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 journalArticlepeer-review

105 Scopus citations


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
Issue number8
StatePublished - Aug 26 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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