title: A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: description of two unrelated cases from Brazil.
abstract: OBJECTIVE
  Monogenic autoinflammatory diseases are disorders of Mendelian inheritance that are characterized by mutations in genes that regulate innate immunity and whose typical features are systemic inflammation without high-titer autoantibodies or antigen-specific T cells. Skin and bone inflammation in the newborn period have been described in 3 of these autoinflammatory disorders: neonatal-onset multisystem inflammatory disease, Majeed syndrome, and deficiency of interleukin-1 (IL-1) receptor antagonist (DIRA) syndrome. This study was undertaken to present the characteristics of the DIRA syndrome in 2 cases from Brazil, and describe a novel mutation in IL1RN.
  
  
  METHODS
  Two unrelated Brazilian patients were evaluated for the clinical signs and symptoms of these 3 disorders, and peripheral blood samples were assessed for mutations in NLRP3, LPIN2, and IL1RN by DNA resequencing analysis. A mutation in IL1RN that encodes a mutant protein was identified, and the expression and function of this mutant protein were compared to those of the wild-type protein.
  
  
  RESULTS
  Both patients presented with pustular dermatitis resembling generalized pustular psoriasis, recurrent multifocal aseptic osteomyelitis, and elevation in the levels of acute-phase reactants, all of which are features most consistent with the DIRA syndrome. Chronic lung disease was observed in 1 of the patients, and jugular venous thrombosis was observed in the other patient. Both patients showed a partial response to corticosteroid therapy, and 1 patient experienced an initial improvement of dermatitis with the use of acitretin. Both patients were homozygous for a novel 15-bp (in-frame) deletion on the IL1RN gene. The mutated protein expressed in vitro had no affinity with the IL-1 receptor, and stimulation of the patients' cells with recombinant human IL-1α or IL-1β led to oversecretion of proinflammatory cytokines, similar to the findings obtained in previously reported patients.
  
  
  CONCLUSIONS
  The presence of the same homozygous novel mutation in IL1RN in 2 unrelated Brazilian patients suggests that this genetic variant may be a founder mutation that has been introduced in the Brazilian population.
authors: Universidade de São Paulo, Sao Paulo, Brazil.
authors: Adriana A
authors: AA
authors: Jesus
authors: Mazen
authors: M
authors: Osman
authors: Clovis A
authors: CA
authors: Silva
authors: Peter W
authors: PW
authors: Kim
authors: Tuyet-Hang
authors: TH
authors: Pham
authors: Massimo
authors: M
authors: Gadina
authors: Barbara
authors: B
authors: Yang
authors: Débora R
authors: DR
authors: Bertola
authors: Magda
authors: M
authors: Carneiro-Sampaio
authors: Polly J
authors: PJ
authors: Ferguson
authors: Blair R
authors: BR
authors: Renshaw
authors: Ken
authors: K
authors: Schooley
authors: Michael
authors: M
authors: Brown
authors: Asma
authors: A
authors: Al-Dosari
authors: Jamil
authors: J
authors: Al-Alami
authors: John E
authors: JE
authors: Sims
authors: Raphaela
authors: R
authors: Goldbach-Mansky
authors: Hatem
authors: H
authors: El-Shanti
mesh_terms: D001938:Brazil; D002352:Carrier Proteins / Q000235:genetics; D002675:Child, Preschool; D005260:Female; D056660:Hereditary Autoinflammatory Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000235:genetics; D010019:Osteomyelitis / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D011565:Psoriasis / Q000175:diagnosis / Q000235:genetics / Q000473:pathology
chemical_list: D002352:Carrier Proteins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; C502575:LPIN2 protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009687:Nuclear Proteins