An Autoinflammatory Disease Due to Homozygous Deletion of the IL1RN Locus

Overview

Journal N Engl J Med

Specialty General Medicine

Date 2009 Jun 5

PMID 19494219

Citations 163

Authors

Sreelatha Reddy

Shuang Jia

Rhonda Geoffrey

Rachel Lorier

Mariko Suchi

Ulrich Broeckel

Martin J Hessner

James Verbsky

Affiliations

Soon will be listed here.

Abstract

We describe a patient with an autoinflammatory disease in which the main clinical features are pustular rash, marked osteopenia, lytic bone lesions, respiratory insufficiency, and thrombosis. Genetic studies revealed a 175-kb homozygous deletion at chromosome 2q13, which encompasses several interleukin-1 family members, including the gene encoding the interleukin-1-receptor antagonist (IL1RN). Mononuclear cells, obtained from the patient and cultured, produced large amounts of inflammatory cytokines, with increasing amounts secreted after stimulation with lipopolysaccharide. A similar increase was not observed in peripheral-blood mononuclear cells from a patient with neonatal-onset multisystem inflammatory disorder (NOMID). Treatment with anakinra completely resolved the symptoms and lesions.

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References

Nicklin M, Hughes D, Barton J, Ure J, Duff G . Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J Exp Med. 2000; 191(2):303-12. PMC: 2195758. DOI: 10.1084/jem.191.2.303. View

Taylor S, Renshaw B, Garka K, Smith D, Sims J . Genomic organization of the interleukin-1 locus. Genomics. 2002; 79(5):726-33. DOI: 10.1006/geno.2002.6752. View

Hull K, Shoham N, Chae J, Aksentijevich I, Kastner D . The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations. Curr Opin Rheumatol. 2002; 15(1):61-9. DOI: 10.1097/00002281-200301000-00011. View

Prieur A, Griscelli C . Arthropathy with rash, chronic meningitis, eye lesions, and mental retardation. J Pediatr. 1981; 99(1):79-83. DOI: 10.1016/s0022-3476(81)80961-4. View

Strand V, Kavanaugh A . The role of interleukin-1 in bone resorption in rheumatoid arthritis. Rheumatology (Oxford). 2004; 43 Suppl 3:iii10-iii16. DOI: 10.1093/rheumatology/keh202. View

Hawkins P, Lachmann H, Aganna E, McDermott M . Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum. 2004; 50(2):607-12. DOI: 10.1002/art.20033. View

Agostini L, Martinon F, Burns K, McDermott M, Hawkins P, Tschopp J . NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004; 20(3):319-25. DOI: 10.1016/s1074-7613(04)00046-9. View

Grossman W, Verbsky J, Barchet W, Colonna M, Atkinson J, Ley T . Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity. 2004; 21(4):589-601. DOI: 10.1016/j.immuni.2004.09.002. View

Horai R, Saijo S, Tanioka H, Nakae S, Sudo K, Okahara A . Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J Exp Med. 2000; 191(2):313-20. PMC: 2195765. DOI: 10.1084/jem.191.2.313. View

10.

Nicklin M, Barton J, Nguyen M, Fitzgerald M, Duff G, Kornman K . A sequence-based map of the nine genes of the human interleukin-1 cluster. Genomics. 2002; 79(5):718-25. DOI: 10.1006/geno.2002.6751. View

11.

Saito M, Nishikomori R, Kambe N, Fujisawa A, Tanizaki H, Takeichi K . Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients. Blood. 2007; 111(4):2132-41. DOI: 10.1182/blood-2007-06-094201. View

12.

Blumberg H, Dinh H, Trueblood E, Pretorius J, Kugler D, Weng N . Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation. J Exp Med. 2007; 204(11):2603-14. PMC: 2118475. DOI: 10.1084/jem.20070157. View

13.

Aksentijevich I, Nowak M, Mallah M, Chae J, Watford W, Hofmann S . De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 2002; 46(12):3340-8. PMC: 4556432. DOI: 10.1002/art.10688. View

14.

Debets R, Timans J, Homey B, Zurawski S, Sana T, Lo S . Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2. J Immunol. 2001; 167(3):1440-6. DOI: 10.4049/jimmunol.167.3.1440. View

15.

Sturn A, Quackenbush J, Trajanoski Z . Genesis: cluster analysis of microarray data. Bioinformatics. 2002; 18(1):207-8. DOI: 10.1093/bioinformatics/18.1.207. View

16.

Hoffman H, Mueller J, Broide D, Wanderer A, Kolodner R . Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001; 29(3):301-5. PMC: 4322000. DOI: 10.1038/ng756. View

17.

Aksentijevich I, Masters S, Ferguson P, Dancey P, Frenkel J, van Royen-Kerkhoff A . An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009; 360(23):2426-37. PMC: 2876877. DOI: 10.1056/NEJMoa0807865. View

18.

Romero R, Gotsch F, Pineles B, Kusanovic J . Inflammation in pregnancy: its roles in reproductive physiology, obstetrical complications, and fetal injury. Nutr Rev. 2008; 65(12 Pt 2):S194-202. DOI: 10.1111/j.1753-4887.2007.tb00362.x. View

19.

Shepherd J, Little M, Nicklin M . Psoriasis-like cutaneous inflammation in mice lacking interleukin-1 receptor antagonist. J Invest Dermatol. 2004; 122(3):665-9. DOI: 10.1111/j.0022-202X.2004.22305.x. View

20.

Towne J, Garka K, Renshaw B, Virca G, Sims J . Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs. J Biol Chem. 2004; 279(14):13677-88. DOI: 10.1074/jbc.M400117200. View