Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

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].

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:

Subscribers log in here

Literature review current through: Sep 2017. | This topic last updated: Jun 06, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Cuisset L, Jeru I, Dumont B, et al. Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis 2011; 70:495.
  2. Hoffman HM, Mueller JL, Broide DH, et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet 2001; 29:301.
  3. Kastner DL, O'Shea JJ. A fever gene comes in from the cold. Nat Genet 2001; 29:241.
  4. Neven B, Callebaut I, Prieur AM, et al. Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU. Blood 2004; 103:2809.
  5. Neven B, Prieur AM, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol 2008; 4:481.
  6. Drenth JP, van der Meer JW. The inflammasome--a linebacker of innate defense. N Engl J Med 2006; 355:730.
  7. Franklin BS, Bossaller L, De Nardo D, et al. The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat Immunol 2014; 15:727.
  8. Baroja-Mazo A, Martín-Sánchez F, Gomez AI, et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol 2014; 15:738.
  9. Eisenbarth SC, Colegio OR, O'Connor W, et al. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 2008; 453:1122.
  10. Tschopp J, Martinon F, Burns K. NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol 2003; 4:95.
  11. Aksentijevich I, D Putnam C, Remmers EF, et al. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum 2007; 56:1273.
  12. Mortimer L, Moreau F, MacDonald JA, Chadee K. NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations. Nat Immunol 2016; 17:1176.
  13. Swanson KV, Ting JP. Reining in uncontrolled inflammasome with PKA. Nat Immunol 2016; 17:1137.
  14. Brydges SD, Broderick L, McGeough MD, et al. Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies. J Clin Invest 2013; 123:4695.
  15. Hull KM, Shoham N, Chae JJ, et al. The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations. Curr Opin Rheumatol 2003; 15:61.
  16. Levy R, Gérard L, Kuemmerle-Deschner J, et al. Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry. Ann Rheum Dis 2015; 74:2043.
  17. Verma D, Eriksson P, Sahdo B, et al. Two adult siblings with atypical cryopyrin-associated periodic syndrome due to a novel M299V mutation in NLRP3. Arthritis Rheum 2010; 62:2138.
  18. Tindall JP, Beeker SK, Rosse WF. Familial cold urticaria. A generalized reaction involving leukocytosis. Arch Intern Med 1969; 124:129.
  19. Doeglas HM, Bleumink E. Familial cold urticaria. Clinical findings. Arch Dermatol 1974; 110:382.
  20. Aganna E, Martinon F, Hawkins PN, et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum 2002; 46:2445.
  21. Thornton BD, Hoffman HM, Bhat A, Don BR. Successful treatment of renal amyloidosis due to familial cold autoinflammatory syndrome using an interleukin 1 receptor antagonist. Am J Kidney Dis 2007; 49:477.
  22. van der Hilst JC, Simon A, Drenth JP. Hereditary periodic fever and reactive amyloidosis. Clin Exp Med 2005; 5:87.
  23. MUCKLE TJ, WELLSM . Urticaria, deafness, and amyloidosis: a new heredo-familial syndrome. Q J Med 1962; 31:235.
  24. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum 2004; 50:607.
  25. Muckle TJ. The 'Muckle-Wells' syndrome. Br J Dermatol 1979; 100:87.
  26. Montealegre Sanchez GA, Hashkes PJ. Neurological manifestations of the Mendelian-inherited autoinflammatory syndromes. Dev Med Child Neurol 2009; 51:420.
  27. Ahmadi N, Brewer CC, Zalewski C, et al. Cryopyrin-associated periodic syndromes: otolaryngologic and audiologic manifestations. Otolaryngol Head Neck Surg 2011; 145:295.
  28. Aganna E, Hawkins PN, Ozen S, et al. Allelic variants in genes associated with hereditary periodic fever syndromes as susceptibility factors for reactive systemic AA amyloidosis. Genes Immun 2004; 5:289.
  29. Dodé C, Cuisset L, Delpech M, Grateau G. TNFRSF1A-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS) and renal amyloidosis. J Nephrol 2003; 16:435.
  30. Aksentijevich I, Nowak M, Mallah M, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum 2002; 46:3340.
  31. Goldfinger S. The inherited autoinflammatory syndrome: a decade of discovery. Trans Am Clin Climatol Assoc 2009; 120:413.
  32. Kuemmerle-Deschner JB, Ozen S, Tyrrell PN, et al. Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS). Ann Rheum Dis 2017; 76:942.
  33. Nakagawa K, Gonzalez-Roca E, Souto A, et al. Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes. Ann Rheum Dis 2015; 74:603.
  34. Omoyinmi E, Melo Gomes S, Standing A, et al. Brief Report: whole-exome sequencing revealing somatic NLRP3 mosaicism in a patient with chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheumatol 2014; 66:197.
