Molecular Diagnosis & Therapy

, Volume 18, Issue 5, pp 549–557 | Cite as

MEFV Mutations in Egyptian Children with Systemic-Onset Juvenile Idiopathic Arthritis

  • Hala M. Lotfy
  • Manal E. Kandil
  • Marianne Samir Makboul Issac
  • Samia Salah
  • Nagwa Abdallah Ismail
  • Mohamed A. Abdel Mawla
Original Research Article


Background and Objectives

Systemic-onset juvenile idiopathic arthritis (SoJIA) is a chronic auto-inflammatory disease of childhood, with a complex genetic trait, which is characterized by arthritis associated with systemic manifestations. Familial Mediterranean fever (FMF) is another auto-inflammatory disorder that is monogenic. There are speculations as to whether Mediterranean fever (MEFV) mutations are among the genetic determinants of SoJIA. Our aim was to explore the frequency and clinical significance of MEFV mutations in Egyptian SoJIA patients. A group of healthy children were assigned to the control group in an attempt to estimate the carrier rate of MEFV mutations in Egypt.


Eighty-four children were recruited in this study; 54 children, age (mean ± standard deviation; 8.31 ± 2.85 years), diagnosed as having SoJIA with no typical symptoms of FMF; 30 healthy age- and gender-matched children served as the control group. All recruited children were screened for 12 common MEFV mutations using a reverse hybridization assay of biotinylated PCR products.


SoJIA patients had a significantly higher frequency of MEFV mutations (66.7 %) than in the healthy control population (16.7 %). V726A was the leading mutation in SoJIA patients, with an allelic frequency of 15.74 %, followed by E148Q, with an allelic frequency of 7.4 %. Children who were carriers of MEFV mutations had an 18 times higher risk of developing SoJIA than wild-type carriers [odds ratio 18.0 (95 % CI 5–69), P < 0.01]. E148Q was the leading mutation, present in 13.3 % of healthy controls.


These findings suggest that MEFV mutations may be responsible for auto-inflammatory diseases other than FMF, and patients with SoJIA, especially those with a positive family history of FMF or SoJIA, should be screened for MEFV mutations in countries where FMF is frequent.


Juvenile Idiopathic Arthritis Familial Mediterranean Fever Familial Mediterranean Fever Patient Time High Risk MEFV Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Acknowledgments and Disclosures

Special thanks to all Rheumatology Clinic members, who helped us in our work, and to our dear patients, who participated in conducting the study. The authors have no conflicts of interest that are directly relevant to the content of this article.

Supplementary material

40291_2014_105_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 19 kb)


