CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES (CAPS)

Cryopyrin-associated periodic syndromes (CAPS) include three disorders that were formerly classified separately:

• Familial cold-associated syndrome (FCAS)
• Muckle-Wells syndrome (MWS)
• Neonatal-onset multisystem inflammatory disease (NOMID) (also called chronic infantile neurological cutaneous and articular syndrome, CINCA)

Since variants in the NLRP3 gene (also NALP3/CIAS1) have been identified as the cause of all three syndromes, it is thought that these disorders represent different degrees of clinical severity of the same pathophysiological change. CAPS are inherited in an autosomal dominant manner; in NOMID, mutations occur predominantly de novo. All ethnic groups can be affected by CAPS. In Germany, 2-7 newly diagnosed patients (aged ≤ 16 years) are estimated per year. The first striking manifestation is an urticaria-like skin rash that develops shortly after birth (NOMID) or in early childhood (all three disorders). In addition, episodes of fever occur, usually accompanied by arthralgias, headache, fatigue, and conjunctivitis. In FCAS, the febrile episodes are triggered by exposure to cold and usually last up to 24 hours. MWS is characterized by the development of progressive sensorineural hearing loss as the disease progresses (often not until adolescence). About 25% of MWS patients develop secondary amyloidosis if untreated. NOMID presents with the most severe phenotype of CAPS. Facial abnormalities such as a prominent forehead and saddle nose deformity are described, and neurological and movement symptoms are typical. Postnatally, chronic progressive aseptic meningitis, sensorineural hearing loss, and optic atrophy often develop. The therapy of choice in CAPS is targeted IL-1 blockade.

The NLRP3 gene product cryopyrin is a key component of the cryopyrin inflammasome, a cytoplasmic protein complex formed as part of the innate immune response that induces IL-1β production. Variants in the NLRP3 gene, presumably through constitutive activation of cryopyrin, lead to increased production of IL-1β even in the absence of exogenous stimuli. Almost all the mutations known to date are located in exon 3 of the NLRP3 gene. However, in approximately 40-60% of patients with classic clinical manifestations of NOMID syndrome, no mutations are found in the entire coding region of the NLRP3 gene.

References

Gattorno et al. 2019, Ann Rheum Dis Epub ahead of print, doi:10.1136 / Booshehri & Hoffman 2019, J Clin Immunol 39:277 / Cuisset et al. 2011, Ann Rheum Dis 70:495 / Lainka et al. 2010, Klin Padiatr 222:356