Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene

Arthritis Rheum. 2004 Dec;50(12):4045-50. doi: 10.1002/art.20633.


Objective: To investigate the involvement of the CIAS1/PYPAF1/NALP3 gene in 7 unrelated Spanish families with recurrent autoinflammatory diseases characterized by early onset, recurrent fever, and a chronic urticarial rash, in whom a clinical diagnosis of cryopyrin-associated periodic syndromes (CAPS) is suspected.

Methods: Clinical symptoms, results of laboratory analyses, and data on previous treatments in members of the 7 families were recorded on a questionnaire specific for hereditary autoinflammatory diseases. All coding regions and intronic flanking boundaries of the CIAS1/PYPAF1/NALP3 gene were amplified by polymerase chain reaction and sequenced.

Results: Five different missense mutations, including 2 de novo and 1 previously unreported mutation (R488K), were identified in exon 3 of the CIAS1/PYPAF1/NALP3 gene in 5 of the 7 affected families. Expanded genetic analysis among the healthy individuals identified incomplete penetrance in 2 families. No mutations were found in 2 of the 3 patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome/neonatal-onset multisystem inflammatory disease (NOMID).

Conclusion: The clinical data suggested a diagnosis of familial cold-induced autoinflammatory syndrome in 3 families, CINCA/NOMID syndrome in 3 others, and a possible Muckle-Wells syndrome, whereas mutational analysis showed different CIAS1/PYPAF1/NALP3 missense mutations in 5 families. These data are consistent with a common molecular basis of these diseases and highlights the phenotypic heterogeneity among CIAS1/PYPAF1/NALP3 gene-associated syndromes. The previously unreported mutation and the incomplete penetrance found in 2 families expand the genetic basis underlying these autoinflammatory syndromes. These findings should alert clinicians to the possible genetic basis of these conditions, even in the absence of a family history, in their attempts to establish an accurate diagnosis and the optimal therapeutic approach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmune Diseases / complications
  • Autoimmune Diseases / genetics*
  • Carrier Proteins / genetics*
  • DNA Mutational Analysis
  • Family Health
  • Female
  • Fever / etiology
  • Fever / genetics
  • Genetic Heterogeneity*
  • Humans
  • Male
  • Mutation, Missense*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Pedigree
  • Recurrence
  • Spain
  • Syndrome
  • Urticaria / etiology
  • Urticaria / genetics


  • Carrier Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human