European Journal of Pediatrics

, Volume 162, Issue 7–8, pp 449–454 | Cite as

Familial mediterranean fever: revisiting an ancient disease

  • Seza OzenEmail author


Familial Mediterranean fever (FMF) is an auto-inflammatory disease characterised by periodic attacks of fever and serositis. Recent genetic and epidemiological research have highlighted the importance of this disease. FMF is the most frequent periodic fever syndrome and is transmitted in an autosomal recessive fashion. The disease is caused by mutations in the gene on the short arm of chromosome 16, coding for the protein "pyrin". Pyrin is mainly expressed in neutrophils and monocytes and is among the proteins involved in the interleukin-1 inflammatory pathway. The recurrent attacks of fever are accompanied by severe abdominal pain, arthritis and/or chest pain along with a marked increase in acute phase reactants. Among these, serum amyloid A protein is especially important since it is the precursor of the amyloid A fibrils deposited in secondary renal amyloidosis. Renal amyloidosis has a grave prognosis. Differential diagnosis from other periodic fever syndromes is especially important in western European countries. Among these hyper IgD syndrome is common in Netherlands and the tumour necrosis factor receptor-associated periodic syndrome is especially common among Scottish and Irish families. Mutation analysis of the gene may be helpful in diagnosing FMF; however, if this is not possible, a trial of colchicine is a helpful diagnostic tool. The indications for life-long colchicine treatment should be discussed with the family. Conclusion: familial mediterranean fever and other auto-inflammatory syndromes should be suspected in children with recurrent febrile attacks. Early diagnosis will save the child from unnecessary work-up and kidney involvement.


