Skip to main content


Log in

Overlap of Familial Mediterranean Fever and Hyper-IgD Syndrome in an Arabic Kindred

  • Astute Clinician Report
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript


Hyperimmunoglobulinemia D Syndrome (HIDS) has rarely been reported in Arabs. Moreover, the simultaneous presence of mutations in MEFV and MVK segregating in the same family is exceptional. We report an Arabic girl presenting since the age of 8-years with two patterns of recurrent episodes of fever, and associated with a spectrum of clinical features suggestive of overlap between familial Mediterranean fever (FMF) and HIDS. Her 19-year old brother presented since the age of 1 year with prolonged episodes of fever and was diagnosed with HIDS at the age of 7 years based on clinical features and homozygosity for p.V377I mutation in MVK. Shorter episodes of fever and abdominal pain more consistent with FMF ensued since the age of 17 years. Genetic testing done for both patients and all other family members revealed simultaneous presence of mutations in MEFV and MVK but with a variable clinical spectrum ranging from asymptomatic to severe manifestations. Both of our patients are homozygous for p.V377I MVK mutation; the girl is a compound heterozygote for p.E148Q/p.P369S/p.R408G and p.E167D/p.F479L MEFV mutations whereas the brother is a compound heterozygote for p.E148Q/p.P369S/p.R408G and p.M680I MEFV mutations. The clinical implications of having more than one mutation in different genes of monogenic autoinflammatory diseases in the same individual are not clear but may explain atypical clinical manifestations such as the overlap features of both FMF and HIDS in this family.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others


  1. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–68.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Samuels J, Ozen S. Familial Mediterranean fever and the other autoinflammatory syndromes: evaluation of the patient with recurrent fever. Curr Opin Rheumatol. 2006;18:108–17.

    Article  PubMed  Google Scholar 

  3. El-Shanti H, Majeed HA, El-Khateeb M. Familial mediterranean fever in Arabs. Lancet. 2006;367:1016–24.

    Article  PubMed  Google Scholar 

  4. 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 (Baltimore). 2008;87:301–10.

    Article  Google Scholar 

  5. Drenth JP, Haagsma CJ, van der Meer JW. Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Medicine (Baltimore). 1994;73:133–44.

    Article  CAS  Google Scholar 

  6. Hammoudeh M. Hyperimmunoglobulinemia D, syndrome in an Arab child. Clin Rheumatol. 2005;24(1):92–4.

    Article  PubMed  Google Scholar 

  7. Houten SM, van Woerden CS, Wijburg FA, Wanders RJ, Waterham HR. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet. 2003;11(2):196–200.

    Article  CAS  PubMed  Google Scholar 

  8. Dodé C, André M, Bienvenu T, Hausfater P, Pêcheux C, Bienvenu J, et al. French Heraditary Recurrent Inflammatory Disorder Study Group. The enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2002;46(8):2181–8.

    Article  PubMed  Google Scholar 

  9. 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(Oxf). 2004;43:26–7.

    Google Scholar 

  10. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. 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.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Chandrakasan S, Chwaine S, Adams M, Fathalla BM. Clinical and genetic profile of children with periodic fever syndromes from a Single Medical Centre in South East Michigan. J Clin Immunol. 2013 Nov 15.

  14. Simon A, van der Meer JW, Vesely R, Myrdal U, Yoshimura K, Duys P, et al. International HIDS Study Group. Approach to genetic analysis in the diagnosis of hereditary autoinflammatory syndromes. Rheumatology. 2006;45:269–73.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

Download references


This work is funded in part by Hamad Medical Corporation / Medical research committee approval 13438/13 and 12168/12 (BF) and Qatar National Research Fund (QNRF), Grant # NPRP 09-374-3-092 (HE, RZT)


Nothing to disclose.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Basil M Fathalla.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moussa, T., Aladbe, B., Taha, R.Z. et al. Overlap of Familial Mediterranean Fever and Hyper-IgD Syndrome in an Arabic Kindred. J Clin Immunol 35, 249–253 (2015).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: