Background. Given the strong genetic background of familial Mediterranean fever (FMF), the frequently reported co-existing diseases in children with FMF should also be investigated in other family members. Therefore, we aimed to examine the medical conditions of first-degree relatives (FDRs) of our pediatric patients with FMF in the present study.

Methods. Chronic diseases of FDRs of pediatric 449 FMF, 147 juvenile idiopathic arthritis (JIA) patients and 93 healthy controls (HC) were questioned during their routine clinical visits for 9 consecutive months.

Results. A total of 1975 FDRs of 449 FMF, 690 FDRs of 147 JIA patients, and 406 FDRs of 93 HC were included into the study. The most common medical conditions were non-atopic asthma (n=71, 3.6%), type 2 DM (n=14, 2%), and tonsillectomy history (n=12, 2.95%) in the FMF, JIA, and HC groups, respectively. Atopic diseases (FMF vs. JIA: p=0.013; FMF vs. HC: p=0.014), rheumatic diseases (FMF vs. JIA: p=0.030; FMF vs. HC: p=0.017), and surgical histories (FMF vs. JIA: p<0.01; FMF vs. HC: p=0.026), including adenoidectomy, tonsillectomy, and appendectomy, were significantly more common in the FMF group than in other groups.

Conclusions. Our novel findings may contribute to understanding the hereditary burden of co-existing diseases in children with FMF and encourage further studies involving genetic screenings. 

Keywords: familial Mediterranean fever, arthritis, juvenile, parents

How to cite

Yıldırım S, Haşlak F, Yıldız M, et al. Health conditions of first-degree relatives of children with familial Mediterranean fever. Turk J Pediatr 2024; 66: 180-190. https://doi.org/10.24953/turkjpediatr.2024.4589


