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Results from a multicentre international registry of familial Mediterranean fever: impact of environment on the expression of a monogenic disease in children
  1. Seza Ozen1,
  2. Erkan Demirkaya2,
  3. Gayane Amaryan3,
  4. Isabelle Koné-Paut4,
  5. Adem Polat2,
  6. Pat Woo5,
  7. Yosef Uziel6,
  8. Consuelo Modesto7,
  9. Martina Finetti8,
  10. Pierre Quartier9,
  11. Efimia Papadopoulou-Alataki10,
  12. Sulaiman M Al-Mayouf11,
  13. Giovanna Fabio12,
  14. Romina Gallizzi13,
  15. Luca Cantarini14,
  16. Joost Frenkel15,
  17. Susan Nielsen16,
  18. Michael Hofer17,
  19. Antonella Insalaco18,
  20. C Acikel2,
  21. Huri Ozdogan19,
  22. Alberto Martini8,
  23. Nicolino Ruperto8,
  24. Marco Gattorno8,
  25. for the Paediatric Rheumatology International Trials Organisation (PRINTO) and the Eurofever Project
  1. 1Department of Pediatrics, Hacettepe University, Ankara, Turkey
  2. 2Department of Pediatric Nephrology and Rheumatology, Gulhane Military Medical Faculty, Ankara, Turkey
  3. 3Centre of Medical Genetics and Primary Health Care, Yerevan, Armenia
  4. 4Centre de Reference National des Maladies Auto-Inflammatoires, CEREMAI, Rhumatologie Pediatrique, CHU Le Kremlin Bicetre (University of Paris SUD), APHP, Le kremlin Bicetre, France
  5. 5Center of Paediatric and Adolescent Rheumatology–UCL, London, UK
  6. 6Department of Pediatrics, Meir Medical Centre, Kfar Saba, Israel
  7. 7Reumatologia, Hospital Valle de Hebron, Barcelona, Spain
  8. 8Pediatria II, Reumatologia, Istituto Giannina Gaslini, Genova, Italy
  9. 9Université Paris-Descartes, Hôpital Necker-Enfants Malades, Centre de référence national pour les Arthrites Juveniles, Unité d'Immunologie, Hématologie et Rhumatologie Pediatrique, Institut Hospitalo-Universitaire IMAGINE, Paris, France
  10. 10Fourth Department of Pediatrics, Aristotle University of Thessaloniki, Papageorgiou Hospital, Thessaloniki, Greece
  11. 11Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  12. 12Internal Medicine, University of Milano and Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Milano, Italy
  13. 13UOC Genetic and Pediatric Immunology, Department of Pediatrics, University of Messina, Messina, Italy
  14. 14Rheumatology Unit, Policlinico le Scotte, University of Siena, Siena, Italy
  15. 15Department of Paediatrics, University Medical Center Utrecht, Utrecht, Netherlands
  16. 16Pediatrisk klinik II, Juliane Marie Centret, Rigshospitalet, Copenaghen, Denmark
  17. 17Paediatric Rheumatology Unit of Western Switzerland, Departments of Paediatrics, CHUV, University Hospital of Lausanne and HUG, Geneva, Switzerland
  18. 18Reumatologia, Ospedale Pediatrico Bambin Gesù, Roma, Italy
  19. 19Ic Hastaliklari ABD, Romatoloji BD, Cerrahpasa Tip Fakultesi, Istanbul, Turkey
  1. Correspondence to Professor Seza Ozen, Department of Pediatrics, Hacettepe University, Ankara 06100, Turkey; sezaozen{at}


Background and aim Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations of the MEFV gene. We analyse the impact of ethnic, environmental and genetic factors on the severity of disease presentation in a large international registry.

Methods Demographic, genetic and clinical data from validated paediatric FMF patients enrolled in the Eurofever registry were analysed. Three subgroups were considered: (i) patients living in the eastern Mediterranean countries; (ii) patients with an eastern Mediterranean ancestry living in western Europe; (iii) Caucasian patients living in western European countries. A score for disease severity at presentation was elaborated.

Results Since November 2009, 346 FMF paediatric patients were enrolled in the Eurofever registry. The genetic and demographic features (ethnicity, age of onset, age at diagnosis) were similar among eastern Mediterranean patients whether they lived in their countries or western European countries. European patients had a lower frequency of the high penetrance M694V mutation and a significant delay of diagnosis (p<0.002). Patients living in eastern Mediterranean countries had a higher frequency of fever episodes/year and more frequent arthritis, pericarditis, chest pain, abdominal pain and vomiting compared to the other two groups. Multivariate analysis showed that the variables independently associated with severity of disease presentation were country of residence, presence of M694V mutation and positive family history.

Conclusions Eastern Mediterranean FMF patients have a milder disease phenotype once they migrate to Europe, reflecting the effect of environment on the expression of a monogenic disease.

  • Familial Mediterranean Fever
  • Epidemiology
  • Gene Polymorphism

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