title: Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Hospital Clínic, Barcelona, Spain. 30864jag@comb.es
authors.forename: Juan I
authors.initials: JI
authors.lastname: Aróstegui
authors.forename: Anna
authors.initials: A
authors.lastname: Aldea
authors.forename: Consuelo
authors.initials: C
authors.lastname: Modesto
authors.forename: Maria Jesús
authors.initials: MJ
authors.lastname: Rua
authors.forename: Federico
authors.initials: F
authors.lastname: Argüelles
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: González-Enseñat
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ramos
authors.forename: Josefa
authors.initials: J
authors.lastname: Rius
authors.forename: Susana
authors.initials: S
authors.lastname: Plaza
authors.forename: Jordi
authors.initials: J
authors.lastname: Vives
authors.forename: Jordi
authors.initials: J
authors.lastname: Yagüe
mesh_terms: D001327:Autoimmune Diseases / Q000150:complications / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005334:Fever / Q000209:etiology / Q000235:genetics; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010375:Pedigree; D012008:Recurrence; D013030:Spain; D013577:Syndrome; D014581:Urticaria / Q000209:etiology / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human