  1. 1.
    Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369(9563):767–78.PubMedCrossRefGoogle Scholar
  2. 2.
    Woo P. Systemic juvenile idiopathic arthritis: diagnosis, management, and outcome. Nat Clin Pract Rheumatol. 2006;2:28–34.PubMedCrossRefGoogle Scholar
  3. 3.
    Behrens EM, Beukelman T, Gallo L, et al. Evaluation of the presentation of systemic onset juvenile rheumatoid arthritis: data from the Pennsylvania systemic onset juvenile arthritis registry (Pasojar). J Rheumatol. 2008;35:343–8.PubMedGoogle Scholar
  4. 4.
    Lin YT, Wang CT, Gershwin ME, et al. The pathogenesis of oligoarticular/polyarticular vs systemic juvenile idiopathic arthritis. Autoimmun Rev. 2011;10:482–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Lovell DJ. Update on treatment of arthritis in children—new treatments, new goals. Bull Hosp Jt Dis. 2006;64:72–6.Google Scholar
  6. 6.
    David J. Amyloidosis in juvenile chronic arthritis. Clin Exp Rheumatol. 1991;9:73–8.PubMedGoogle Scholar
  7. 7.
    Immonen K, Savolainen HA, Hakala M. Why can we no longer find juvenile idiopathic arthritis-associated amyloidosis in childhood or in adolescence in Finland? Scand J Rheumatol. 2007;36:402–3.PubMedCrossRefGoogle Scholar
  8. 8.
    Pascual V, Allantaz F, Arce E, et al. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med. 2005;201:1479–86.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008;371:998–1006.PubMedCrossRefGoogle Scholar
  10. 10.
    Ozen S, Hoffman HM, Frenkel J, Kastner D. Familial Mediterranean fever (FMF) and beyond: a new horizon. Fourth International Congress on the Systemic Autoinflammatory Diseases held in Bethesda, USA, 6–10 November 2005. Ann Rheum Dis. 2006;65:961–4.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    de Benedetti F, Meazza C, Vivarelli M, et al. Functional and prognostic relevance of the −173 polymorphism of the macrophage migration inhibitory factor gene in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2003;48:1398–407.PubMedCrossRefGoogle Scholar
  12. 12.
    Ogilvie EM, Fife MS, Thompson SD, et al. The −174 G allele of the interleukin-6 gene confers susceptibility to systemic arthritis in children: a multicenter study using simplex and multiplex juvenile idiopathic arthritis families. Arthritis Rheum. 2003;48:3202–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Ayaz NA, Özen S, Bilginer Y, et al. MEFV mutations in systemic onset juvenile idiopathic arthritis. Rheumatology. 2009;48:23–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Cantarini L, Lucherini OM, Simonini G, et al. Systemic-onset juvenile idiopathic arthritis complicated by early onset amyloidosis in a patient carrying a mutation in the MEFV gene. Rheumatol Int. 2012;32:465–7. doi: 10.1007/s00296-009-1331-7.PubMedCrossRefGoogle Scholar
  15. 15.
    Touitou I, Notarnicola C, Grandemange S. Identifying mutations in autoinflammatory diseases: towards novel genetic tests and therapies? Am J Pharmacogenomics. 2004;4(2):109–18.PubMedCrossRefGoogle Scholar
  16. 16.
    de Jesus AA, Goldbach-Mansky R. Monogenic autoinflammatory diseases: concept and clinical manifestations. Clin Immunol. 2013;147:155–74.CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Ozen S, Bilginer Y. A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol. 2014;10:135–47. doi: 10.1038/nrrheum.2013.174.PubMedCrossRefGoogle Scholar
  18. 18.
    Centola M, Wood G, Frucht DM, et al. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood. 2000;95:3223–31.PubMedGoogle Scholar
  19. 19.
    Onen F. Familial Mediterranean fever. Rheumatol Int. 2006;26:489–96.PubMedCrossRefGoogle Scholar
  20. 20.
    Samuels J, Aksentijevich I, Torosyan Y, et al. Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore). 1998;77:268–97.CrossRefGoogle Scholar
  21. 21.
    Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet. 1998;351:659–64.PubMedCrossRefGoogle Scholar
  22. 22.
    Infevers: an online database for autoinflammatory mutations. Accessed 11 Jan 2014. Milhavet F, Cuisset L, Hoffman HM, et al. The infevers autoinflammatory mutation online registry: update with new genes and functions. Hum Mutat. 2008;29(6):803–8. doi: 10.1002/humu.20720.PMID:18409191.
  23. 23.
    Hershko AY, Ben-Chetrit E. The MEFV E148Q allele: a deleterious mutation or harmless variation? Clin Exp Rheumatol. 2006;24(Suppl. 42):S51–2.PubMedGoogle Scholar
  24. 24.
    Ben-Chetrit E, Lerer I, Malamud E, et al. The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant? Hum Mutat. 2000;15:385–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. International League of Associations for Rheumatology. J Rheumatol. 2004;31(2):390–2.PubMedGoogle Scholar
  26. 26.
    Tchernitchko D, Legendre M, Delahaye A, et al. Clinical evaluation of a reverse hybridization assay for the molecular detection of twelve MEFV gene mutations. Clin Chem. 2003;49:1942–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Petty R, Cassidy JY, Kastner D. Chronic arthritis in childhood. In: Cassidy JT, Petty RE, Laxer RM, Lindsley CB, editors. Textbook of pediatric rheumatology. 6th ed. Philadelphia: Saunders; 2011. p. 272–86.CrossRefGoogle Scholar
