Abstract
Familial Mediterranean fever (FMF) is the most frequent periodic syndrome characterized by recurrent attacks of polyserositis. Fever, abdominal pain, chest pain, and arthritis/arthralgia are the leading symptoms. It is an autosomal recessive disorder, which primarily affects Jewish, Armenian, Turkish, and Arab populations. The FMF gene (MEFV) has recently been cloned to chromosome 16p, which encodes pyrin. Genotype-phenotype correlation is not well established. Amyloidosis is the most severe complication of FMF. The SAA1-α/α genotype was associated with an increased risk of amyloidosis. Colchicine treatment not only decreases the frequency and severity of attacks, but also prevents amyloidosis. Certain vasculitides, namely Henoch-Schonlein purpura and polyarteritis nodosa, are more frequent among FMF patients.
Similar content being viewed by others
References
Sohar E, Gafni J, Pras M, Heller H (1967) Familial Mediterranean fever. A survey of 470 cases and review of literature. Am J Med 43:227–253
Siegal S (1945) Benign paroxysmal peritonitis. Ann Intern Med 23:1–21
Heller H, Sohar E, Sherf L (1958) Familial Mediterranean fever. Arch Intern Med 102:50–71
Schwartz J (1960) Periodic peritonitis, onset simultaneously with menstruation. Ann Intern Med 53:407–411
Ehrenfeld EN, Eliakim M, Rachmilewitz M (1961) Recurrent polyserositis (familial Mediterranean fever: periodic disease). A report of fifty-five cases. Am J Med 31:107–123
Artunkal S, Seyahi V (1955) Five cases of periodic disease. Turk Tıb Cem Mec 21:282
Yarkin C, Bankman N (1957) La maladie periodique en Turquie. Presse Med 65:1633
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 familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet 64:949–962
Lee WY, Tsai S, Kao JH, Lai MY (1993) Taiwanese patient with recurrent polyserositis: report of a case. J Formos Med Assoc 92:1013–1016
Takahashi M, Ebe T, Kohara T, Inagaki M, Isonuma H, Hibiya I, Mori T, Watanabe K, Ikemoto H (1992) Periodic fever compatible with familial Mediterranean fever. Intern Med 31:893–898
Daniels M, Shohat T, Brenner-Ullman A, Shohat M (1995) Familial Mediterranean fever: high gene frequency among the non-Ashkenazic and Ashkenazic Jewish populations in Israel. Am J Med Genet 55:311–314
Ozen S, Karaaslan Y, Ozdemir O, Saatci U, Bakkaloglu A, Koroglu E, Tezcan S (1998) Prevalence of juvenile chronic arthritis and familial Mediterranean fever in Turkey: a field study. J Rheumatol 25:2445–2449
Torosyan L, Aksentijevich I, Sarkisian T (2000) A population based survey reveals an extremely high FMF carrier frequency in Armenia suggesting heterozygote advantage. Am J Hum Genet 67:404 (abstract 2275)
Yilmaz E, Ozen S, Balci B, Duzova A, Topaloglu R, Besbas N, Saatci U, Bakkaloglu A, Ozguc M (2001) Mutation frequency of Familial Mediterranean Fever and evidence for a high carrier rate in the Turkish population. Eur J Hum Genet 9:553–555
The International FMF Consortium (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90:797–807
The French FMF Consortium (1997) A candidate gene for familial Mediterranean fever. Nat Genet 17:25–31
Henry J, Ribouchon MT, Offer C, Pontarotti P (1997) B30.2-like domain proteins: a growing family. Biochem Biophys Res Commun 235:162–165
Vernet C, Boretto J, Mattei MG, Takahashi M, Jack LJ, Mather IH, Rouquier S, Pontarotti P (1993) Evolutionary study of multigenic families mapping close to the human MHC class I region. J Mol Evol 37:600–612
