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Hereditary Cryopyrin-Associated Periodic Syndromes (Cryopyrinopathies)

By Apostolos Kontzias, MD, Assistant Professor of Medicine and Director, Autoinflammatory Clinic, Cleveland Clinic Foundation

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The hereditary cryopyrin-associated periodic syndromes are a group of autoinflammatory conditions triggered by cold ambient temperatures; they include familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem autoinflammatory disease.

Hereditary cryopyrin-associated periodic syndromes (CAPS) represent a spectrum of progressively severe disease. They are due to mutations in the gene encoding the protein cryopyrin, which mediates inflammation and IL-1β processing. Cryopyrin activity is augmented, triggering increased release of IL-1β from the NLRP3 inflammasome; the result is inflammation and fever. The lack of a confirmed genetic mutation may not preclude the diagnosis of CAPS because 40% of patients who have neonatal-onset multisystem autoinflammatory disease, 25% who have Muckle-Wells syndrome, and 10% of who have familial cold autoinflammatory syndrome do not have identifiable mutations based on standard genetic testing. Many of these patients exhibit somatic mosaicism, causing their phenotype.

Typically, familial cold autoinflammatory syndrome (FCAS) causes a cold-induced urticarial rash accompanied by fever and sometimes arthralgias. The condition often appears in the first year of life.

Muckle-Wells syndrome (MWS) causes intermittent fevers, urticarial rash, joint pain, and progressive deafness; 25% of patients develop renal amyloidosis.

Neonatal-onset multisystem autoinflammatory disease (NOMID) tends to cause joint and limb deformities, facial deformities, chronic aseptic meningitis, cerebral atrophy, uveitis, papillary edema, delayed development, and amyloidosis, in addition to fever and a migratory urticarial rash. As many as 20% of patients die by age 20 if untreated.

Cryopyrin-associated periodic syndromes are inherited as autosomal dominant disorders. They are treated with anakinra or canakinumab (1, 2).

Treatment references

  • 1. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al: Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360(23):2416–2425, 2009. doi: 10.1056/NEJMoa0810787.

  • 2. Sibley CH, Plass N, Snow J, et al: Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: A cohort study to determine three- and five-year outcomes. Arthritis Rheum 64(7):2375–2386, 2012. doi: 10.1002/art.34409.

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