  1. Yildiz M, Adrovic A, Tasdemir E, et al. Evaluation of co-existing diseases in children with familial Mediterranean fever. Rheumatol Int 2020; 40: 57-64. https://doi.org/10.1007/s00296-019-04391-9
  2. Yalçınkaya F, Özen S, Özçakar ZB, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford) 2009; 48: 395-398. https://doi.org/10.1093/rheumatology/ken509
  3. Padeh S, Berkun Y. Familial Mediterranean fever. Curr Opin Rheumatol 2016; 28: 523-529. https://doi.org/10.1097/BOR.0000000000000315
  4. Ayaz NA, Tanatar A, Karadağ ŞG, Çakan M, Keskindemirci G, Sönmez HE. Comorbidities and phenotype-genotype correlation in children with familial Mediterranean fever. Rheumatol Int 2021; 41: 113-120. https://doi.org/10.1007/s00296-020-04592-7
  5. Ozdogan H, Ugurlu S. Familial Mediterranean fever. Presse Med 2019; 48: e61-e76. https://doi.org/10.1016/j.lpm.2018.08.014
  6. Balcı-Peynircioğlu B, Kaya-Akça Ü, Arıcı ZS, et al. Comorbidities in familial Mediterranean fever: analysis of 2000 genetically confirmed patients. Rheumatology (Oxford) 2020; 59: 1372-1380. https://doi.org/10.1093/rheumatology/kez410
  7. Sönmez HE, Esmeray P, Batu ED, et al. Is age associated with disease severity and compliance to treatment in children with familial Mediterranean fever? Rheumatol Int 2019; 39: 83-87. https://doi.org/10.1007/s00296-018-4123-0
  8. Akpolat T, Özkaya O, Özen S. Homozygous M694V as a risk factor for amyloidosis in Turkish FMF patients. Gene 2012; 492: 285-289. https://doi.org/10.1016/j.gene.2011.10.012
  9. Ganapati A, Arunachal G, Arya S, et al. Study of familial aggregation of autoimmune rheumatic diseases in Asian Indian patients with systemic lupus erythematosus. Rheumatol Int 2019; 39: 2053-2060. https://doi.org/10.1007/s00296-019-04355-z
  10. James JA, Chen H, Young KA, et al. Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients. EBioMedicine 2019; 42: 76-85. https://doi.org/10.1016/j.ebiom.2019.03.063
  11. Pohjankoski H, Kautiainen H, Kotaniemi K, Korppi M, Savolainen A. Diabetes, coeliac disease, multiple sclerosis and chronic arthritis in first-degree relatives of patients with juvenile idiopathic arthritis. Acta Paediatr 2012; 101: 767-771. https://doi.org/10.1111/j.1651-2227.2012.02658.x
  12. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004; 31: 390-392.
  13. Aypar E, Ozen S, Okur H, Kutluk T, Besbas N, Bakkaloglu A. Th1 polarization in familial Mediterranean fever. J Rheumatol 2003; 30: 2011-2013.
  14. Umetsu DT, DeKruyff RH. Th1 and Th2 CD4+ cells in the pathogenesis of allergic diseases. Proc Soc Exp Biol Med 1997; 215: 11-20. https://doi.org/10.3181/00379727-215-44109
  15. Sackesen C, Bakkaloglu A, Sekerel BE, et al. Decreased prevalence of atopy in paediatric patients with familial Mediterranean fever. Ann Rheum Dis 2004; 63: 187-190. https://doi.org/10.1136/ard.2003.007013
  16. Aydoğmuş Ç, Ayaz NA, Çakan M, et al. Is there any difference regarding atopy between children with familial Mediterranean fever and healthy controls? Allergol Immunopathol (Madr) 2017; 45: 549-552. https://doi.org/10.1016/j.aller.2016.12.006
  17. Amet C, Selçuk Duru N, Elevli M, Çivilibal M. Atopy in children and adolescents with familial Mediterranean fever. J Pediatr Res 2015; 2: 118-121. https://doi.org/10.4274/jpr.41636
  18. Celiksoy MH, Dogan C, Erturk B, Keskin E, Ada BS. The MEFV gene and its association with familial Mediterranean fever, severe atopy, and recurrent respiratory tract infections. Allergol Immunopathol (Madr) 2020; 48: 430-440. https://doi.org/10.1016/j.aller.2019.12.010
  19. Ibrahim JN, Jounblat R, Delwail A, et al. Ex vivo PBMC cytokine profile in familial Mediterranean fever patients: Involvement of IL-1β, IL-1α and Th17-associated cytokines and decrease of Th1 and Th2 cytokines. Cytokine 2014; 69: 248-254. https://doi.org/10.1016/j.cyto.2014.06.012
  20. Ovadia A, Livneh A, Feld O, et al. T helper 17 polarization in familial Mediterranean fever. Genes Immun 2013; 14: 212-216. https://doi.org/10.1038/gene.2013.6
  21. Wang YH, Wills-Karp M. The potential role of interleukin-17 in severe asthma. Curr Allergy Asthma Rep 2011; 11: 388-394. https://doi.org/10.1007/s11882-011-0210-y
  22. Prystowsky JB, Pugh CM, Nagle AP. Current problems in surgery. Appendicitis. Curr Probl Surg 2005; 42: 688-742. https://doi.org/10.1067/j.cpsurg.2005.07.005
  23. Simon A, van der Meer JW, Drenth JP. Familial Mediterranean fever-a not so unusual cause of abdominal pain. Best Pract Res Clin Gastroenterol 2005; 19: 199-213. https://doi.org/10.1016/j.bpg.2004.11.009
  24. Ben-Chetrit E, Levy M. Colchicine prophylaxis in familial Mediterranean fever: reappraisal after 15 years. Semin Arthritis Rheum 1991; 20: 241-246. https://doi.org/10.1016/0049-0172(91)90019-v
  25. Lidar M, Doron A, Kedem R, Yosepovich A, Langevitz P, Livneh A. Appendectomy in familial Mediterranean fever: clinical, genetic and pathological findings. Clin Exp Rheumatol 2008; 26: 568-573.