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 Institute of Health. Medicine (Baltimore) 77:268–297
Kastner DL (1998) FMF: the genetics of inflammation. Hosp Prac 33:131–158
Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C, Kingma DW, Horwitz ME, Mansfield E, Holland SM, O'Shea JJ, Rosenberg HF, Malech HL, Kastner DL (2000) The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 95:3223–3231
Mansfield E, Chae JJ, Komarow HD, Brotz TM, Frucht DM, Aksentijevich I, Kastner DL (2001) The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments. Blood 98:851–859
Shohat M, Magal N, Shohat T, Chen X, Dagan T, Mimouni A, Danon Y, Lotan R, Ogur G, Sirin A, Schlezinger M, Halpern GJ, Schwabe A, Kastner D, Rotter JI, Fischel-Ghodsian N (1999) Phenotype-genotype correlation in familial Mediterranean fever: evidence for an association between Met694Val and amyloidosis. Eur J Hum Genet 7:287–292
Livneh A, Langevitz P, Shinar Y, Zaks N, Kastner DL, Pras M, Pras E (1999) MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever. Amyloid 6:1–6
Ben-Chetrit E, Urieli-Shoval S, Calko S, Abeliovich D, Matzner Y (2002) Molecular diagnosis of FMF: lessons from a study of 446 unrelated individuals. Clin Exp Rheumatol 20 [Suppl 26]:S25–S29
Majeed HA, El-Shanti H, Al-Khateeb MS, Rabaiha ZA (2002) Genotype/phenotype correlations in Arab patients with familial Mediterranean fever. Semin Arthritis Rheum 31:371–376
Brik R, Shinawi M, Kepten I, Berant M, Gershoni-Baruch R (1999) Familial Mediterranean fever: clinical and genetic characterization in a mixed pediatric population of Jewish and Arab patients. Pediatrics 103:e70
Cattan D, Dervichian M, Thomas M, Dode C, Touitou I (2001) MEFV mutations and phenotype-genotype correlations in North African Jews and Armenians with familial Mediterranean fever. Isr Med Assoc J 3:803–804
Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R (2001) Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet 9:634–637
Yalcinkaya F, Cakar N, Misirlioglu M, Tumer N, Akar N, Tekin M, Tastan H, Kocak H, Ozkaya N, Elhan AH (2000) Genotype-phenotype correlation in a large group of Turkish patients with familial Mediterranean fever: evidence for mutation independent amyloidosis. Rheumatology 39:67–72
Akar N, Misiroglu M, Yalcinkaya F, Akar E, Cakar N, Tumer N, Akcakus M, Tastan H, Matzner Y (2000) MEFV mutations in Turkish patients suffering from familial Mediterranean fever. Hum Mutat 15:118–119
Touitou I (2001) The spectrum of familial Mediterranean fever (FMF) mutations. Eur J Hum Genet 9:473–483
Yalcinkaya F, Topaloglu R, Yilmaz E, Emre S, Erken E, on behalf of the Turkish FMF Study Group (2002) Distribution of MEFV mutations and phenotype genotype analysis in Turkish patients with FMF: a nationwide study (abstract). Clin Exp Rheumatol 20 [Suppl 26]:S90
Aksentijevich I, Kastner DL, and the International FMF Consortium (1997) Microsatellite haplotypes and MEFV mutations: exploring the genealogy of FMF. In: Sohar E, Gafni J, Pras M (eds) Proceedings of the 1st International Conference on FMF, Jerusalem, 1997. Freund, Tel Aviv, pp 246–251
Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40:1879–1885
