Journal of Clinical Immunology

, Volume 34, Issue 1, pp 104–113 | Cite as

Clinical and Genetic Profile of Children with Periodic Fever Syndromes from a Single Medical Center in South East Michigan

  • Shanmuganathan Chandrakasan
  • Saurabh Chiwane
  • Matthew Adams
  • Basil M. Fathalla
Original Research



To report a cohort of children with periodic fever syndromes (PFS) from Southeast Michigan.


A retrospective review of medical records for patients referred for periodic fever over 5 years.


Sixty-six patients including 21 FMF, 15 PFAPA, four TRAPS and one patient with combined HIDS and FMF were included. In addition, 25 patients were categorized as clinical PFS (cPFS) based on their clinical features however their genetic workup was either negative or inconclusive. Majority of the patients with FMF were from Middle Eastern background (88 %), but positive family history was noted in only 55 % of cases. Mean age at diagnosis was 40.8 months with a mean delay in diagnosis of 24 months. Most common MEFV mutations were p.M694V and p.M694I. Four patients with TRAPS were from mixed European descent and age at onset of symptoms was 6, 12, 12, and 84 months respectively. TNFRSF1A sequence variants in the TRAPS patients included p.R121Q (R92Q) and p.C99G (C70G); one patient had a rare occurrence of a concurrent p.V726A/-MEFV mutation. One patient with HIDS and FMF presented with atypical overlapping PFS clinical manifestations and genetic evaluation showed a unique combination of p.I268T/p.V377I MVK mutations and p.E230K/-MEFV variant. All patients with PFAPA group were from mixed European descent, symptoms started at a mean age of 34.6 months with a mean delay in diagnosis of 23.3 months. Symptoms started during infancy in six patients. All patients fulfilled the diagnostic criteria for PFAPA. The mean age of onset of symptoms in cPFS group was 17.2 months. Empiric colchicine and glucocorticosteroids controlled flares in majority of patients with cPFS. No evidence of amyloidosis was found in this entire cohort of 66 patients after a mean of 29.2 months of follow-up.


PFS can present with atypical manifestations and should not be excluded based on a negative family history. Concomitant mutations in different autoinflammatory disorders genes can be present and possibly explain atypical manifestations. Various therapies may be considered even if genetic testing is inconclusive or negative.