  26. Kaşifoğlu T, Cansu DU, Korkmaz C. Frequency of abdominal surgery in patients with familial Mediterranean fever. Intern Med 2009; 48: 523-526. https://doi.org/10.2169/internalmedicine.48.1602
  27. Lachmann HJ, Sengül B, Yavuzşen TU, et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology (Oxford) 2006; 45: 746-750. https://doi.org/10.1093/rheumatology/kei279
  28. Özer S, Yılmaz R, Sönmezgöz E, et al. Simple markers for subclinical inflammation in patients with familial Mediterranean fever. Med Sci Monit 2015; 21: 298-303. https://doi.org/10.12659/MSM.892289
  29. Veres T, Amarilyo G, Abu Ahmad S, et al. Familial periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome; is it a separate disease? Front Pediatr 2022; 9: 800656. https://doi.org/10.3389/fped.2021.800656
  30. Adrovic A, Sahin S, Barut K, Kasapcopur O. Familial Mediterranean fever and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: shared features and main differences. Rheumatol Int 2019; 39: 29-36. https://doi.org/10.1007/s00296-018-4105-2
  31. Yamagami K, Nakamura T, Nakamura R, et al. Familial Mediterranean fever with P369S/R408Q exon3 variant in pyrin presenting as symptoms of PFAPA. Mod Rheumatol 2017; 27: 356-359. https://doi.org/10.1080/14397595.2017.1267173
  32. Gozen ED, Yildiz M, Kara S, et al. Long-term efficacy of tonsillectomy/adenotonsillectomy in patients with periodic fever aphthous stomatitis pharyngitis adenitis syndrome with special emphasis on co-existence of familial Mediterranean fever. Rheumatol Int 2023; 43: 137-145. https://doi.org/10.1007/s00296-022-05210-4
  33. Tekin M, Yalçinkaya F, Tümer N, Cakar N, Koçak H. Familial Mediterranean fever and acute rheumatic fever: a pathogenetic relationship? Clin Rheumatol 1999; 18: 446-449. https://doi.org/10.1007/s100670050136
  34. Kalyoncu M, Acar BC, Cakar N, et al. Are carriers for MEFV mutations “healthy”? Clin Exp Rheumatol 2006; 24: S120-S122.
  35. Yıldız M, Haşlak F, Adrovic A, Barut K, Kasapçopur Ö. Autoinflammatory diseases in childhood. Balkan Med J 2020; 37: 236-246. https://doi.org/10.4274/balkanmedj.galenos.2020.2020.4.82
  36. Castro SA, Dorfmueller HC. A brief review on group A streptococcus pathogenesis and vaccine development. R Soc Open Sci 2021; 8: 201991. https://doi.org/10.1098/rsos.201991
  37. Borman P, Gökoğlu F, Taşbaş O, Yilmaz M, Yorgancioğlu ZR. Familial Mediterranean fever-related spondyloarthropathy. Singapore Med J 2009; 50: e116-e119.
  38. Langevitz P, Livneh A, Zemer D, Shemer J, Pras M. Seronegative spondyloarthropathy in familial Mediterranean fever. Semin Arthritis Rheum 1997; 27: 67-72. https://doi.org/10.1016/s0049-0172(97)80007-8
  39. Ozer E, Seker D, Taner E, et al. The frequency of juvenile spondyloarthropathies in childhood familial Mediterranean fever. Clin Exp Rheumatol 2018; 36: 141-145.
  40. Ozdogan H, Arisoy N, Kasapçapur O, et al. Vasculitis in familial Mediterranean fever. J Rheumatol 1997; 24: 323-327.
  41. Beşer OF, Kasapçopur O, Cokuğraş FC, Kutlu T, Arsoy N, Erkan T. Association of inflammatory bowel disease with familial Mediterranean fever in Turkish children. J Pediatr Gastroenterol Nutr 2013; 56: 498-502. https://doi.org/10.1097/MPG.0b013e31827dd763
  42. Özçakar ZB, Çakar N, Uncu N, Çelikel BA, Yalçinkaya F. Familial Mediterranean fever-associated diseases in children. QJM 2017; 110: 287-290. https://doi.org/10.1093/qjmed/hcw230
  43. Erden A, Batu ED, Seyhoğlu E, et al. Increased psoriasis frequency in patients with familial Mediterranean fever. Ups J Med Sci 2018; 123: 57-61. https://doi.org/10.1080/03009734.2017.1423425
  44. Barut K, Guler M, Sezen M, Kasapçopur O. Inceased frequency of psoriasis in the families of the children with familial Mediterranean fever. Clin Exp Rheumatol 2016; 34: S137.
  45. Ozdogan H, Ugurlu S, Uygunoglu U, et al. The efficacy of anti- IL-1 treatment in three patients with coexisting familial Mediterranean fever and multiple sclerosis. Mult Scler Relat Disord 2020; 45: 102332. https://doi.org/10.1016/j.msard.2020.102332
  46. Salehzadeh F, Enteshari Moghaddam A. Coexisting diseases in patients with familial Mediterranean fever. Open Access Rheumatol 2020; 12: 65-71. https://doi.org/10.2147/OARRR.S252071
  47. Yahalom G, Kivity S, Lidar M, et al. Familial Mediterranean fever (FMF) and multiple sclerosis: an association study in one of the world’s largest FMF cohorts. Eur J Neurol 2011; 18: 1146-1150. https://doi.org/10.1111/j.1468-1331.2011.03356.x
  48. Elhani I, Dumont A, Vergneault H, et al. Association between familial Mediterranean fever and multiple sclerosis: a case series from the JIR cohort and systematic literature review. Mult Scler Relat Disord 2021; 50: 102834. https://doi.org/10.1016/j.msard.2021.102834
  49. Ceylan G, Erten S, Ercan K. Co-existence of familial Mediterranean fever and multiple sclerosis in two patients. Acta Reumatol Port 2014; 39: 342-344.
  50. Kümpfel T, Gerdes LA, Wacker T, et al. Familial Mediterranean fever-associated mutation pyrin E148Q as a potential risk factor for multiple sclerosis. Mult Scler 2012; 18: 1229-1238. https://doi.org/10.1177/1352458512437813