Tunca M, Akar S, SirinA, Onen F, Cobankara V, on behalf of the Turkish FMF Study Group (2002) The results of a nationwide, multicenter analysis of the clinical and genetic characteristics of the Turkish FMF patients (abstract). Clin Exp Rheumatol 20 [Suppl 26]:S92
Dewalle M, Domingo C, Rozenbaum M, Ben-Chetrit E, Cattan D, Bernot A, Dross C, Dupont M, Notarnicola C, Levy M, Rosner I, Demaille J, Touitou I (1998) Phenotype-genotype correlation in Jewish patients suffering from familial Mediterranean fever. Eur J Hum Genet 6:95–97
Cazeneuve C, Sarkisian T, Pecheux C, Dervichian M, Nedelec B, Reinert P, Ayvazyan A, Kouyoumdjian JC, Ajrapetyan H, Delpech M, Goossens M, Dode C, Grateau G, Amselem S (1999) MEFV gene analysis in Armenian patients with familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694 V homozygous genotype-genetic and therapeutic implications. Am J Hum Genet 65:88–97
Booth DR, Gillmore JD, Booth SE, Pepys MB, Hawkins PN (1998) Pyrin/marenostrin mutations in familial Mediterranean fever. Q J Med 91:603–606
Yalcınkaya F, Akar N, Misirlioglu M (1998) Familial Mediterranean fever-amyloidosis and the Val726Ala mutation. N Engl J Med 338:993–994
Saatci U, Yalcinkaya F, Oner A, Besbas N, Baskin E, on behalf of the Turkish FMF Study Group (2002) Renal involvement in Turkish patients with FMF (abstract). Clin Exp Rheumatol 20 [Suppl 26]:S89
Balci B, Tinaztepe K, Yilmaz E, Gucer S, Ozen S, Topaloglu R, Besbas N, Ozguc M, Bakkaloglu A (2002) MEFV mutations in familial Mediterranean fever phenotype II patients with renal amyloidosis in childhood: a retrospective clinicopathological and molecular study. Nephrol Dial Transplant 17:1921–1923
Ozdemir AL, Sokmen C (1969) Familial Mediterranean fever among the Turkish people. Am J Gastroenterol 51:311–316
Saatci U, Ozen S, Ozdemir S, Bakkaloglu A, Besbas N, Topaloglu R, Arslan S (1997) Familial Mediterranean fever in children: report of a large series and discussion of the risk and prognostic factors of amyloidosis. Eur J Pediatr 156:619–623
Barakat MH, Karnik AM, Mejeed HW, El-Sobki NA, Fennech MM (1986) Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs. A study of 175 patients and review of the literature. Q J Med 837–847
Rogers DB, Shohat M, Petersen GM, Bickal J, Congleton J, Schwabe AD, Rotter JI (1989) Familial Mediterranean fever in Armenians: autosomal recessive inheritance with high gene frequency. Am J Med Genet 34:168–172
Aivasian AA, Savgoridniaia AM, Abramiam MK (1977) Immunogenesis of periodic disease Klin Med (Mosk) 55:41–97
Benson MB, Cohen AS (1979) Serum amyloid A protein in amyloidosis, rheumatic and neoplastic diseases. Arthritis Rheum 22:36–42
Cazeneuve C, Ajrapetyan H, Papin S, Roudot-Thoraval F, Genevieve D, Mndjoyan E, Papazian M, Sarkisian A, Babloyan A, Boissier B, Duquesnoy P, Kouyoumdjian JC, Girodon-Boulandet E, Grateau G, Sarkisian T, Amselem S (2000) Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever. Am J Hum Genet 67:1136–1143
Bakkaloglu A, Duzova A, Balci B, Besbas N, Topaloglu R, Ozen S (2002) The effect of SAA1, SAA2 polymorphisms on renal amyloidosis and A-SAA levels in patients with FMF (abstract). Clin Exp Rheumatol 20 [Suppl 26]:S80
Tunca M, Kirkali G, Soytürk M, Akar S, Pepys MB, Hawkins PN (1999) Acute phase response and evolution of familial Mediterranean fever. Lancet 353:1415
