title: An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
abstract: BACKGROUND
  Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone.
  
  
  METHODS
  We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN.
  
  
  RESULTS
  We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly.
  
  
  CONCLUSIONS
  We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA.
authors.forename: Ivona
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authors.lastname: Aksentijevich
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Ferguson
authors.forename: Paul
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authors.lastname: Dancey
authors.forename: Joost
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authors.lastname: Frenkel
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authors.lastname: van Royen-Kerkhoff
authors.forename: Ron
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authors.lastname: Laxer
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authors.lastname: Tedgård
authors.forename: Edward W
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authors.forename: Tuyet-Hang
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authors.lastname: Pham
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authors.forename: Netanya G
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authors.initials: DL
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authors.forename: Maria L
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authors.lastname: Turner
authors.forename: Suvimol
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authors.lastname: Hill
authors.forename: John A
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authors.lastname: Butman
authors.forename: Rayfel
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authors.lastname: Schneider
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authors.lastname: Babyn
authors.forename: Hatem I
authors.initials: HI
authors.lastname: El-Shanti
authors.forename: Elena
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authors.lastname: Pope
authors.forename: Karyl
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authors.lastname: Barron
authors.forename: Xinyu
authors.initials: X
authors.lastname: Bing
authors.forename: Arian
authors.initials: A
authors.lastname: Laurence
authors.forename: Chyi-Chia R
authors.initials: CC
authors.lastname: Lee
authors.forename: Dawn
authors.initials: D
authors.lastname: Chapelle
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Clarke
authors.forename: Kamal
authors.initials: K
authors.lastname: Ohson
authors.forename: Marc
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authors.lastname: Nicholson
authors.forename: Massimo
authors.initials: M
authors.lastname: Gadina
authors.forename: Barbara
authors.initials: B
authors.lastname: Yang
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Korman
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: P Martin
authors.initials: PM
authors.lastname: van Hagen
authors.forename: A Elisabeth
authors.initials: AE
authors.lastname: Hak
authors.forename: Marjan
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authors.lastname: Huizing
authors.forename: Proton
authors.initials: P
authors.lastname: Rahman
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.forename: Raphaela
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authors.lastname: Goldbach-Mansky
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000235:genetics / Q000502:physiology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors; D008297:Male; D009154:Mutation; D010375:Pedigree; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053583:Interleukin-1beta; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1