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Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children

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Abstract

Autoinflammatory diseases (AIDs) are characterized by recurrent, self-limiting systemic inflammation. Disorders include hereditary recurrent fever (HRF) syndromes such as hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). To determine the incidence of HIDS and report clinical and genetic characteristics together with the underlying MVK genotypes in German children, a prospective active surveillance was conducted in Germany during a period of 3 years. Monthly inquiries were sent to 370 children’s hospitals by the German Paediatric Surveillance Unit (Clinic-ESPED, n1) and to two laboratories (Laboratory-ESPED, n2) performing genetic analyses. Inclusion criteria were a MVK mutation–positive patient ≤16 years of age with more than three self-limiting episodes of fever >38.5°C associated with increased inflammation markers. Clinical, epidemiological, and genetic data were assessed via questionnaires. Eight out of 16 patients were identified in Clinic-ESPED (n1) and 15 of 16 in Laboratory-ESPED (n2). Clinical and laboratory surveys overlapped in 7 of 16 cases. Incidence of HIDS was estimated to be 0.39 (95% CI: 0.22, 0.64) per 106 person-years. HIDS symptoms generally started in infancy with recurrent fever episodes lasting 3–12 (median, 4.5) days and recurring every 1–12 weeks. Fever was accompanied by abdominal pain, vomiting, diarrhea, cervical lymphadenopathy, and sometimes by headache, skin and joint symptoms. The patients carried 11 different MVK mutations mostly in compound heterozygosity (75%, 12 out of 16). The most frequent mutation was p.Val377Ile (81%, 13 out of 16). In Germany, the incidence of HIDS is very low with 0.39 per 106 person-years.

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Abbreviations

AID:

Autoinflammatory disease

MVK:

Mevalonate kinase

HIDS:

Hyperimmunoglobulinemia D and periodic fever syndrome

MKD:

MVK deficiency

HRF:

Hereditary recurrent fever syndromes

ESPED:

German Paediatric Surveillance Unit for rare paediatric diseases

References

  1. Drenth JP, Cuisset L, Grateau G et al (1999) Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet 22:178–181

    Article  PubMed  CAS  Google Scholar 

  2. Houten SM, Kuis W, Duran M et al (1999) Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet 22:175–177

    Article  PubMed  CAS  Google Scholar 

  3. Korppi M, van Gijn ME, Antila K (2011) Hyperimmunoglobulinemia D and periodic fever syndromes in children. Review on therapy with biological drugs and case report. Acta Paediatr 100:21–25

    Article  PubMed  CAS  Google Scholar 

  4. Simon A, Kremer HPH, Wevers RA et al (2004) Mevalonate kinase deficiency. Evidence for a phenotypic continuum. Neurology 62:994–997

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  6. Simon A, van der Meer JW, Vesely R et al (2006) International HIDS Study Group. Approach to genetic analysis in the diagnosis of hereditary autoinflammatory syndromes. Rheumatology 45:269–273

    Article  PubMed  CAS  Google Scholar 

  7. Grateau G, Duruöz MT (2010) Autoinflammatory conditions: when to suspect? How to treat? Best Pract Res Clin Rheumatol 24(3):401–411

    Article  PubMed  Google Scholar 

  8. Lainka E, Neudorf U, Lohse P et al (2009) Incidence of TNFRSF1A mutations in German children: epidemiological, clinical and genetic characteristics. Rheumatology 48:987–991

    Article  PubMed  CAS  Google Scholar 

  9. Lainka E, Neudorf U, Lohse P et al (2010) Analysis of Cryopyrin-associated periodic syndromes (CAPS) in German children: epidemiological, clinical and genetic characteristics. Klin Padiatr 222:356–361

    Article  PubMed  CAS  Google Scholar 

  10. Sornsakrin M, Wenner K, Ganschow R (2009) B cell cytopenia in two brothers with hyper-IgD and periodic fever syndrome. Eur J Pediatr 168:825–831

    Article  PubMed  CAS  Google Scholar 

  11. Hospach T, Lohse P, Heilbronner H et al (2005) Pseudodominant inheritance of the hyperimmunoglobulinemia D with periodic fever syndrome in a mother and her two monozygotic twins. Arthritis Rheum 52(11):3606–3610

    Article  PubMed  CAS  Google Scholar 

  12. Hoffmann F, Lohse P, Stojanov S et al (2005) Identification of a novel mevalonate kinase gene mutation in combination with the common MVK V377I substitution and the low-penetrance TNFRSF1A R92Q mutation. Eur J Hum Genet 13:510–512

    Article  PubMed  CAS  Google Scholar 

  13. Simon A, Mariman EC, van der Meer JW, Drenth JP (2003) A founder effect in the hyperimmunoglobulinemia D and periodic fever syndrome. Am J Med 114:148–152

    Article  PubMed  CAS  Google Scholar 

  14. De Sanctis S, Nozzi M, Del Torto M et al (2010) Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr 36:57

    Article  PubMed  Google Scholar 

  15. Grose C (2005) Periodic fever in children with hyperimmunoglobulinemia D and mevalonate kinase mutations. Pediatr Infect Dis J 24(6):573–574