Duzova A, Bakkaloglu A, Yilmaz E, Besbas N, Topaloglu R, Besbas N (2002) Role of A-SAA in monitoring subclinical inflammation and in colchicine dosage in familial Mediterranean fever (abstract). Clin Exp Rheumatol 20 [Suppl 26]:S81
Bakkaloglu A, Duzova A, Balci B, Besbas N, Topaloglu R, Ozen S (2002) The effect of SAA-1, SAA-2 gene polymorphisms on renal amyloidosis and A-SAA levels in patients with FMF (abstract). Clin Exp Rheumatol 20 [Suppl 26]:S80
Said R, Hamzeh Y, Said S, Tarawneh M, al-Khateeb M (1992) Spectrum of renal involvement in familial Mediterranean fever. Kidney Int 41:414–419
Said R, Hamzeh Y, Tarawneh M, el-Khateeb M, Abdeen M, Shaheen A (1989) Rapidly progressive glomerulonephritis in patients with familial Mediterranean fever. Am J Kidney Dis 14:412–416
Yalcinkaya F, Tumer N, Tulunay O, Tekin M (1997) FMF related non-amyloid glomerular diseases. In: Sohar E, Gafni J, Pras M (eds) Proceedings of the 1st International Conference on FMF, Jerusalem, 1997. Freund, Tel Aviv, pp 175–180
Bakkaloglu A, Ozen S, Topaloğlu R, Dusunsel R, Simsek H, on behalf of the Turkish FMF Study Group (2002) Associated diseases in Turkish FMF patients: are patients predisposed to develop vasculitides (abstract). Clin Exp Rheumatol 20 [Suppl 26]:S90
Ozdogan H, Arisoy N, Kasapcapur O, Sever L, Caliskan S, Tuzuner N, Mat C, Yazici H (1997) Vasculitis in familial Mediterranean fever. J Rheumatol 24:323–327
Glikson M, Galun E, Schlesinger M, Cohen D, Haskell L, Rubinow A, Eliakim M (1989) Polyarteritis nodosa and familial Mediterranean fever: a report of 2 cases and review of the literature. J Rheumatol 16:536–539
Tinaztepe K, Gucer S, Bakkaloglu A, Tinaztepe B (1997) Familial Mediterranean fever and polyarteritis nodosa: experience of five pediatric cases. A causal relationship or coincidence? Eur J Pediatr 156:505–506
Tekin M, Yalcinkaya F, Tumer N, Akar N, Misirlioglu M, Cakar N (2000) Clinical, laboratory and molecular characteristics of children with familial Mediterranean fever-associated vasculitis. Acta Paediatr 89:177–182
Kocak H, Cakar N, Hekimoglu B, Atakan C, Akkök N, Unal S (1996) The coexistence of familial Mediterranean fever and polyarteritis nodosa. Pediatr Nephrol 10:631–633
Langevitz P, Zemer D, Livneh A, Shemer J, Pras M (1994) Protracted febrile myalgia in patients with familial Mediterranean fever. J Rheumatol 21:1708–1709
Savi M, Asinari G, Gaudiano V, Olivetti G, Neri TM (1978) Unusual immunologic findings in familial Mediterranean fever. Arch Intern Med 138:644–645
Zlotnick A, Levo Y, Fishel R, Ehrenfeld M, Levy M, Shouval D, Eliakin M (1979) Circulating immune complexes in familial Mediterranean fever, systemic lupus erythematosus and HBsAg carriers. Harefuah 99:55–57
Schlesinger M, Kopolovic J, Viskoper RJ, Ron N (1983) A case of familial Mediterranean fever with cutaneous vasculitis and immune complexes nephritis: light, electron, and immunofluorescent study of renal biopsy. Am J Clin Pathol 80:511–514
Henckes M, Roskams T, Vanneste S, Van Damme B, Vanrenterghem Y (1994) Polyarteritis nodosa type vasculitis in a patient with familial Mediterranean fever treated with cyclosporin A. Transpl Int 7:292–296
Ben-Chetrit E, Yazici H (2002) Thoughts on the proposed links between Behçet's disease and familial Mediterranean fever. Clin Exp Rheumatol 20 [Suppl 26]:S1–S2
Goldfinger SE (1972) Colchicine for familial Mediterranean fever. N Engl J Med 287:1302
