Cryopyrin associated periodic syndromes (CAPS)

What are cryopyrin associated periodic syndromes (CAPS) and what causes them?

  • • Autoinflammatory syndrome caused by autosomal dominant, gain-of-function mutations in gene for cryopyrin (NLRP3; formerly denoted CIAS1).
  • • Cryopyrin mutations result in constitutive activation of the inflammasome and subsequent increase in proinflammatory cytokines, including IL-1β.
  • • CAPS includes three clinically distinguishable syndromes, although there is symptom overlap.

Three major phenotypes of CAPS

Neonatal onset multisystem inflammatory disease (NOMID):

  • • Most severe monogenetic autoinflammatory syndrome.
  • • Symptoms begin at birth or early infancy; classic triad of rash (commonly urticaria), arthropathy, and chronic aseptic meningitis. Sensorineural hearing loss. Daily fever and other multisystem abnormalities are common.
  • • Lymphadenopathy and hepatosplenomegaly may occur in some patients.
  • • Growth restriction and abnormal facies (frontal bossing, “saddle-shaped” nose, protruding eyes) may occur.
  • • Focal epiphyseal overgrowth may be substantial in some patients and confused with malignancy.
  • • Renal AA can occur.
  • • Mortality rate ∼20% before adulthood.
  • Muckle Wells syndrome:
  • • Intermediate in severity among CAPS presentations.
  • • Fever, headache, urticarial rash, limb pain, conjunctivitis, arthralgias > arthritis, sensorineural hearing loss.
  • • Symptoms commonly develop in adolescence.
  • • Renal AA can occur.
  • • Variable duration/frequency of flares: attacks on average last 2 to 3 days, but duration can be irregular or even continuous in some patients.
  • Familial cold autoinflammatory syndrome (FCAS):
  • • Mildest form of CAPS.
  • • Self-limited episodes of urticarial rash, fever, arthralgia, conjunctivitis, headache, malaise, and diaphoresis following cold exposure (or even a relative drop in temperature).
  • • Begins in infancy (95% of patients); can decrease in severity over time.
  • • Average time to symptom onset following exposure ∼6 hours.
  • • Flare duration: hours to 2 to 3 days (commonly <24 hours).
  • • Rash: ubiquitous among patients; urticaria, erythematous macules and petechiae have been described; often begin on extremities.
  • • Renal AA is rare.
  • • Ice cube test (observing for immediate appearance of skin changes after contact) is negative. This helps distinguish FCAS from acquired cold urticaria, which is a nongenetic condition that does not present in infancy and lacks systemic features.
  • • Absence of deafness, periorbital edema, lymphadenopathy, and serositis.
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