers, risk factors, outcomes and therapy

    Nat Rev Rheumatol

    (2010)
  • R. Gershoni-Baruch et al.

    Male sex coupled with articular manifestations cause a 4-fold increase in susceptibility to amyloidosis in patients with familial Mediterranean fever homozygous for the M694V-MEFV mutation

    J Rheumatol

    (2003)
  • R. Gershoni-Baruch et al.

    The contribution of genotypes at the MEFV and SSA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever

    Arthritis Rheum

    (2003)
  • N. Stoffman et al.

    Higher than expected carrier rates for FMF in various Jewish ethnic groups

    Eur J Hum Genet

    (2000)
  • A. Livneh et al.

    MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever

    Amyloid

    (1999)
  • E. Ben-Chetrit et al.

    Amyloidosis induced, end-stage renal disease in patients with familial Mediterranean fever is highly associated with point mutations in the MEFV gene

    Ann Rheum Dis

    (2001)
  • B. Balci et al.

    MEFV gene mutations in familial Mediterranean fever phenotype II patients with renal amyloidosis in childhood: a retrospective clinico-pathological and molecular study

    Nephrol Dial Transplant

    (2002)
  • F. Yalçinkaya et al.

    Familial Mediterranean fever amyloidosis and the Val1726Ala mutation

    N Eng J Med

    (1998)
  • M. Pras

    Familial Mediterranean fever: from the clinical syndrome to the cloning of the pyrin gene

    Scand J Rheumatol

    (1998)
  • B.N. Cronstein et al.

    The inflammatory process of gout and its treatment

    Arthritis Res Ther

    (2006)
  • G. Nuki

    Colchicine: a critical appraisal of its mechanism of action and efficacy in crystal-induced inflammation

    Curr Rheumatol Rep

    (2008)
  • E. Ben-Chetrit et al.

    Mechanism of the anti-inflammatory effect of colchicine in rheumatic diseases: a possible new outlook through microarray analysis

    Rheumatology (Oxford)

    (2006)
  • C. Cerquaglia et al.

    Pharmacological and clinical basis of treatment of familial Mediterranean fever (FMF) with colchicine or analogues: an update

    Curr Drug Targets Inflamm Allergy

    (2005)
  • D. Camus et al.

    ‘Silent’ carriage of two familial Mediterranean fever gene mutations in large families with only a single identified patient

    Clin Genet

    (Oct. 14 2011)
  • E. Ben-Chetrit et al.

    Familial Mediterranean fever and menstruation

    BJOG

    (2001)
  • M. Lidar et al.

    The prodrome: a prominent yet overlooked pre-attack manifestation of familial Mediterranean fever

    J Rheumatol

    (2006)
  • R. Manna et al.

    Clinical features of familial Mediterranean fever: an Italian overview

    Eur Rev Med Pharmacol Sci

    (2009)
  • M. Shohat et al.

    Familial Mediterranean fever — a review

    Genet Med

    (2011)
  • M. Lidar et al.

    Familial Mediterranean fever: clinical, molecular and management advancements

    Neth J Med

    (2007)
  • Cited by (73)

    • How to prescribe a genetic test for the diagnosis of autoinflammatory diseases?

      2019, Presse Medicale
      Citation Excerpt :

      Problems encountered during molecular diagnosis of the FMF, the most common SAID, are well characterised. In 20–25% of the patients with the clinical diagnosis of FMF and a positive response to colchicine therapy, the second variant in the MEFV gene has not been identified [84]. Moreover, some MEFV variants have been reported to cause dominant FMF, namely p.M694del, p.T577N, p.T577S and p.T577A [13].

    • Screening of the most common MEFV mutations in a large cohort of Egyptian patients with Familial Mediterranean fever

      2018, Gene Reports
      Citation Excerpt :

      Furthermore, other genes could be responsible for causing FMF (Jéru et al., 2013). Moreover; several possibilities including the presence of mutations in another autoinflammatory gene, epigenetic or post-translational modifications, environmental factors as well as having hidden biomarkers might play a role in heterozygosity as a casualty of FMF in our patients (Booty et al., 2009, Moradian et al., 2010, Soriano and Manna, 2012; Erdem et al., 2017). The term “missing heritability”, usually used to describe the gap between predictive transmission models of complex traits and statistical explanatory power of susceptibility genes identified by genome-wide association studies (GWAS), could also apply to this particular situation (Manolio et al., 2009).

    • An Update on Familial Mediterranean Fever

      2023, International Journal of Molecular Sciences
    View all citing articles on Scopus
    View full text