Familial Mediterranean fever in the pediatric population

Main Article Content

Pilar Llobet-Agulló
Laura Sanromà-Nogués
Isabel Maria Salguero-Pérez
Juan I. Aróstegui
Sonia Corral-Arboledas
Maria Teresa Coll-Sibina
Lluïsa Masiques-Mas


Amyloid A, Anti-IL1, Colchicine, Familial Mediterranean fever, Fever


Familial Mediterranean fever (FMF) is the most frequent autoinflammatory disorder characterized by short, repeated, and self-limiting crises of fever and serositis. The disease was described as autosomal recessive hereditary transmission secondary to variants of the MEFV (MEditerranean FeVer) gene, even though a variable proportion of patients only present a heterozygous variant. FMF is very common in certain ethnic groups (Turkish, Armenian, Arab, and Jewish), even though it has been described throughout the Mediterranean and elsewhere in the world. The clinical manifestations are variable, with secondary amyloidosis being the most serious complication of the disorder. Treatment and prophylaxis are mainly based on the administration of colchicine, which prevents the crises and avoids complications in most cases. This study reviews the course of seven pediatric patients diagnosed with FMF during the period 2010–2018 at a district hospital. Most of the patients were of Caucasian origin, with onset at an early age in the form of fever as the main symptom, and some patients moreover presented less frequent manifestations (pericardial effusion, sensorineural hearing loss). Two cases presented plasmatic amyloid A protein elevation that subsided with the treatment. All the patients initially received colchicine, and one of them required prescription of anakinra, which was replaced by canakinumab due to a serious adverse reaction. There were no cases of consanguinity, and all the patients were of Mediterranean origin. The subjects showed a favorable course over the years, which was attributed to the early diagnosis and treatment provided.

Abstract 76 | pdf Downloads 20 HTML Downloads 5 XML Downloads 0


1. Shohat M. Familial Mediterranean fever. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. 2000 (Updated 2016 Dec 15). Available from: https://www.ncbi.nlm.nih.gov/books/NBK1227/ [Accessed 21 February 2021].

2. Marek-Yagel D, Berkun Y, Padeh S. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum. 2009;60:1862. 10.1002/art.24570

3. Ben-Chetrit E, Touitou I. Familial Mediterranean fever in the world. Arthritis Rheum. 2009;61:1447. 10.1002/art.24458

4. Infevers: An online database for autoinflammatory mutations [Internet]. Available from: https://infevers.umai-montpellier.fr/ [Accesed May 2021].

5. Arostegui JI. Hereditary systemic autoinflammatory diseases. Reumatol Clin. 2011;7(1):45–50. 10.1016/j.reuma.2010.01.010

6. Westermark GT, Fändrich M, Westermark P. AA amyloidosis: Pathogenesis and targeted therapy. Annu Rev Pathol. 2015;10:321. 10.1146/annurev-pathol-020712-163913

7. Gattorno M, Hofer M, Federici S. Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019;78(8):1025–32. 10.1136/annrheumdis-2019-215048

8. Özen S. Update on the epidemiology and disease outcome of familial Mediterranean fever. Best Pract Res Clin Rheumatol. 2018;32:254–60. 10.1016/j.berh.2018.09.003

9. Eurofever registry [Internet]. Available from: https://www.printo.it/eurofever/score_criteria [Accessed 21 April 2021].

10. Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G. EULAR recommendations for the managementof familial Mediterranean fever. Ann Rheum Dis. 2016;75:644–51. 10.1136/annrheumdis-2015-208690

11. De Benedetti F, Gattorno M, Anton J, Ben-Chetrit E, Frenkel J, Hoffman HM. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med. 2018;378:1908–19. 10.1056/NEJMoa1706314

12. Bayram MT, Çankaya T, Bora E. Risk factors for subclinical inflammation in children with Familial Mediterranean fever. Rheumatol Int. 2015;35:1393. 10.1007/s00296-015-3227-z

13. Arpacı A, Doğan S, Erdoğan HF, El Ç, Cura SE. Presentation of a new mutation in FMF and evaluating the frequency of distribution of the MEFV gene mutation in our region with clinical findings. Mol Biol Rep. 2021 Mar;48(3):2025–33. 10.1007/s11033-020-06040-y

14. Dode C, Pecheux C, Cazeneuve C, Cattan D, Dervichian M, Goossens M. Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of familial Mediterranean fever. Am J Med Genet. 2000;92:241–6. 10.1002/(SICI)1096-8628(20000605)92:4%3C241::AID-AJMG3%3E3.0.CO;2-G

15. Shinar Y, Livneh A, Langevitz P. Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol. 2000;27:1703.

16. Giancane G, Ter Haar NM, Wulffraat N, Vastert SJ, Barron K, Hentgen V. Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis. 2015 Apr;74(4):635–41. 10.1136/annrheumdis-2014-206844

17. Touitou I. The spectrum of familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001;9(7):473–83. 10.1038/sj.ejhg.5200658

18. Yalçinkaya F, Ozen S, Ozçakar ZB, Aktay N, Cakar N, Düzova A. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford). 2009 Apr;48(4):395–8. 10.1093/rheumatology/ken509

19. Ozçakar ZB, Yalçınkaya F, Cakar N. Application of the new pediatric criteria and Tel Hashomer criteria in heterozygous patients with clinical features of FMF. Eur J Pediatr. 2011;170:1055. 10.1007/s00431-011-1404-y

20. Berkun Y, Eisenstein EM. Diagnostic criteria of familial Mediterranean fever. Autoimmun Rev. 2014 Apr–May;13(4–5):388–90. 10.1016/j.autrev.2014.01.045

21. Polat A, Acikel C, Sozeri B, Dursun I, Kasapcopur O, Gulez N. Comparison of the efficacy of once-and twice-daily colchicine dosage in pediatric patients with familial Mediterranean fever—A randomized controlled noninferiority trial. Arthritis Res Ther. 2016;18:85. 10.1186/s13075-016-0980-7

22. Özen S, Kone-Paut I, Gül A. Colchicine resistance and intolerance in familial Mediterranean fever: Definition, causes, and alternative treatments. Semin Arthritis Rheum. 2017;47:115–20. 10.1016/j.semarthrit.2017.03.006

23. Eroglu FK, Besbas N, Topaloglu R, Özen S. Treatment of colchicine-resistant familial Mediterranean fever in children and adolescents. Rheumatol Int. 2015;35:1733–7. 10.1007/s00296-015-3293-2

24. Idescat. [Internet]. Available from: https://www.idescat.es/poblacioestrangera/?b=1&geo=cat&nac=a#Plegable=geo [Accesed May 2021].