title: A novel mutation in the CIAS1/NLRP3 gene associated with an unexpected phenotype of cryopyrin-associated periodic syndromes.
abstract: OBJECTIVE
  Cryopyrin-associated periodic syndromes (CAPS) comprise a spectrum of distinct, rare, autosomal dominant autoinflammatory disorders of increasing severity caused by NLRP3 gene mutations.
  
  
  METHODS
  We describe a 13-year-old female who presented, in the initial phase of the disease, recurrent episodes of high fever, pericarditis, arthralgia, arthritis of the knees, abdominal pain and marked increase in inflammatory markers. In the subsequent months she developed recurrent episodes of chest pain, skin rash and swelling of the subcutaneous tissue, without fever, and with spontaneous resolution.
  
  
  RESULTS
  Molecular analysis of the CIAS1 gene revealed the presence of the Q703K variant and also a c.1105C>A mutation in the heterozygous state, that predicts a L369M amino acid substitution. The latter variant has never been reported. The L369M mutation was predicted to significantly affect protein structure (scoring as 'dangerous' and 'deleterious') by the Variant Effect Predictor tool. Therapy with anakinra was started with rapid disappearance of clinical symptoms and normalization of CRP levels in 24 hours.
  
  
  CONCLUSIONS
  The rapid response to IL-1 inhibition suggests that the disease of this patient is driven by IL-1 and supports the conclusion that this novel mutation is pathogenic and may be associated with a new CAPS phenotype. The role played by the concomitant presence of the mutation Q703K remains to be clarified.
authors.affiliation: Division of Rheumatology, Department of Pediatric Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. insalaco@opbg.net.
authors.forename: Antonella
authors.initials: A
authors.lastname: Insalaco
authors.forename: Giusi
authors.initials: G
authors.lastname: Prencipe
authors.forename: Paola Sabrina
authors.initials: PS
authors.lastname: Buonuomo
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
authors.forename: Claudia
authors.initials: C
authors.lastname: Bracaglia
authors.forename: Manuela
authors.initials: M
authors.lastname: Pardeo
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nicolai
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Benedetti
mesh_terms: D000293:Adolescent; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002352:Carrier Proteins / Q000235:genetics*; D056587:Cryopyrin-Associated Periodic Syndromes / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010641:Phenotype; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human