Familial mediterranean fever 



chronic infantile neurological cutaneous arthropathy


familial cold urticaria


familial cold auto-inflammatory syndrome


familial mediterranean fever


hyperimmunoglobulinaemia D syndrome




mevalonate kinase


Muckle-Wells syndrome


polyarteritis nodosa


serum amyloid A protein


tumour necrosis factor-receptor associated periodic fever syndrome


  1. 1.
    Akarsu N, Ozen S,Saatci U, Bakkaloglu A, Besbas N,Sarfarazi M (1997) Genetic linkage study of FMF to 16p13.3 and evidence for genetic heterogeneity in the Turkish population. J Med Genet 34: 573–578CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Aksentijevich I, Torosyan Y, Samuels J, Centola M, Pras E, Chae JJ, Oddoux C, Wood G, Azzaro MP, Palumbo G, Giustolisi R, Pras M, Ostrer H, Kastner DL(1999) Mutation and haplotype studies of FMF reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Askhenazi Jewish population. Am J Hum Genet 64:949—962CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ben-Chetrit E, Levy M (1998) Colchicine: 1998 update. Semin Arhtr Rheum 28: 48–59CrossRefGoogle Scholar
  4. 4.
    Ben-Chetrit E, Levy M (1998) Familial mediterranean fever. Lancet 351: 659–664CrossRefPubMedGoogle Scholar
  5. 5.
    Booth DR, Lachmann HJ, Gillmore JD, Booth SE, Hawkins PN (2001) Prevalence and significance of the FMF gene mutation encoding pyrin Q148. QJM 94: 527–531CrossRefPubMedGoogle Scholar
  6. 6.
    Cakar N, Yalcinkaya F, Ozkaya N, Tekin M, Akar N, Kocak H, Misirlioglu M, Akar E, Tumer N (2001) FMF associated amyloidosis in childhood: clinical features, course and outcome. Clin Exp Rheum 19[Suppl 124]: s63–s67Google Scholar
  7. 7.
    Cazeneuve C, Ajrapetyan H, Papin S et al (2000) Identification of MEFV independent modifying genetic factors for FMF. Am J Hum Genet 67: 1136–1143PubMedPubMedCentralGoogle Scholar
  8. 8.
    Centola M, Wood G, Frucht DM et al (2000) The gene for FMF, MEFV is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 95: 3223–3231PubMedGoogle Scholar
  9. 9.
    Drenth JPH, van der Meer JWM. Hereditary periodic fevers (2001) N Engl J Med 345: 1748–1757Google Scholar
  10. 10.
    Drenth JP, Cuisset L, Grateau G et al (1999) Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. Nat Genet 22: 178–181CrossRefPubMedGoogle Scholar
  11. 11.
    Feldmann J, Prieur AM, Quartier P, Berquin P, Cortis E, Teillac-Hamel D, Fischer A (2002) Chronic infantile neurological cutaneous and articular syndrome syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet 71: 198—203CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Familial mediterranean fever consortium (1997) A candidate gene for familial mediterranean fever. Nat Genet 17: 25–31CrossRefGoogle Scholar
  13. 13.
    Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R (2001) Familial mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet 9: 3--7CrossRefGoogle Scholar
  14. 14.
    Gumucio DL, Diaz A, Schaner P, Richards N, Babcock C, Schaller M, Cesena T (2002) Fire and ice: the role of pyrin domain containing proteins in inflammation and apoptosis. Clin Exp Rheum 20[Suppl 26]: s45--s53Google Scholar
  15. 15.
    Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD (2001) Mutation of a new gene encoding a putative pyrin-like protein causes FCAS and MWS. Nat Genet 29: 301–305CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Houten SM, Kuis W, Duran M et al (1999) Mutations in MVK encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. Nat Genet 22: 175–177CrossRefPubMedGoogle Scholar
  17. 17.
    International familial mediterranean fever consortium (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial mediterranean fever. Cell 90: 797–807CrossRefGoogle Scholar
  18. 18.
    Kastner DL (1998) Familial mediterranean fever: the genetics of inflammation. Hosp Prac 33: 131–158CrossRefGoogle Scholar
  19. 19.
    Korkmaz C, Ozdogan H, Kasapcopur O, Yazici H (2002) Acute phase response in familial mediterranean fever. Ann Rheum Dis 61: 79–81CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Livneh A, Langevitz P, Zemer D et al (1997) Criteria for the diagnosis of familial mediterranean fever. Arthritis Rheum 40: 1879–1885CrossRefPubMedGoogle Scholar
  21. 21.
    Mansfield E, Chae JJ, Komarow HD et al (2001) The familial mediterranean fever protein pyrin associates with microtubules and co-localizes with actin filaments. Blood 98: 851–859CrossRefPubMedGoogle Scholar
  22. 22.
    McDermott MF, Aksentijevich I, Galon J et al (1999) Germline mutations in the extracellular domains of the 55 kDa TNF receptor define a family of dominantly inherited auto-inflammatory syndromes. Cell 97: 133–144CrossRefPubMedGoogle Scholar
  23. 23.
    Ozen S (1999) Vasculopathy, Behcet's disease and familial mediterranean fever. Curr Opin Rheum 11: 393–398CrossRefGoogle Scholar
  24. 24.
    Ozen S (2002) What advantage did the heterozygotes for MEFV mutations have if any? Clin Exp Rheum 20[suppl 26]: s69Google Scholar
  25. 25.
    Ozen S, Karaasan Y,Ozdemir O, Saatci U, Bakkaloglu A,Tezcan S (1998) Prevalence of juvenile chronic arthritis and familial mediterranean fever in Turkey: a field study. J Rheumatol 25: 2445–2449PubMedGoogle Scholar
  26. 26.
    Ozen S, Ben-Chetrit E, Bakkaloglu A et al (2001) Polyarteritis nodosa in patients with familial mediterranean fever: a concomitant disease or a feature of FMF? Semin Arthritis Rheum 30: 281–287CrossRefPubMedGoogle Scholar
  27. 27.
    Pras M (2002) Familial mediterranean fever: past, present and future. Clin Exp Rheum 20[Suppl 26]: s66Google Scholar
  28. 28.
    Saatci U, Ozen S, Ozdemir S et al (1997) FMF in children: report of a large series. Eur J Pediatr 156:619–623CrossRefGoogle Scholar
  29. 29.
    Samuels J, Aksentijevich I, Torosyan Y, Centola M, Deng Z, Sood R, Kastner DL (1998) Familial mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine 77: 268–297CrossRefPubMedGoogle Scholar
  30. 30.
    Shinozaki K, Agematsu K, Yasui K et al (2002) Familial mediterranean fever in 2 Japanese families. J Rheumatol 29: 1324–1325PubMedGoogle Scholar
  31. 31.
    Shohat M, Lotan R, Magai N et al (1998) Amyloidosis in familial mediterranean fever is associated with a specific ancestral haplotype in the MEFV locus. Mol Genet Metab 65: 197–202CrossRefPubMedGoogle Scholar
  32. 32.
    Touitou I (2001) The spectrum of familial mediterranean fever mutations. Eur J Hum Genet 9: 473–483CrossRefPubMedGoogle Scholar
  33. 33.
    Tunca M, Kırkalı G, Soytuk M, Akar S,Pepys M, Hawkins P (1999) Acute phase response and evolution of familial mediterranean fever (letter). Lancet 353: 1415CrossRefPubMedGoogle Scholar
  34. 34.
    Tunca M, Akar S, Sirin A, Onen F, Cobankara V and the Turkish FMF Study Group (2002) The results of a nationwide analysis of the characteristics of Turkish familial mediterranean fever patients (abstract). Clin Exp Rheum 20[Suppl 26]: s70Google Scholar
  35. 35.
    Yalcinkaya F, Akara N, Misirlioglu A (1998) Familial mediterranean fever amyloidosis and the Val 726Ala mutation. N Engl J Med 338: 993CrossRefPubMedGoogle Scholar
  36. 36.
    Yilmaz E, Ozen S, Balci B et al (2001) Mutation frequency of familial mediterranean fever and evidence of a high carrier rate in the Turkish population. Eur J Hum Genet 9: 553–555CrossRefPubMedGoogle Scholar
  37. 37.
    Zemer D, Livneh A, Danon YI, Pras M, Sohar E (1991) Long term colchicine treatment in children with familial mediterrranean fever. Arthr Rheum 34: 973–977CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  1. 1.Department of Paediatric Nephrology and RheumatologyHacettepe University Faculty of MedicineAnkaraTurkey

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