title: Relative CD4 lymphopenia and a skewed memory phenotype are the main immunologic abnormalities in a child with Omenn syndrome due to homozygous RAG1-C2633T hypomorphic mutation.
abstract: We report a child with Omenn syndrome (OS) due to homozygous RAG1-C2633T mutations who had an unusual clinical and immunological presentation. She had delayed onset of OS-associated clinical features, had cleared a number of potentially fatal pathogens including respiratory syncytial virus, parainfluenza-3 virus and rotavirus, and was thriving at diagnosis. Laboratory assessment showed normal T and B lymphocyte number and function. T-cell-receptor repertoire in the blood was relatively diverse and her primary immunologic abnormality was skewing of circulating T-cells to the memory phenotype. A compelling explanation for the perplexing combination in OS of atopic/autoimmune and immunologic features has proven elusive. Homozygous RAG1-C2633T hypomorphic mutation may lead to significant residual immunity and a skewed memory phenotype. Our findings suggest that, in addition to host-genetic factors, environment, and/or pathogens, hypomorphic RAG mutations may differentially impact on V(D)J recombination activity and hence lead to a variable ability to sustain T and B cell lymphopoiesis. Importantly, this case emphasizes that such hypomorphic mutations may promote an attenuated phenotype, complicating the diagnosis of primary immunodeficiency (PID).
authors.affiliation: Division of Allergy and Immunology, Montreal Children's Hospital, McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: McCusker
authors.forename: Simon
authors.initials: S
authors.lastname: Hotte
authors.forename: Francoise
authors.initials: F
authors.lastname: Le Deist
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Hirschfeld
authors.forename: David
authors.initials: D
authors.lastname: Mitchell
authors.forename: Van-Hung
authors.initials: VH
authors.lastname: Nguyen
authors.forename: Remi
authors.initials: R
authors.lastname: Gagnon
authors.forename: Bruce
authors.initials: B
authors.lastname: Mazer
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008231:Lymphopenia / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D009154:Mutation / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000235:genetics / Q000276:immunology*; D012867:Skin / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C064658:RAG-1 protein