  28. 28.
    Comak E, Dogan CS, Akman S, et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr. 2013;172:1061–7. doi: 10.1007/s00431-013-2003-x.PubMedCrossRefGoogle Scholar
  29. 29.
    Yeniay BS, Karaca NE, Yuksel SE, et al. Juvenile psoriatic arthritis carrying familial Mediterranean fever gene mutations in a 14-year-old Turkish girl. J Dermatol. 2007;34:344–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Ozen S, Bakkaloglu A, Yilmaz E, et al. Mutations in the gene for familial Mediterranean fever: do they predispose to inflammation? J Rheumatol. 2003;30:2014–8.PubMedGoogle Scholar
  31. 31.
    Booth DR, Lachmann HJ, Gillmore JD, et al. Prevalence and significance of the familial Mediterranean fever gene mutation encoding pyrin Q148. QJM. 2001;94:527–31.PubMedCrossRefGoogle Scholar
  32. 32.
    Olgun A, Akman S, Kurt I, et al. MEFV mutations in familial Mediterranean fever: association of M694V homozygosity with arthritis. Rheumatol Int. 2005;25:255–9. doi: 10.1007/s00296-003-0433-x.PubMedCrossRefGoogle Scholar
  33. 33.
    Rabinovich E, Livneh A, Langevitz P, et al. Severe disease in patients with rheumatoid arthritis carrying a mutation in the Mediterranean fever gene. Ann Rheum Dis. 2005;64:1009–14.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Migita K, Nakamura T, Maeda Y, et al. MEFV mutations in Japanese rheumatoid arthritis patients. Clin Exp Rheumatol. 2008;26:1091–4.PubMedGoogle Scholar
  35. 35.
    Settin A, El-Baz R, Abd Rasool M, et al. Clinical and molecular diagnosis of familial Mediterranean fever in Egyptian children. J Gastrointest Liver Dis. 2007;16(2):141–5.Google Scholar
  36. 36.
    El Gezery DA, Abou-Zeid AA, Hashad DI, et al. MEFV gene mutations in Egyptian patients with familial Mediterranean fever. Genet Test Mol Biomarkers. 2010;14(2):263–8. doi: 10.1089/gtmb.2009.0180.PubMedCrossRefGoogle Scholar
  37. 37.
    Talaat HS, Mohamed MF, El Rifai NM, et al. The expanded clinical profile and the efficacy of colchicine therapy in Egyptian children suffering from familial Mediterranean fever: a descriptive study. Ital J Pediatr. 2012;38:66.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    El-Garf A, Salah S, Iskander I, et al. MEFV mutations in Egyptian patients suffering from familial Mediterranean fever: analysis of 12 gene mutations. Rheumatol Int. 2010;30:1293–8. doi: 10.1007/s00296-009-1140-z.PubMedCrossRefGoogle Scholar
  39. 39.
    Temtamy SA, Aglan MS, Meguid NA, Teebi AS. Chapter 8: genetic disorders in Egypt. In: Teebi AS, editor. Genetic disorders among Arab populations. 2nd ed. Heidelberg: Springer; 2010. doi: 10.1007/978-3-642-05080-0_8.
  40. 40.
    Lachmann HJ, Sengul B, Yavuzs TU, et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology (Oxford). 2006;45:746–50.CrossRefGoogle Scholar
  41. 41.
    Aggarwal A, Agarwal V, Danda D, et al. Outcome in juvenile rheumatoid arthritis in India. Indian Pediatr. 2004;41:180–4.PubMedGoogle Scholar
  42. 42.
    Salah S, Hamshary A, Lotfy H, et al. Juvenile idiopathic arthritis, the Egyptian experience. J Med Sci. 2009;9(2):98–102.CrossRefGoogle Scholar
  43. 43.
    Al-Alami JR, Tayeh MK, Najib DA, et al. Familial Mediterranean fever mutation frequencies and carrier rates among a mixed Arabic population. Saudi Med J. 2003;24(10):1055–9.PubMedGoogle Scholar
  44. 44.
    Ait-Idir D, Khilan A, Djerdjouri B, et al. Spectrum of mutations and carrier frequency of familial Mediterranean fever gene in the Algerian population. Rheumatology. 2011;50:2306–10. doi: 10.1093/rheumatology/ker328.PubMedCrossRefGoogle Scholar
  45. 45.
    Medlej-Hashim M, Serre JL, Corbani S, et al. Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet. 2005;48:412–20.PubMedCrossRefGoogle Scholar
  46. 46.
    Mattit H, Joma M, Al-Cheikh S, et al. Familial Mediterranean fever in the Syrian population: gene mutation frequencies, carrier rates and phenotype–genotype correlation. Eur J Med Genet. 2006;49:481–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Oberkanins C, Weinhäusel A, Kriegshäuser G, et al. Genetic testing for familial Mediterranean fever in Austria by means of reverse-hybridization teststrips. Clin Chem. 2003;49(11):1948–50.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Hala M. Lotfy
    • 1
  • Manal E. Kandil
    • 2
  • Marianne Samir Makboul Issac
    • 3
  • Samia Salah
    • 1
  • Nagwa Abdallah Ismail
    • 2
  • Mohamed A. Abdel Mawla
    • 2
  1. 1.Department of Pediatrics, Faculty of MedicineCairo UniversityCairoEgypt
  2. 2.Pediatrics DepartmentNational Research CenterCairoEgypt
  3. 3.Department of Clinical and Chemical Pathology, Faculty of MedicineCairo UniversityCairoEgypt

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