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.