Ozkan E, Okur O, Ekmekci A, Ozcan R, Tag T (1972) A new approach to the treatment of periodic fever. Med Bull Istanbul 44–49
Zemer D, Revach M, Pras M, Modan B, Schor S, Sohar E, Gafni J (1974) A controlled trial of colchicine in preventing attacks of familial Mediterranean fever. N Engl J Med 291:932–934
Molad Y, Reibman J, Levin RI, Cronstein BN (1992) A new mode of action for an old drug: colchicine decrease surface expression of adhesion molecules on both neutrophils (PMNs) and endothelium (abstract). Arthritis Rheum 35 [Suppl]:S35
Caner JEZ (1965) Colchicine inhibition of chemotaxis. Arthritis Rheum 8:757–764
Wallace SL (1974) Colchicine. Semin Arthritis Rheum 3:369–381
Andreu JM, Timasheff SN (1982) Interaction of tubulin with single ring analogue of colchicine. Biochemistry 21:534–543
Ben-Chetrit E, Levy N (1998) Colchicine: 1998 update. Semin Arthritis Rheum 28:48–59
Rabinovitch O, Zemer D, Kukia E, Sohar E, Mashiach S (1992) Colchicine treatment in conception and pregnancy: two hundred thirty-one pregnancies in patients with familial Mediterranean fever. Am J Reprod Immunol 28:245–246
Barkai G, Meital Y, Chetrit A, Barell V, Aviram A, Zemer D (1997) Evaluation of pregnancy outcome among FMF colchicine treated women (abstract). 1st International Conference on FMF, September 1997, Jerusalem, Israel
Tunca M, Tankurt E, Akbaylar Akpinar H, Akar S, Hizli N, Gonen O (1997) The efficacy of interferon alpha on colchicine resistant familial Mediterranean fever attacks: a pilot study. Br J Rheumatol 36:1005–1008
Seyahi E, Ozdogan H, Masatlioglu S, Yazici H (2002) Successful treatment of familial Mediterranean fever attacks with thalidomide in a colchicine resistant patient. Clin Exp Rheumatol 20 [Suppl 26]:S43–S44
Milledge J, Shaw PJ, Mansour A, Williamson S, Bennetts B, Roscioli T, Curtin J, Christodoulou J (2002) Allogeneic bone marrow transplantation: cure for familial Mediterranean fever. Blood 100:774–777
Drenth JP, Cuisset L, Grateau G, Vasseur C, Velde-Visser SD van de, Jong JG de, Beckmann JS, Meer JW van der, Delpech M (1999) Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. Nat Genet 22:178–181
McDermott EM, Smillie DM, Powell RJ (1997) Clinical spectrum of familial Hibernian fever: a 14-year follow-up study of the index case and extended family. Mayo Clin Proc 72:806–817
Padeh S, Brezniak N, Zemer D, Pras E, Livneh A, Langevitz P, Migdal A, Pras M, Passwell JH (1999) Periodic fever, aphthous stomatitis, pharyngitis and adenopathy syndrome: clinical characteristics and outcome. J Pediatr 135:98–101
Muckle TJ, Wells MV (1962) Urticaria, deafness and amyloidosis: a hereditary syndrome. QJM 31:235–247
Cuisset L, Drenth JP, Berthelot JM, Meyrier A, Vaudour G, Watts RA, Scott DG, Nicholls A, Pavek S, Vasseur C, Beckmann JS, Delpech M, Grateau G (1999) Genetic linkage of Muckle-Wells syndrome to chromosome 1q44. Am J Hum Genet 65:1054–1059
Prieur AM, Griscelli C, Lampert F, Truckenbrodt H, Guggenheim MA, Lovell DJ, Pelkonnen P, Chevrant-Breton J, Ansell BM (1987) A chronic, infantile, neurologic, cutaneous and articular (CINCA) syndrome. A specific entity analysed in 30 patients. Scand J Rheumatol 66:57–68
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bakkaloglu, A. Familial Mediterranean fever. Pediatr Nephrol 18, 853–859 (2003). https://doi.org/10.1007/s00467-003-1185-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-003-1185-2