Advertisement

Monatsschrift Kinderheilkunde

, Volume 151, Issue 10, pp 1064–1071 | Cite as

Familiäres Mittelmeerfieber

Klinik und molekulargenetische Befunde bei 40 Kindern in Berlin
  • J. Rakob
  • I. Touitou
  • T. Kallinich
  • R. Rossi
  • R. Keitzer
Originalien
  • 249 Downloads

Zusammenfassung

Hintergrund

Die autosomal-rezessive Erkrankung Familiäres Mittelmeerfieber (FMF) betrifft vorwiegend Patienten aus dem südlichen und östlichen Mittelmeerraum. Das Manifestationsalter liegt in 90% der Fälle vor dem 20. Lebensjahr. Nach Identifizierung und Klonierung des verantwortlichen Mediterranean-Fever (MEFV)-Gens kann die Diagnose FMF in den meisten Fällen auch molekulargenetisch gesichert werden.

Stichprobe

Bei 40 Kindern aus Berlin (Alter 2–17 Jahre), von denen 27 aus der Türkei und 13 aus dem Libanon stammen, wurde wegen FMF-verdächtiger Symptomatik oder positiver Familienanamnese nach Mutationen im MEFV-Gen gesucht.

Ergebnisse und Diskussion

Das Alter bei Beginn der FMF-Symptomatik lag bei 2,5 Jahren, die Anamnesedauer bis zur Diagnosestellung bei 0,5–12 Jahren. Homozygot (vornehmlich Mutation M694 V) waren 14 Patienten, compound-heterozygot 12 Patienten und heterozygot 8 Patienten. Die Trias Fieber, Bauchschmerzen und Arthralgie war bei 50% aller Patienten zu beobachten, in der Gruppe der für die Mutation M694 V homozygoten Patienten mit 93% deutlich häufiger. Diese Patienten sprachen gut auf die Kolchizintherapie an.

Schlüsselwörter

Familiäres Mittelmeerfieber Fiebersyndrom MEFV-Gen Kolchizin 

Abstract

Background

Familial Mediterranean Fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever often combined with polyserositis. Persons of eastern and southern Mediterranean origin are affected most frequently. In 90% of affected patients, manifestation is seen before 20 years of age. Following identification and cloning of the responsible Mediterranean Fever (MEFV) gene, FMF can in most instances be verified by mutational analysis.

Patients

We report on 40 children of Turkish (n=27) and Lebanese (n=13) origin between 2 and 17 years of age. Mutational analysis of the MEFV gene was performed because of symptoms suggestive for FMF or a positive family history.

Results

The mean age at commencement of FMF symptoms was 2.5 years, and the time to definite diagnosis ranged from 0.5 to 12 years. Following identification of 24 index patients, FMF could be confirmed for 16 additional family members. Half of all patients were homozygous, predominantly for the mutation M694 V (n=14). Twelve patients were found to be compound heterozygous and eight showed heterozygosity only. Fever was present in 88% of all patients, 50% were symptomatic with the triad of fever, abdominal pain, and arthralgia. Erysipelas-like skin lesions occurred in 20%. In patients with homozygosity for the mutation M694 V the triad of fever, abdominal pain, and arthralgia was seen in 93% of our patients. In this group colchicine therapy proved to be very effective.

Conclusions

The discovery of the MEFV gene and the ongoing identification of mutations has facilitated early detection of FMF. Especially patients with homozygosity for the mutation M694 V are prone to a severe clinical course, but they respond favorably to colchicine therapy. The variability of the clinical presentation is related to both allelic heterogeneity and additional disease-contributing factors other than the MEFV gene.

