title: Hypomorphic Rag mutations can cause destructive midline granulomatous disease.
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.
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. sderavin@niaid.nih.gov
authors.forename: Suk See
authors.initials: SS
authors.lastname: De Ravin
authors.forename: Edward W
authors.initials: EW
authors.lastname: Cowen
authors.forename: Kol A
authors.initials: KA
authors.lastname: Zarember
authors.forename: Narda L
authors.initials: NL
authors.lastname: Whiting-Theobald
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kuhns
authors.forename: Netanya G
authors.initials: NG
authors.lastname: Sandler
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Pietro L
authors.initials: PL
authors.lastname: Poliani
authors.forename: Yu Nee
authors.initials: YN
authors.lastname: Lee
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Kang
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
authors.forename: Julie E
authors.initials: JE
authors.lastname: Niemela
authors.forename: Mary
authors.initials: M
authors.lastname: Fontana-Penn
authors.forename: Sara H
authors.initials: SH
authors.lastname: Sinal
authors.forename: Harry L
authors.initials: HL
authors.lastname: Malech
mesh_terms: D000293:Adolescent; D000818:Animals; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D006105:Granulomatous Disease, Chronic / Q000209:etiology* / Q000473:pathology* / Q000601:surgery; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D016130:Immunophenotyping; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics*; D045522:Recombinases / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000209:etiology* / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013934:Thymectomy; D014157:Transcription Factors; D019076:Transgenes / Q000502:physiology; D000096927:AIRE Protein
chemical_list: D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D007074:Immunoglobulin G; D045522:Recombinases; D014157:Transcription Factors; D000096927:AIRE Protein; C418974:FOXP3 protein, human; C064658:RAG-1 protein