Journal article
An Autoinflammatory Disease with Deficiency of the Interleukin-1-Receptor Antagonist
The New England journal of medicine, Vol.360(23), pp.2426-2437
2009
DOI: 10.1056/NEJMoa0807865
PMCID: PMC2876877
PMID: 19494218
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-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.
Details
- Title: Subtitle
- An Autoinflammatory Disease with Deficiency of the Interleukin-1-Receptor Antagonist
- Creators
- Polly J FERGUSON - University of lowa, Iowa City, United StatesIvona AKSENTIJEVICH - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesHatem I EI-SHANTI - Shafallah Medical Genetics Center, Doha, QatarSeth L MASTERS - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesMatthew BOOTY - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesXinyu Bing - University of lowa, Iowa City, United StatesJacob D ESTES - National Cancer Institute, United StatesNetanya G SANDLER - Vaccine Research Center, United StatesNicole PLASS - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesDeborah L STONE - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesMaria L TURNER - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesSuvimol HILL - Clinical Center, United StatesJohn A BUTMAN - Clinical Center, United StatesRayfel SCHNEIDER - University of Toronto, Toronto, CanadaPaul BABYN - University of Toronto, Toronto, CanadaElena POPE - University of Toronto, Toronto, CanadaKaryl BARRON - National Institute of Allergy and Infectious Diseases, United StatesArian LAURENCE - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesChyi-Chia R LEE - National Cancer Institute, United StatesDawn CHAPELLE - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesGillian I CLARKE - Memorial University of Newfoundland, St. John's, CanadaKamal OHSON - Memorial University of Newfoundland, St. John's, CanadaMarc NICHOLSON - Memorial University of Newfoundland, St. John's, CanadaPaul DANCEY - Memorial University of Newfoundland, St. John's, CanadaMassimo GADINA - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesBarbara YANG - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesBenjamin D KORMAN - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesPeter K GREGERSEN - Feinstein Institute, Manhasset, NY, United StatesP. Martin VAN HAGEN - Erasmus University Medical Center, Rotterdam, NetherlandsA. Elisabeth HAK - Erasmus University Medical Center, Rotterdam, NetherlandsMarjan HUIZING - National Human Genome Research Institute, Bethesda, MD, United StatesProton RAHMAN - Memorial University of Newfoundland, St. John's, CanadaDaniel C DOUEK - Vaccine Research Center, United StatesElaine F REMMERS - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesJoost FRENKEL - University of Utrecht, Utrecht, NetherlandsDaniel L KASTNER - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesRaphaela GOLDBACH-MANSKY - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United StatesAnnet VAN ROYEN-KERKHOFF - University of Utrecht, Utrecht, NetherlandsRon LAXER - University of Toronto, Toronto, CanadaUlf TEDGARD - Lund University, Maimö, SwedenEdward W COWEN - National Cancer Institute, United StatesTuyet-Hang PHAM - National Institute of Arthritis and Musculoskeletal and Skin Diseases, United States
- Resource Type
- Journal article
- Publication Details
- The New England journal of medicine, Vol.360(23), pp.2426-2437
- DOI
- 10.1056/NEJMoa0807865
- PMID
- 19494218
- PMCID
- PMC2876877
- NLM abbreviation
- N Engl J Med
- ISSN
- 0028-4793
- eISSN
- 1533-4406
- Publisher
- Massachusetts Medical Society; Waltham, MA
- Language
- English
- Date published
- 2009
- Academic Unit
- Critical Care; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Rheumatology, Allergy, and Immunology
- Record Identifier
- 9984070296702771
Metrics
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