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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. (ClinicalTrials.gov number, NCT00059748
[ClinicalTrials.gov]
.)
Source Information
From the National Institute of Arthritis and Musculoskeletal and Skin Diseases (I.A., S.L.M., T.-H.P., M.B., N.P., D.L.S., A.L., D.C., M.G., B.Y., B.D.K., E.F.R., D.L.K., R.G.-M.); National Cancer Institute (E.W.C., J.D.E., M.L.T., C.-C.R.L.); Vaccine Research Center (N.G.S., D.C.D.); National Institute of Allergy and Infectious Diseases (K.B.); Clinical Center (S.H., J.A.B.); and National Human Genome Research Institute (M.H.) — all in Bethesda, MD; University of Iowa, Iowa City (P.J.F., X.B.); Memorial University of Newfoundland, St. John's, Canada (P.D., G.I.C., K.O., M.N., P.R.); University of Utrecht, Utrecht, the Netherlands (J.F., A.R.-K.); University of Toronto, Toronto (R.L., R.S., P.B., E.P.); Lund University, Malmö, Sweden (U.T.); Shafallah Medical Genetics Center, Doha, Qatar (H.I.E.-S.); Feinstein Institute, Manhasset, NY (P.K.G.); and Erasmus University Medical Center, Rotterdam, the Netherlands (P.M.H., A.E.H.).
Drs. Aksentijevich, Masters, and Ferguson contributed equally to this article.
Address reprint requests to Dr. Goldbach-Mansky at Bldg. 10, Rm. 6D-47B, 10 Center Dr., Bethesda, MD 20892, or at goldbacr{at}mail.nih.gov.
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