Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Cryopyrin-Associated Periodic Syndromes (CAPS) [G03.1, G44.8, L50.8, M08.9]

OMIM numbers: 120100 (FCAS), 191900 (MWS), 607115 (NOMID), 606416 (NLRP3)

Dr. rer. nat. Barbara Bangol, Dr. med. Kaimo Hirv

Scientific Background

The following disorders belong to the group of cryopyrin-associated periodic syndromes:

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

Since mutations in the NLRP3 gene (also NALP3/CIAS1) were identified as cause for all three syndromes, it is assumed that these syndromes are different severities of the same pathophysiological change. CAPS show an autosomal dominant inheritance; in NOMID mutations occur mainly de novo. Any ethnicity can be affected by CAPS. In Germany, the number of newly diagnosed patients (age ≤ 16 years) per year is estimated to be 2–7. The first noticeable manifestation is an urticaria-like skin rash that develops shortly after birth (NOMID) or during early childhood in all three conditions. In addition, fever episodes occur, usually accompanied by arthralgia, headache, fatigue and conjunctivitis. In the case of FCAS the fever is triggered by exposition to cold and takes up to 24 hours in most cases. MWS is characterized by progressive sensorineural hearing loss that develops in the course of the disease (frequently no earlier than adolescence). Approximately 25% of all MWS patients develop secondary amyloidosis. NOMID shows the most severe phenotype of CAPS. Facial abnormalities such as a prominent forehead and saddle nose are described; neurologic and articular signs and symptoms are typical. Frequently, a chronic progressive aseptic meningitis, sensorineural hearing loss and optic atrophy occur postnatally. Treatment of choice for CAPS is targeted IL-1 blockade.

The NLRP3 gene product cryopyrin is the key component of the cryopyrin inflammasome, a cytoplasmic protein complex which is formed in the course of the innate immune response and which induces IL-1β production. Mutations in the NLRP3 gene lead to an increased production of IL-1β even in the absence of exogenous stimuli, most likely due to a constitutive activation of cryopyrin. Almost all of the mutations known so far are localized in exon 3 of the NLRP3 gene. However, in approximately 40–60% of all patients with classic clinical manifestations of the NOMID syndrome no mutations are found in the entire coding region of the NLRP3 gene.