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Cryopyrin-associated periodic syndromes and related disorders

Peter A Nigrovic, MD
Section Editors
E Richard Stiehm, MD
Sheldon L Kaplan, MD
Deputy Editor
Elizabeth TePas, MD, MS


Three clinically overlapping, interleukin-1 (IL-1)-associated, autoinflammatory disorders are known collectively as the cryopyrin-associated periodic syndromes (CAPS) or cryopyrinopathies: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID, also known as chronic infantile neurologic cutaneous and articular [CINCA] syndrome). The cryopyrinopathies are rare, with an estimated prevalence of 1 in 360,000 in a French study [1]. A related but distinct autoinflammatory disorder is due to deficiency of the IL-1 receptor antagonist (DIRA).

There are a number of other periodic autoinflammatory disorders that often present with periodic fever. These disorders are discussed separately. (See "Periodic fever syndromes and other autoinflammatory diseases: An overview".)


Genetics — All three cryopyrinopathies arise from mutations in a single gene, NLRP3, at chromosome 1q44, encoding a protein called cryopyrin (also known as NALP3 [nacht domain-, leucine-rich repeat- and pyrin domain-containing protein 3] or PYPAF1 [pyrin domain-containing apoptotic protease activating factor 1-like protein]; cryopyrin is derived from the Greek words for icy cold and fire) [2-4]. The mode of inheritance is autosomal dominant with variable penetrance.

Pathogenesis — Cryopyrin is important in innate immunity as part of the multiprotein NALP3 inflammasome complex [5]. It belongs to a family of NLR (nucleotide-binding domain and leucine-rich repeat-containing) proteins that respond to intracellular pathogens and other danger signals.

Cryopyrin serves as a scaffold for assembly of the inflammasome complex. This complex is responsible, through a cascade of interactions involving caspase 1, for activation of the potent proinflammatory cytokines interleukin-1-beta (IL-1-beta) and interleukin-18 (IL-18) by cleavage of their inactive precursors [5,6]. In addition to its intracellular function, the NALP3 inflammasome can be released from activated macrophages, where it can amplify inflammation by continuing to activate IL-1-beta in the extracellular milieu and in neighboring phagocytes [7,8].

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Literature review current through: Dec 2017. | This topic last updated: Jun 06, 2017.
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