  35. Gattorno M, Martini A. Treatment of autoinflammatory syndromes. Curr Opin Pediatr 2010; 22:771.
  36. Maksimovic L, Stirnemann J, Caux F, et al. New CIAS1 mutation and anakinra efficacy in overlapping of Muckle-Wells and familial cold autoinflammatory syndromes. Rheumatology (Oxford) 2008; 47:309.
  37. Ross JB, Finlayson LA, Klotz PJ, et al. Use of anakinra (Kineret) in the treatment of familial cold autoinflammatory syndrome with a 16-month follow-up. J Cutan Med Surg 2008; 12:8.
  38. Hoffman HM, Rosengren S, Boyle DL, et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 2004; 364:1779.
  39. Leslie KS, Lachmann HJ, Bruning E, et al. Phenotype, genotype, and sustained response to anakinra in 22 patients with autoinflammatory disease associated with CIAS-1/NALP3 mutations. Arch Dermatol 2006; 142:1591.
  40. Hawkins PN, Lachmann HJ, McDermott MF. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome. N Engl J Med 2003; 348:2583.
  41. Gillmore JD, Lovat LB, Persey MR, et al. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 2001; 358:24.
  42. Mirault T, Launay D, Cuisset L, et al. Recovery from deafness in a patient with Muckle-Wells syndrome treated with anakinra. Arthritis Rheum 2006; 54:1697.
  43. Yamazaki T, Masumoto J, Agematsu K, et al. Anakinra improves sensory deafness in a Japanese patient with Muckle-Wells syndrome, possibly by inhibiting the cryopyrin inflammasome. Arthritis Rheum 2008; 58:864.
  44. Rodriguez-Smith J, Lin YC, Tsai WL, et al. Cerebrospinal Fluid Cytokines Correlate With Aseptic Meningitis and Blood-Brain Barrier Function in Neonatal-Onset Multisystem Inflammatory Disease: Central Nervous System Biomarkers in Neonatal-Onset Multisystem Inflammatory Disease Correlate With Central Nervous System Inflammation. Arthritis Rheumatol 2017; 69:1325.
  45. Matsubayashi T, Sugiura H, Arai T, et al. Anakinra therapy for CINCA syndrome with a novel mutation in exon 4 of the CIAS1 gene. Acta Paediatr 2006; 95:246.
  46. Seitz M, Kamgang RK, Simon HU, Villiger PM. Therapeutic interleukin (IL) 1 blockade normalises increased IL1 beta and decreased tumour necrosis factor alpha and IL10 production in blood mononuclear cells of a patient with CINCA syndrome. Ann Rheum Dis 2005; 64:1802.
  47. Granel B, Serratrice J, Disdier P, Weiller PJ. Dramatic improvement with anakinra in a case of chronic infantile neurological cutaneous and articular (CINCA) syndrome. Rheumatology (Oxford) 2005; 44:689.
  48. Matsubara T, Hasegawa M, Shiraishi M, et al. A severe case of chronic infantile neurologic, cutaneous, articular syndrome treated with biologic agents. Arthritis Rheum 2006; 54:2314.
  49. Caroli F, Pontillo A, D'Osualdo A, et al. Clinical and genetic characterization of Italian patients affected by CINCA syndrome. Rheumatology (Oxford) 2007; 46:473.
  50. Goldbach-Mansky R, Dailey NJ, Canna SW, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med 2006; 355:581.
  51. Goldbach-Mansky R, Shroff SD, Wilson M, et al. A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum 2008; 58:2432.
  52. Hoffman HM, Throne ML, Amar NJ, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum 2008; 58:2443.
  53. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 2009; 360:2416.
  54. Sibley CH, Chioato A, Felix S, et al. A 24-month open-label study of canakinumab in neonatal-onset multisystem inflammatory disease. Ann Rheum Dis 2015; 74:1714.
  55. Kallinich T, Hoffman HM, Roth J, Keitzer R. The clinical course of a child with CINCA/NOMID syndrome improved during and after treatment with thalidomide. Scand J Rheumatol 2005; 34:246.
  56. Walker UA, Hoffman HM, Williams R, et al. Brief Report: Severe Inflammation Following Vaccination Against Streptococcus pneumoniae in Patients With Cryopyrin-Associated Periodic Syndromes. Arthritis Rheumatol 2016; 68:516.
  57. Jaeger VK, Hoffman HM, van der Poll T, et al. Safety of vaccinations in patients with cryopyrin-associated periodic syndromes: a prospective registry based study. Rheumatology (Oxford) 2017; 56:1484.
  58. Aksentijevich I, Masters SL, Ferguson PJ, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med 2009; 360:2426.
  59. Reddy S, Jia S, Geoffrey R, et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med 2009; 360:2438.
  60. Minkis K, Aksentijevich I, Goldbach-Mansky R, et al. Interleukin 1 receptor antagonist deficiency presenting as infantile pustulosis mimicking infantile pustular psoriasis. Arch Dermatol 2012; 148:747.
  61. Brau-Javier CN, Gonzales-Chavez J, Toro JR. Chronic cutaneous pustulosis due to a 175-kb deletion on chromosome 2q13: excellent response to anakinra. Arch Dermatol 2012; 148:301.
  62. Cowen EW, Goldbach-Mansky R. DIRA, DITRA, and new insights into pathways of skin inflammation: what's in a name? Arch Dermatol 2012; 148:381.