Cryopyrin-associated periodic syndromes

Abstract

Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurological cutaneous and articular syndrome (CINCA) represent the clinical spectrum associated with mutations of NLRP3gene, coding for cryopyrin. FCAS is characterized by urticarial rash, arthralgia, and fever spikes of short duration induced by cold exposure. MWS patients display recurrent episodes of urticaria-like eruptions, fever, malaise, and arthralgia associated with the late development of sensorineural hearing loss and amyloidosis. CINCA represents the most severe condition and is characterized by a neonatal-onset urticaria-like rash, fever, central nervous system involvement (mental retardation, chronic aseptic meningitis, increased intracranial pressure, papilledema, cerebral atrophy, sensorineural hearing loss), chronic inflammatory arthropathy, and skeletal dysplasia. Cryopyrin is a member of NOD-like receptor protein family. In the presence of a number of stimuli, cryopyrin oligomerizes and binds the adaptor protein ASC. This association activates directly two molecules of Caspase-1 which, in turn, converts pro-IL-1β to the mature, active 17 kDa form. Mutations in the cryopyrin gene in humans are associated with its gain of function that lead to an excessive and faster production of IL-1β. Treatment with IL-1 blockers dramatically controls disease activity.