Keywords

Familial Mediterranean Fever Fever syndrome  MEFV-gene Colchicine Polyserositis 

Literatur

  1. 1.
    Ayesh SK, Azar Y, Babior BM, Maztner Y (1993) Inactivation of interleukin-8 by the C5a-inactivating protease from serosal fluid. Blood 81:1424–1427PubMedGoogle Scholar
  2. 2.
    Ben-Chetrit E, Lerer I, Malamud E, Domingo C, Abeliovich D (2000) The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant? Hum Mutat 15:385–386Google Scholar
  3. 3.
    Ben-Chetrit E, Levy M (1998) Familial Mediterranean fever. Lancet 351:659–664PubMedGoogle Scholar
  4. 4.
    Brenner-Ullman A, Melzer-Ofir H, Daniels M, Shohat M (1994) Possible protection against asthma in heterozygotes for Familial Mediterranean fever. Am J Med Genet 53:172–175PubMedGoogle Scholar
  5. 5.
    Brik R, Litmanovitz D, Berkowitz D, Shamir R, Rosenthal E, Shinawi M, Gershoni-Baruch R (2001) Incidence of familial Mediterranean fever (FMF) mutations among children of Mediterranean extraction with functional abdominal pain. J Peditatr 138:759–762CrossRefGoogle Scholar
  6. 6.
    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:e70PubMedGoogle Scholar
  7. 7.
    Cazeneuve C, Ajrapetyan H, Papin S, Roudot-Thoraval F, Geneviève 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 modifiying genetic factors for Familial Mediterranean fever. Am J Hum Genet 67:1136–1143PubMedGoogle Scholar
  8. 8.
    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 55:311–314PubMedGoogle Scholar
  9. 9.
    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 (FMF). Eur J Hum Genet 6:95–97PubMedGoogle Scholar
  10. 10.
    Dodé C, Pêcheux C, Cazeneuve C, Cattan D, Dervichian M, Goossens M, Delpech M, Amselem S, Grateau G (2000) Mutations in the MEFV gene in a large series of patients with clinical diagnosis of familial Mediterranean fever. Am J Med Genet 92:241–246CrossRefPubMedGoogle Scholar
  11. 11.
    Drenth JPH, van der Meer JWM (2001) Hereditary Periodic Fever. New Engl J Med 345:1748–1757CrossRefPubMedGoogle Scholar
  12. 12.
    Gershoni-Baruch R, Shinawi M, Livneh A (2002) The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever. Eur J Hum Genet 10:145–149Google Scholar
  13. 13.
    Goldfinger SE (1972) Colchicine for Familial Mediterranean fever. N Engl J Med 287:1302Google Scholar
  14. 14.
    Kone Paut I, Dubuc M, Sportouch J, Minodier P, Garnier JM, Touitou I (2000) Phenotype-genotype correlation in 91 Patients with familial Mediterranean fever reveals a high frequency of cutaneomucous features. Rheumatology 39:1275–1279Google Scholar
  15. 15.
    Livneh A, Langevitz P, Zemer D, Padeh S, Migdal A, Sohar E, Pras M (1996) The changing face of Familial Mediterranean fever. Semin Arthritis Rheum 26:612–627PubMedGoogle Scholar
  16. 16.
    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 40:1879–1885PubMedGoogle Scholar
  17. 17.
    Livneh A, Zemer D, Langevitz P (1994) Colchicine treatment of AA amyloidosis of familial mediterranean fever: an analysis of factors affecting outcome. Arthritis Rheum 27:1184–1191Google Scholar
  18. 18.
    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 98:851–859CrossRefPubMedGoogle Scholar
  19. 19.
    Matzner Y, Brzezinski A (1984) C5a-inhibitor deficiency in peritoneal fluids from patients with familial Mediterranean fever. N Engl J Med 311:287–290PubMedGoogle Scholar
  20. 20.
    Mimouni A, Magal N, Stoffman N, Shohat T, Minasian A, Krasnov M, Halpern GJ, Rotter JI, Fischel-Ghodsian N, Danon YL, Shohat M (2000) Familial Mediterranean Fever: Effects of genotype and ethnicity on inflammatory attacks and amyloidosis. Pediatrics 105:e70PubMedGoogle Scholar
  21. 21.
    Pras E, Livneh A, Barlow JE (1998) Clinical differences between North-Afrikan and Iraqi Jews with Familial Mediterranean fever (FMF). Am J Med Genet 75:216–219CrossRefPubMedGoogle Scholar
  22. 22.
    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 34:168–172PubMedGoogle Scholar
  23. 23.
    Sohar E, Gafni J, Pras M, Heller H (1967) Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 43:227–253PubMedGoogle Scholar
  24. 24.
    Tekin M, Yalçinkaya F, Tümer N, Akar N, Misirlioglu M, Çakar (2000) Clinical, laboratory and molecular characteristics of children with Familial Mediterranean Fever-associated vasculitis. Acta Paediatr 89:177–182CrossRefPubMedGoogle Scholar
  25. 25.
    The French FMF Consortium (1997) A candidate gene for familial Mediterranean fever. Nat Genet, 17:25–31Google Scholar
  26. 26.
    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 90:797–807PubMedGoogle Scholar
  27. 27.
    Touitou I (2001) The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 9:473–483Google Scholar
  28. 28.
    Touitou I, Ben-Chetrit E, Notarnicola C, Doming C, Dewalle M, Dross C, Dupont M, Demaille J, Rosner I, Rozenbaum M (1998) Familial Mediterranian fever, clinical and genetic features in Druzes and Iraqui Jews: a preliminary study. J Rheumatol 25:916–919PubMedGoogle Scholar
  29. 29.
    Touitou I, Picot MC, Domingo C, Notarnicola C, Cattan, D, Demaille J, Kone-Paut I (2001) The MICA region determines the first modifier locus in familial Mediterranean fever. Arthritis Rheum 44:163–169CrossRefPubMedGoogle Scholar
  30. 30.
    Tunca M, Kirkali G, Soyturk M, Akar S, Peyps MB, Hawkins PN (1999) Acute phase response and evolution of familial Mediterranean fever. Lancet 353:1415CrossRefGoogle Scholar
  31. 31.
    Zemer D, Livneh A, Danon YL, Pras M, Sohar E (1991) Long-term colchicine treatment in children with familial Mediterranean fever. Arthritis Rheum 34:973–977PubMedGoogle Scholar
  32. 32.
    Galon J, Aksentijevich I, McDermott F, O'Shea JJ, Kastner DL (2000) TNFRSF1A mutations and autoinflammatory syndromes. Curr Opin Immunol 12:479–486Google Scholar
  33. 33.
    Kastner DL, O'Shea JJ (2001) A fever gene comes in from the cold. Nat Genet 29:241–242Google Scholar
  34. 34.
    McDermott MF (2002) Genetic clues to understanding periodic fevers, and possible therapies. Trends Mol Med 8:550–554Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • J. Rakob
    • 1
    • 4
  • I. Touitou
    • 2
  • T. Kallinich
    • 3
  • R. Rossi
    • 1
  • R. Keitzer
    • 3
  1. 1.Klinik für Kinder- und Jugendmedizin, Klinikum Neukölln, Berlin
  2. 2.Laboratoire de génétique moléculaire et chromosomique, Hôpital de Villeneuve, Montpellier, Frankreich
  3. 3.Pädiatrische Pneumologie und Immunologie, Otto-Heubner-Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Charité, Humboldt-Universität Berlin
  4. 4.Klinik für Kinder- und Jugendmedizin, Klinikum Neukölln Berlin

Personalised recommendations