Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Suk See De Ravin, Edward W. Cowen, Kol A. Zarember, Narda L. Whiting-Theobald, Douglas B. Kuhns, Netanya G. Sandler, Daniel C. Douek, Stefania Pittaluga, Pietro L. Poliani, Yu Nee Lee, Luigi D. Notarangelo, Lei Wang, Frederick W. Alt, Elizabeth M. Kang, Joshua D. Milner, Julie E. Niemela, Mary Fontana-Penn, Sara H. Sinal, Harry L. Malech

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Destructive midline granulomatous disease characterized by necrotizing granulomas of the head and neck is most commonly caused by Wegener granulomatosis, natural killer/T-cell lymphomas, cocaine abuse, or infections. An adolescent patient with myasthenia gravis treated with thymectomy subsequently developed extensive granulomatous destruction of midface structures, palate, nasal septum, airways, and epiglottis. His lymphocyte numbers, total immunoglobulin G level, and T-cell receptor (TCR) repertoire appeared normal. Sequencing of Recombination activating gene-1 (Rag1) showed compound heterozygous Rag1 mutations; a novel deletion with no recombinase activity and a missense mutation resulting in 50% Rag activity. His thymus was dysplastic and, although not depleted of T cells, showed a notable absence of autoimmune regulator (AIRE) and Foxp3+ regulatory T cells. This distinct Rag-deficient phenotype characterized by immune dysregulation with granulomatous hyperinflammation and autoimmunity, with relatively normal T and B lymphocyte numbers and a diverse TCR repertoire expands the spectrum of presentation in Rag deficiency. This study was registered at www.clinicaltrials.gov as #NCT00128973.

Original languageEnglish (US)
Pages (from-to)1263-1271
Number of pages9
JournalBlood
Volume116
Issue number8
DOIs
StatePublished - Aug 26 2010
Externally publishedYes

Fingerprint

RAG-1 Genes
T-cells
Lymphocyte Count
T-Cell Antigen Receptor
Lymphocytes
Epiglottis
T-Lymphocytes
Nasal Septum
Cocaine-Related Disorders
Thymectomy
Recombinases
Mutation
Granulomatosis with Polyangiitis
Natural Killer T-Cells
Palate
T-Cell Lymphoma
Myasthenia Gravis
Regulatory T-Lymphocytes
Missense Mutation
Genes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

De Ravin, S. S., Cowen, E. W., Zarember, K. A., Whiting-Theobald, N. L., Kuhns, D. B., Sandler, N. G., ... Malech, H. L. (2010). Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood, 116(8), 1263-1271. https://doi.org/10.1182/blood-2010-02-267583

Hypomorphic Rag mutations can cause destructive midline granulomatous disease. / De Ravin, Suk See; Cowen, Edward W.; Zarember, Kol A.; Whiting-Theobald, Narda L.; Kuhns, Douglas B.; Sandler, Netanya G.; Douek, Daniel C.; Pittaluga, Stefania; Poliani, Pietro L.; Lee, Yu Nee; Notarangelo, Luigi D.; Wang, Lei; Alt, Frederick W.; Kang, Elizabeth M.; Milner, Joshua D.; Niemela, Julie E.; Fontana-Penn, Mary; Sinal, Sara H.; Malech, Harry L.

In: Blood, Vol. 116, No. 8, 26.08.2010, p. 1263-1271.

Research output: Contribution to journalArticle

De Ravin, SS, Cowen, EW, Zarember, KA, Whiting-Theobald, NL, Kuhns, DB, Sandler, NG, Douek, DC, Pittaluga, S, Poliani, PL, Lee, YN, Notarangelo, LD, Wang, L, Alt, FW, Kang, EM, Milner, JD, Niemela, JE, Fontana-Penn, M, Sinal, SH & Malech, HL 2010, 'Hypomorphic Rag mutations can cause destructive midline granulomatous disease', Blood, vol. 116, no. 8, pp. 1263-1271. https://doi.org/10.1182/blood-2010-02-267583
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 Aug 26;116(8):1263-1271. https://doi.org/10.1182/blood-2010-02-267583
De Ravin, Suk See ; Cowen, Edward W. ; Zarember, Kol A. ; Whiting-Theobald, Narda L. ; Kuhns, Douglas B. ; Sandler, Netanya G. ; Douek, Daniel C. ; Pittaluga, Stefania ; Poliani, Pietro L. ; Lee, Yu Nee ; Notarangelo, Luigi D. ; Wang, Lei ; Alt, Frederick W. ; Kang, Elizabeth M. ; Milner, Joshua D. ; Niemela, Julie E. ; Fontana-Penn, Mary ; Sinal, Sara H. ; Malech, Harry L. / Hypomorphic Rag mutations can cause destructive midline granulomatous disease. In: Blood. 2010 ; Vol. 116, No. 8. pp. 1263-1271.
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