Hypomorphic Rag mutations can cause destructive midline granulomatous disease.
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.
De Ravin
Suk See
SS
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. sderavin@niaid.nih.gov
Cowen
Edward W
EW
Zarember
Kol A
KA
Whiting-Theobald
Narda L
NL
Kuhns
Douglas B
DB
Sandler
Netanya G
NG
Douek
Daniel C
DC
Pittaluga
Stefania
S
Poliani
Pietro L
PL
Lee
Yu Nee
YN
Notarangelo
Luigi D
LD
Wang
Lei
L
Alt
Frederick W
FW
Kang
Elizabeth M
EM
Milner
Joshua D
JD
Niemela
Julie E
JE
Fontana-Penn
Mary
M
Sinal
Sara H
SH
Malech
Harry L
HL
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
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