"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-1ß cleavage from biologically inactive pro-IL-1ß. 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-1ß expression by patient monocytes resulted in increased IL-6 and TNF-α secretion, as compared to control cells. The addition of the IL-1ß receptor antagonist (anakinra) reversed these effects. In response to LPS stimulation, patient monocytes produced high level of IL-1ß, 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-1ß antagonists. Further research is warranted, particularly in order to investigate pathophysiological mechanisms in "mutation negative" individuals.