Abstract
We describe a boy who developed autoinflammatory (chronic sterile multifocal osteomyelitis) and autoimmune (autoimmune cytopenias; vitiligo) phenotypes who subsequently developed disseminated granulomatous disease. Whole exome sequencing revealed homozygous RAG1 mutations thus expanding the spectrum of combined immunodeficiency with autoimmunity and granuloma that can occur with RAG deficiency.
This is a preview of subscription content, log in via an institution to check access.
References
Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, et al. RAG mutations in human B cell-negative SCID. Science. 1996;274(5284):97–9. Epub 1996/10/04.
Villa A, Santagata S, Bozzi F, Imberti L, Notarangelo LD. Omenn syndrome: a disorder of Rag1 and Rag2 genes. J Clin Immunol. 1999;19(2):87–97. Epub 1999/05/05.
Villa A, Santagata S, Bozzi F, Giliani S, Frattini A, Imberti L, et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell. 1998;93(5):885–96. Epub 1998/06/18.
de Villartay JP, Lim A, Al-Mousa H, Dupont S, Dechanet-Merville J, Coumau-Gatbois E, et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest. 2005;115(11):3291–9. Epub 2005/11/09.
Ehl S, Schwarz K, Enders A, Duffner U, Pannicke U, Kuhr J, et al. A variant of SCID with specific immune responses and predominance of gamma delta T cells. J Clin Invest. 2005;115(11):3140–8. Epub 2005/10/08.
Walter JE, Rucci F, Patrizi L, Recher M, Regenass S, Paganini T, et al. Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency. J Exp Med. 2010;207(7):1541–54. Epub 2010/06/16.
Avila EM, Uzel G, Hsu A, Milner JD, Turner ML, Pittaluga S, et al. Highly variable clinical phenotypes of hypomorphic RAG1 mutations. Pediatrics. 2010;126(5):e1248–52. Epub 2010/10/20.
Schuetz C, Huck K, Gudowius S, Megahed M, Feyen O, Hubner B, et al. An immunodeficiency disease with RAG mutations and granulomas. N Engl J Med. 2008;358(19):2030–8. Epub 2008/05/09.
De Ravin SS, Cowen EW, Zarember KA, Whiting-Theobald NL, Kuhns DB, Sandler NG, et al. Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood. 2010;116(8):1263–71. Epub 2010/05/22.
Jansson A, Renner ED, Ramser J, Mayer A, Haban M, Meindl A, et al. Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology (Oxford). 2007;46(1):154–60. Epub 2006/06/20.
Bjorksten B, Gustavson KH, Eriksson B, Lindholm A, Nordstrom S. Chronic recurrent multifocal osteomyelitis and pustulosis palmoplantaris. J Pediatr. 1978;93(2):227–31.
Laxer RM, Shore AD, Manson D, King S, Silverman ED, Wilmot DM. Chronic recurrent multifocal osteomyelitis and psoriasis–a report of a new association and review of related disorders. Semin Arthritis Rheum. 1988;17(4):260–70.
Bognar M, Blake W, Agudelo C. Chronic recurrent multifocal osteomyelitis associated with Crohn’s disease. Am J Med Sci. 1998;315(2):133–5.
Ferguson PJ, Chen S, Tayeh MK, Ochoa L, Leal SM, Pelet A, et al. Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet. 2005;42(7):551–7. Epub 2005/07/05.
Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360(23):2426–37. Epub 2009/06/06.
Reddy S, Jia S, Geoffrey R, Lorier R, Suchi M, Broeckel U, et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med. 2009;360(23):2438–44. Epub 2009/06/06.
Herlin T, Fiirgaard B, Bjerre M, Kerndrup G, Hasle H, Bing X, et al. Efficacy of anti-IL-1 treatment in Majeed syndrome. Ann Rheum Dis. 2012. Epub 2012/10/23.
Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061–73. Epub 2010/10/29.
Zhang ZY, Zhao XD, Jiang LP, Liu EM, Cui YX, Wang M, et al. Clinical characteristics and molecular analysis of three Chinese children with Omenn syndrome. Pediatr Allergy Immunol Off Publ Eur Soc Pediatr Allergy Immunol. 2011;22(5):482–7. Epub 2011/07/21.
Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992;68(5):869–77. Epub 1992/03/06.
Menoret S, Fontaniere S, Jantz D, Tesson L, Thinard R, Remy S, et al. Generation of Rag1-knockout immunodeficient rats and mice using engineered meganucleases. Faseb J. 2013;27(2):703–11. Epub 2012/11/15.
Atreya R, Zimmer M, Bartsch B, Waldner MJ, Atreya I, Neumann H, et al. Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14(+) macrophages. Gastroenterology. 2011;141(6):2026–38. Epub 2011/08/31.
Mitoma H, Horiuchi T, Tsukamoto H, Tamimoto Y, Kimoto Y, Uchino A, et al. Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor alpha-expressing cells: comparison among infliximab, etanercept, and adalimumab. Arthritis Rheum. 2008;58(5):1248–57. Epub 2008/04/29.
van Deventer SJ. Transmembrane TNF-alpha, induction of apoptosis, and the efficacy of TNF-targeting therapies in Crohn’s disease. Gastroenterology. 2001;121(5):1242–6. Epub 2001/10/26.
Al-Herz W, Nanda A. Skin manifestations in primary immunodeficient children. Pediatr Dermatol. 2011;28(5):494–501. Epub 2011/04/02.
Acknowledgments
This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health [1R01AR059703-01A1 PJF and AGB].
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Reiff, A., Bassuk, A.G., Church, J.A. et al. Exome Sequencing Reveals RAG1 Mutations in a Child with Autoimmunity and Sterile Chronic Multifocal Osteomyelitis Evolving into Disseminated Granulomatous Disease. J Clin Immunol 33, 1289–1292 (2013). https://doi.org/10.1007/s10875-013-9953-7
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1007/s10875-013-9953-7