Rheumatology International

, Volume 32, Issue 9, pp 2629–2636

“Mutation negative” familial cold autoinflammatory syndrome (FCAS) in an 8-year-old boy: clinical course and functional studies

  • C. M. Hedrich
  • N. Bruck
  • D. Paul
  • G. Hahn
  • M. Gahr
  • A. Rösen-Wolff
Original Article

DOI: 10.1007/s00296-011-2019-3

Cite this article as:
Hedrich, C.M., Bruck, N., Paul, D. et al. Rheumatol Int (2012) 32: 2629. doi:10.1007/s00296-011-2019-3

Abstract

Cryopyrinopathies are a subgroup of autoinflammatory syndromes. Most cases have mutations in the CIAS1/NLRL3 gene, encoding the cryopyrin/NLRP3 protein. Cryopyrin, together with other proteins, is involved in the assembly of the cryopyrin/NLRP3 inflammasome. Mutations in CIAS1/NLRP3 result in increased IL-1β cleavage from biologically inactive pro-IL-1β. This results in systemic inflammation and three associated disorders of different severity, forming a clinical continuum with overlapping features. The mildest from, familial cold autoinflammatory syndrome (FCAS), is characterized by remitting fevers, urticaria-like rash, polyarthralgia/arthritis, and usually caused by cold exposure. More severe forms are Muckle-Wells syndrome (MWS) and CINCA/NOMID. We report an 8-year-old boy with FCAS, who presented with overlapping features with MWS. He showed good response to seasonal anakinra treatment. Mutation analysis in CIAS1/NLRP3, PYCARD, and CASP1 was performed. Serum cytokine profiles, and cytokine expression from resting monocytes, and in response to mild hypothermia, and LPS stimulation were determined. Mutations in CIAS1/NLRP3, PYCARD, and CASP1 were not found. In response to mild hypothermia, an enhanced IL-1β expression by patient monocytes resulted in increased IL-6 and TNF-α secretion, as compared to control cells. The addition of the IL-1β receptor antagonist (anakinra) reversed these effects. In response to LPS stimulation, patient monocytes produced high level of IL-1β, IL-6 and TNF-α. This was markedly less pronounced in control monocytes. FCAS results in cold-induced cytokine dysregulation and systemic inflammation. Symptoms can be treated, using IL-1β antagonists. Further research is warranted, particularly in order to investigate pathophysiological mechanisms in “mutation negative” individuals.

Keywords

FCAS Inflammation Cytokines Anakinra Cryopyrin Fever 

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • C. M. Hedrich
    • 1
  • N. Bruck
    • 1
  • D. Paul
    • 1
  • G. Hahn
    • 2
  • M. Gahr
    • 1
  • A. Rösen-Wolff
    • 1
  1. 1.Christian Hedrich, Children’s Hospital Dresden, Pediatric Rheumatology and ImmunologyUniversity Medical Center “Carl Gustav Carus”, Technical University DresdenDresdenGermany
  2. 2.Pediatric Radiology, Children’s Hospital DresdenUniversity Medical Center “Carl Gustav Carus”, Technical University DresdenDresdenGermany

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