    Article  PubMed  Google Scholar 

  16. Simon A, Cuisset L, Vincent MF et al (2001) Molecular analysis of the mevalonate kinase gene in a cohort of patients with the Hyper-IgD and periodic fever syndrome: its application as a diagnostic tool. Ann Intern Med 135:338–343

    PubMed  CAS  Google Scholar 

  17. Van der Hilst JCH, Bodar EJ, Barron KS et al (2008) Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore) 87(6):301–310

    Article  Google Scholar 

  18. Gattorno M, Sormani MP, D’Osualdo A et al (2008) A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children. Arthritis Rheum 58:1823–1832

    Article  PubMed  CAS  Google Scholar 

  19. D’Osualdo A, Picco P, Caroli F et al (2005) MVK mutations and associated clinical features in Italian patients affected with autoinflammatory disorders and recurrent fever. Eur J Hum Genet 13:314–320

    Article  PubMed  Google Scholar 

  20. Piram M, Frenkel J, Gattorno M et al (2011) A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-inflammatory diseases activity index) consensus conference. Ann Rheum Dis 70:309–314

    Article  PubMed  Google Scholar 

  21. Van der Hilst JCH, Frenkel J (2010) Hyperimmunoglobulin D syndrome in childhood. Curr Rheumatol Rep 12(2):101–107

    Article  PubMed  Google Scholar 

  22. Steichen O, van der Hilst JCH, Simon A et al (2009) A clinical criterion to exclude the hyperimmunoglobulin D syndrome (mild mevalonate kinase deficiency) in patients with recurrent fever. J Rheumatol 36(8):1677–1681

    Article  PubMed  Google Scholar 

  23. Stojanov S, Kastner DL (2005) Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr Opin Rheumatol 17:586–599

    Article  PubMed  CAS  Google Scholar 

  24. Ryan JG, Kastner DL (2008) Fevers, genes, and innate immunity. Curr Top Microbiol Immunol 321:169–184

    Article  PubMed  CAS  Google Scholar 

  25. Cuisset L, Drenth JPH, Simon A (2001) Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome. Eur J Hum Genet 9:260–266

    Article  PubMed  CAS  Google Scholar 

  26. Bodar EJ, Drenth JPH, van der Meer JWM et al (2009) Dysregulation of innate immunity: hereditary periodic fever syndromes. Br J Haematol 144(3):279–302

    Article  PubMed  CAS  Google Scholar 

  27. Rigante D (2009) Autoinflammatory syndromes behind the scenes of recurrent fevers in children. Med Sci Monit 15(8):RA179–RA187

    PubMed  Google Scholar 

  28. Stojanov S, Lohse P, Lohse P et al (2004) 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 50(6):1951–1958

    Article  PubMed  CAS  Google Scholar 

  29. Federici L, Rittore-Domingo C et al (2006) A decision tree for genetic diagnosis of HPF in unselected patients. Ann Rheum Dis 65:1427–1432

    Article  PubMed  CAS  Google Scholar 

  30. Touitou I, Hentgen V, Koné-Paut I (2009) Web resources for rare auto-inflammatory diseases: towards a common patient registry. Rheumatology 48(6):665–669

    Article  PubMed  Google Scholar 

  31. Lainka E, Bielak M, Hilger V et al (2011) Translational research network and patient registry for auto-inflammatory diseases (AID-Net). Rheumatology 50:237–242

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Additionally, the authors thank the following colleagues for their collaboration: Clinic-ESPED R. Ganschow, R. Lepler (Hamburg), J. Neubert (Düsseldorf), E. Holz (Eisenhüttenstadt), T. Kallinich (Berlin), C. Brandis (Schleswig), T. Hospach (Stuttgart), B. Belohradsky (München). Laboratory-ESPED H. Ruebsamen (Department of Clinical Chemistry—Großhadern, University of Munich, Munich), S. Burwinkel (Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg). The authors thank U. Göbel and B. Heinrich from the ESPED registry. E. Lainka gratefully acknowledges the helpful discussions with and comments made by Oliver Weiergräber (Forschungszentrum Jülich, Germany).

Conflict of interest

All authors declared no conflicts of interest.

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Authors and Affiliations

  1. Department of Paediatric Rheumatology, Children’s Hospital, University Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany

    E. Lainka, U. Neudorf & M. Bielak

  2. Department of Molecular Medicine, Institute for Laboratory Medicine, Blessing and colleagues, Singen, Germany

    P. Lohse

  3. Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany

    C. Timmann

  4. Department of Infectious Diseases and Immunology, Children’s Hospital, University of Munich, Munich, Germany

    S. Stojanov & K. Huss

  5. Institute of Social Paediatrics and Adolescent Medicine, University of Munich, Munich, Germany

    R. von Kries

  6. Department of Paediatrics, HELIOS-Klinikum Krefeld, Krefeld, Germany

    T. Niehues

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  1. E. Lainka
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  2. U. Neudorf
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  3. P. Lohse
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  4. C. Timmann
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  5. M. Bielak
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  6. S. Stojanov
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  7. K. Huss
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  8. R. von Kries
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Correspondence to E. Lainka.

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Lainka, E., Neudorf, U., Lohse, P. et al. Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children. Rheumatol Int 32, 3253–3260 (2012). https://doi.org/10.1007/s00296-011-2180-8

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  • DOI: https://doi.org/10.1007/s00296-011-2180-8

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