An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist

Ivona Aksentijevich, Seth L. Masters, Polly J. Ferguson, Paul Dancey, Joost Frenkel, Annet Van Royen-Kerkhoff, Ron Laxer, Ulf Tedgård, Edward W. Cowen, Tuyet Hang Pham, Matthew Booty, Jacob D. Estes, Netanya G. Sandler, Nicole Plass, Deborah L. Stone, Maria L. Turner, Suvimol Hill, John A. Butman, Rayfel Schneider, Paul BabynHatem I. El-Shanti, Elena Pope, Karyl Barron, Xinyu Bing, Arian Laurence, Chyi Chia R. Lee, Dawn Chapelle, Gillian I. Clarke, Kamal Ohson, Marc Nicholson, Massimo Gadina, Barbara Yang, Benjamin D. Korman, Peter K. Gregersen, P. Van Martin Hagen, A. Elisabeth Hak, Marjan Huizing, Proton Rahman, Daniel C. Douek, Elaine F. Remmers, Daniel L. Kastner, Raphaela Goldbach-Mansky

Research output: Contribution to journalArticlepeer-review

649 Scopus citations


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-1β 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. ( number, NCT00059748.).

Original languageEnglish (US)
Pages (from-to)2426-2437
Number of pages12
JournalNew England Journal of Medicine
Issue number23
StatePublished - Jun 4 2009
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine


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