title: "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.affiliation: Christian Hedrich, Children's Hospital Dresden, Pediatric Rheumatology and Immunology, University Medical Center Carl Gustav Carus, Technical University Dresden, Fetscherstr. 74, 01307 Dresden, Germany. christian.hedrich@uniklinikum-dresden.de
authors.forename: C M
authors.initials: CM
authors.lastname: Hedrich
authors.forename: N
authors.initials: N
authors.lastname: Bruck
authors.forename: D
authors.initials: D
authors.lastname: Paul
authors.forename: G
authors.initials: G
authors.lastname: Hahn
authors.forename: M
authors.initials: M
authors.lastname: Gahr
authors.forename: A
authors.initials: A
authors.lastname: Rösen-Wolff
mesh_terms: D018501:Antirheumatic Agents / Q000627:therapeutic use; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics*; D020170:Caspase 1 / Q000235:genetics*; D002648:Child; D056587:Cryopyrin-Associated Periodic Syndromes / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D016207:Cytokines / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D008297:Male; D009000:Monocytes / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D020170:Caspase 1