title: Late Onset Hypomorphic RAG2 Deficiency Presentation with Fatal Vaccine-Strain VZV Infection.
abstract: OBJECTIVE
  Hypomorphic mutations in RAG1 and RAG2 are associated with significant clinical heterogeneity and symptoms of immunodeficiency or autoimmunity may be late in appearance. As a result, immunosuppressive medications may be introduced that can have life-threatening consequences. We describe a previously healthy 13-month-old girl presenting with rash and autoimmune hemolytic anemia, while highlighting the importance of vigilance and consideration of an underlying severe immunodeficiency disease prior to instituting immunosuppressive therapy.
  
  
  METHODS
  Given clinical deterioration of the patient and a temporal association with recently administered vaccinations, virus genotyping was carried out via 4 real-time Forster Resonance Energy Transfer PCR protocols targeting vaccine-associated single nucleotide polymorphisms. Genomic DNA was extracted from whole blood and analyzed via the next-generation sequencing method of sequencing-by-synthesis. Immune function studies included immunophenotyping of peripheral blood lymphocytes, mitogen-induced proliferation and TLR ligand-induced production of TNFα. Analysis of recombination activity of wild-type and mutant RAG2 constructs was performed.
  
  
  RESULTS
  Virus genotyping revealed vaccine-strain VZV, mumps, and rubella. Next-generation sequencing identified heterozygosity for RAG2 R73H and P180H mutations. Profound lymphopenia was associated with intense corticosteroid therapy, with some recovery after steroid reduction. Residual, albeit low, RAG2 protein activity was demonstrated.
  
  
  CONCLUSIONS
  Because of the association of RAG deficiency with late-onset presentation and autoimmunity, live virus vaccination and immunosuppressive therapies are often initiated and can result in negative consequences. Here, hypomorphic RAG2 mutations were linked to disseminated vaccine-strain virus infections following institution of corticosteroid therapy for autoimmune hemolytic anemia.
authors.affiliation: Department of Pediatrics, National Jewish Health, 1400 Jackson Street, K801, Denver, CO, 80206-2761, USA.
authors.forename: Cullen M
authors.initials: CM
authors.lastname: Dutmer
authors.affiliation: Department of Pediatric Infectious Diseases, University of Colorado School of Medicine, Aurora, CO, USA.|Center for Global Health, Colorado School of Public Health, Aurora, CO, USA.
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Asturias
authors.affiliation: Department of Pediatric Infectious Diseases, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Christiana
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Dishop
authors.affiliation: Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: D Scott
authors.initials: DS
authors.lastname: Schmid
authors.affiliation: Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Bellini
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Irit
authors.initials: I
authors.lastname: Tirosh
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Yu Nee
authors.initials: YN
authors.lastname: Lee
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Department of Pediatrics, National Jewish Health, 1400 Jackson Street, K801, Denver, CO, 80206-2761, USA. gelfande@njc.org.
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000009:adverse effects; D000744:Anemia, Hemolytic, Autoimmune / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006562:Herpes Zoster / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy; D014645:Herpesvirus 3, Human / Q000502:physiology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D000305:Adrenal Cortex Hormones; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; D014765:Viral Vaccines
keywords: RAG2; T cell lymphopenia; immunosuppression; vaccine-strain virus infection