Periodic fever syndromes familial Mediterranean fever HIDS TRAPS PFAPA 



Autoinflammatory disorders


Cryopyrin-associated periodic syndromes


Familial Mediterranean Fever


Hyper Ig-D Syndrome


Pyogenic Arthritis, Pustulosis, and Acne syndrome


Periodic fevers with Aphthous Stomatitis, Pharyngitis, and Adenitis syndrome


Periodic Fever Syndromes


TNF-Receptor Associated Periodic Fever Syndrome





  1. 1.
    McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97:133–44.PubMedCrossRefGoogle Scholar
  2. 2.
    Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–68.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Stojanov S, Kastner DL. Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr Opin Rheumatol. 2005;17:586–99.PubMedCrossRefGoogle Scholar
  4. 4.
    Samuels J, Aksentijevich I, Torosyan Y, Centola M, Deng Z, Sood R, 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. 1998;77:268–97.PubMedCrossRefGoogle Scholar
  5. 5.
    Wurster VM, Carlucci JG, Feder Jr HM, Edwards KM. Long-term follow-up of children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J Pediatr. 2011;159:958–64. Epub 2011 Jul 27.PubMedCrossRefGoogle Scholar
  6. 6.
    U.S. Census Bureau. 2010 American community survey. Retrieved March 5, 2012, from
  7. 7.
    El-Shanti H, Majeed HA, El-Khateeb M. Familial Mediterranean fever in Arabs. Lancet. 2006;25(367):1016–24.CrossRefGoogle Scholar
  8. 8.
    Van der Hilst JC, Bodar EJ, Barron KS, Frenkel J, Drenth JP, van der Meer JW, et al. International HIDS study group. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine. 2008;87:301–10.PubMedCrossRefGoogle Scholar
  9. 9.
    Cantarini L, Lucherini OM, Muscari I, Frediani B, Galeazzi M, Brizi MG, et al. Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): state of the art and future perspectives. Autoimmun Rev. 2012;12:38–43.PubMedCrossRefGoogle Scholar
  10. 10.
    Simon A, van der Meer JWM, Vesely R, Myrdal U, Yoshimura K, Duys P, et al. Approach to genetic analysis in the diagnosis of hereditary autoinflammatory syndromes. Rheumatology. 2006;45:269–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Gattorno M, Sormani MP, D’Osualdo A, Pelagatti MA, Caroli F, Federici S, et al. A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children. Arthritis Rheum. 2008;58:1823–32.PubMedCrossRefGoogle Scholar
  12. 12.
    Dodé C, André M, Bienvenu T, Hausfater P, Pêcheux C, Bienvenu J, et al. French hereditary recurrent inflammatory disorder study group. The enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2002;46:2181–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Arkwright PD, McDermott MF, Houten SM, Frenkel J, Waterham HR, Aganna E, et al. Hyper IgD syndrome (HIDS) associated with in vitro evidence of defective monocyte TNFRSF1A shedding and partial response to TNF receptor blockade with etanercept. Clin Exp Immunol. 2002;130:484–8.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Stojanov S, Lohse P, McDermott MF, Renner ED, Kéry A, Mirakian R, et al. Periodic fever due to a novel TNFRSF1A mutation in a heterozygous Chinese carrier of MEFV E148Q. Rheumatology (Oxford). 2004;43:526–7.CrossRefGoogle Scholar
  15. 15.
    Stojanov S, Lohse P, Lohse P, Hoffmann F, Renner ED, Zellerer S, et al. Molecular analysis of the MVK and TNFRSF1A genes in patients with a clinical presentation typical of the hyperimmunoglobulinemia D with periodic fever syndrome: a low-penetrance TNFRSF1A variant in a heterozygous MVK carrier possibly influences the phenotype of hyperimmunoglobulinemia D with periodic fever syndrome or vice versa. Arthritis Rheum. 2004;50:1951–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Granel B, Serratrice J, Dodé C, Grateau G, Disdier P, Weiller PJ. Overlap syndrome between FMF and TRAPS in a patient carrying MEFV and TNFRSF1A mutations. Clin Exp Rheumatol. 2007;25(4 Suppl 45):S93–5.PubMedGoogle Scholar
  17. 17.
    Singh-Grewal D, Chaitow J, Aksentijevich I, Christodoulou J. Coexistent MEFV and CIAS1 mutations manifesting as familial Mediterranean fever plus deafness. Ann Rheum Dis. 2007;66:1541.PubMedCrossRefGoogle Scholar
  18. 18.
    Marek-Yagel D, Berkun Y, Padeh S, Lidar M, Shinar Y, Bar-Joseph I, et al. Role of the R92Q TNFRSF1A mutation in patients with familial Mediterranean fever. Arthritis Care Res. 2010;62:1294–8.CrossRefGoogle Scholar
  19. 19.
    Ben-Chetrit E, Lerer I, Malamud E, Domingo C, Abeliovich D. The E148Q mutation in the MEFV gene: is it a disease causing mutation or a sequence variant? Hum Mutat. 2000;15:285–6.CrossRefGoogle Scholar
  20. 20.
    Topaloglu R, Ozaltin F, Yilmaz E, Ozen S, Balci B, Besbas N, et al. E148Q is a disease-causing MEFV mutation: a phenotypic evaluation in patients with familial Mediterranean fever. Ann Rheum Dis. 2005;64:750–2.PubMedCrossRefGoogle Scholar
  21. 21.
    Kaşifoğlu T, Calişir C, Cansu DU, Korkmaz C. The frequency of sacroiliitis in familial Mediterranean fever and the role of HLA-B27 and MEFV mutations in the development of sacroiliitis. Clin Rheumatol. 2009;28:41–6. Epub 2008 Sep 16.PubMedCrossRefGoogle Scholar
  22. 22.
    Balaban B, Yasar E, Ozgul A, Dincer K, Kalyon TA. Sacroiliitis in familial Mediterranean fever and seronegative spondyloarthropathy: importance of differential diagnosis. Rheumatol Int. 2005;25:641–4. Epub 2005 Feb 12.PubMedCrossRefGoogle Scholar
  23. 23.
    Türkmen M, Soylu OB, Kasap B, Güneş S, Tüfekçi O, Soylu A, et al. Growth in familial mediterranean fever: effect of attack rate, genotype and colchicine treatment. J Pediatr Endocrinol Metab. 2008;21:789–92.PubMedCrossRefGoogle Scholar
  24. 24.
    Ozçakar ZB, Kadioğlu G, Siklar Z, Kavaz A, Nur Aksanal F, Berberoğlu M, et al. The effect of colchicine on physical growth in children with familial mediterranean fever. Eur J Pediatr. 2010;169:825–8. Epub 2009 Dec 17.PubMedCrossRefGoogle Scholar
  25. 25.
    Uslu N, Yüce A, Demir H, Saltik-Temizel IN, Usta Y, Yilmaz E, et al. The association of inflammatory bowel disease and Mediterranean fever gene (MEFV) mutations in Turkish children. Dig Dis Sci. 2010;55:3488–94. Epub 2010 Mar 21.PubMedCrossRefGoogle Scholar
  26. 26.
    Sari S, Egritas O, Dalgic B. The familial Mediterranean fever (MEFV) gene may be a modifier factor of inflammatory bowel disease in infancy. Eur J Pediatr. 2008;167:391–3. Epub 2007 May 23.PubMedCrossRefGoogle Scholar
  27. 27.
    Villani AC, Lemire M, Louis E, Silverberg MS, Collette C, Fortin G, et al. Genetic variation in the familial Mediterranean fever gene (MEFV) and risk for Crohn’s disease and ulcerative colitis. PLoS One. 2009;28(4):e7154.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Shanmuganathan Chandrakasan
    • 1
  • Saurabh Chiwane
    • 1
  • Matthew Adams
    • 2
  • Basil M. Fathalla
    • 3
    • 4
    • 5
  1. 1.Department of PediatricsChildren’s Hospital of MichiganDetroitUSA
  2. 2.Division of Pediatric Rheumatology, Children’s Hospital of MichiganWayne State University School of MedicineDetroitUSA
  3. 3.Division of Pediatric Rheumatology, Children’s Hospital of MichiganWayne State University School of MedicineDetroitUSA
  4. 4.Weill Cornell Medical CollegeAd DohaQatar
  5. 5.Section of Pediatric Rheumatology, Department of PediatricsHamad General HospitalDohaQatar

Personalised recommendations