Cryopyrin-associated periodic syndromes and related disorders
- Peter A Nigrovic, MD
Peter A Nigrovic, MD
- Associate Professor of Medicine
- Harvard Medical School
- Section Editors
- E Richard Stiehm, MD
E Richard Stiehm, MD
- Editor-in-Chief — Allergy and Immunology
- Section Editor — Immunology and Immunodeficiency
- Distinguished Research Professor of Pediatrics
- David Geffen School of Medicine at UCLA
- Sheldon L Kaplan, MD
Sheldon L Kaplan, MD
- Editor-in-Chief — Pediatrics
- Section Editor — Pediatric Infectious Diseases
- Professor and Vice Chairman for Clinical Affairs
- Baylor College of Medicine
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 . 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".)
CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES
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 . 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].To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
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- CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES
- Clinical features of specific disorders
- - Familial cold autoinflammatory syndrome
- - Muckle-Wells syndrome
- - Neonatal-onset multisystem inflammatory disease
- Treatment of cryopyrinopathies
- - Anakinra
- - Rilonacept (IL-1 trap)
- - Canakinumab
- - Other agents
- - Vaccination in CAPS
- DEFICIENCY OF THE IL-1-RECEPTOR ANTAGONIST (DIRA)
- Clinical presentation
- SUMMARY AND RECOMMENDATIONS