Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Author:

De Ravin, S. S.

Cowen, E. W.

Zarember, K. A.

Whiting-Theobald, N. L.

Kuhns, D. B.

Sandler, N. G.

Douek, D. C.

Pittaluga, S.

Poliani, P. L.

Lee, Y. N.

Notarangelo, L. D.

Wang, L.

Alt, F. W.

Kang, E. M.

Milner, J. D.

Niemela, J. E.

Fontana-Penn, M.

Sinal, S. H.

Malech, H. L.
Author Address

[De Ravin, Suk See; Zarember, Kol A.; Whiting-Theobald, Narda L.; Kang, Elizabeth M.; Milner, Joshua D.; Malech, Harry L.] NIAID, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. [Cowen, Edward W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Kuhns, Douglas B.] SAIC Frederick Inc, Clin Serv Program, Frederick, MD USA. [Sandler, Netanya G.; Douek, Daniel C.] NCI, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Poliani, Pietro L.] Univ Brescia, Dept Pathol, Brescia, Italy. [Lee, Yu Nee; Notarangelo, Luigi D.; Wang, Lei; Alt, Frederick W.] Harvard Univ, Sch Med, Div Immunol, Childrens Hosp Boston, Boston, MA USA. [Niemela, Julie E.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Fontana-Penn, Mary; Sinal, Sara H.] Wake Forest Univ, Dept Pediat, Sch Med, Winston Salem, NC 27109 USA.;De Ravin, SS, NIAID, Lab Host Defenses, NIH, CRC 5W Rm 5-3816,10 Ctr Dr, Bethesda, MD 20892 USA.;sderavin@niaid.nih.gov

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. (Blood. 2010; 116(8): 1263-1271)

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