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Hereditary Cryopyrin-Associated Periodic Syndromes (Cryopyrinopathies)

By

Apostolos Kontzias

, MD, Stony Brook University School of Medicine

Last full review/revision Jan 2022| Content last modified Sep 2022
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The hereditary cryopyrin-associated periodic syndromes are a group of autosomal dominant autoinflammatory conditions triggered by cold ambient temperatures; they include familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem autoinflammatory disease. Diagnosis is clinical. Treatment is with interleukin-1 beta inhibitors.

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 interleukin-1 beta (IL-1 beta) processing

Cryopyrin activity is augmented, triggering increased release of IL-1 beta from the NLRP3 inflammasome; the result is inflammation and fever. The lack of a confirmed genetic mutation does 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.

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.

Autoinflammatory periodic fever disorders

Autoinflammatory periodic fever disorders

CAPS = cryopyrin-associated periodic syndromes; FMF = familial Mediterranean fever; NOMID = neonatal-onset multisystem inflammatory disease; PFAPA = periodic fevers with aphthous stomatitis, pharyngitis, and adenitis; TRAPS = tumor necrosis factor receptor–associated periodic syndrome.

Adapted from Sag E, Bilginer Y, Ozen S: Autoinflammatory diseases with periodic fevers. Curr Rheumatol Rep 19(7):41, 2017. doi: 10.1007/s11926-017-0670-8

Diagnosis

  • Clinical criteria

Proposed diagnostic criteria for CAPS include increased markers of inflammation and at least 2 of the following:

  • Urticarial-like rash

  • Episodes triggered by cold and/or stress

  • Sensorineural hearing loss

  • Musculoskeletal symptoms, including arthralgias, arthritis, and myalgias

  • Chronic aseptic meningitis

  • Skeletal abnormalities, including epiphyseal overgrowth and frontal bossing

Although early age of onset makes the diagnosis of CAPS more likely, CAPS should also be considered in people with a late age of onset because of the disease's rarity (such that it is often not considered), mild phenotypes (which can escape recognition in early life), and somatic mutations (no family history) (2 Diagnosis references The hereditary cryopyrin-associated periodic syndromes are a group of autosomal dominant autoinflammatory conditions triggered by cold ambient temperatures; they include familial cold autoinflammatory... read more ).

Diagnosis references

Treatment

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

  • 3. Hoffman HM, Throne ML, Amar NJ, et al: Long-term efficacy and safety profile of rilonacept in the treatment of cryopyrin-associated periodic syndromes: Results of a 72-week open-label extension study. Clin Ther 34(10):2091–2103, 2012. doi: 10.1016/j.clinthera.2012.09.009

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