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

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.

• Authors: C M Hedrich, N Bruck, D Paul, G Hahn, M Gahr, A Rösen-Wolff
• Journal: Rheumatology international (Rheumatol Int) Vol. 32 Issue 9 Pg. 2629-36 (Sep 2012) ISSN: 1437-160X [Electronic] Germany
• PMID: 21833523 (Publication Type: Case Reports, Journal Article)

Chemical References

• Antirheumatic Agents
• CARD Signaling Adaptor Proteins
• Carrier Proteins
• Cytokines
• Cytoskeletal Proteins
• Interleukin 1 Receptor Antagonist Protein
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• PYCARD protein, human
• Caspase 1

Topics

• Antirheumatic Agents (therapeutic use)
• CARD Signaling Adaptor Proteins
• Carrier Proteins (genetics)
• Caspase 1 (genetics)
• Child
• Cryopyrin-Associated Periodic Syndromes (drug therapy, genetics, physiopathology)
• Cytokines (metabolism)
• Cytoskeletal Proteins (genetics)
• DNA Mutational Analysis
• Humans
• Interleukin 1 Receptor Antagonist Protein (therapeutic use)
• Male
• Monocytes (metabolism)
• Mutation (genetics)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Treatment Outcome