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].
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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