Late Onset Hypomorphic RAG2 Deficiency Presentation with Fatal Vaccine-Strain VZV Infection

Cullen M. Dutmer, Edwin J. Asturias, Christiana Smith, Megan K. Dishop, D. Scott Schmid, William J. Bellini, Irit Tirosh, Yu Nee Lee, Luigi D. Notarangelo, Erwin W. Gelfand*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Purpose: 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.

Original languageEnglish
Pages (from-to)754-760
Number of pages7
JournalJournal of Clinical Immunology
Issue number8
StatePublished - 1 Nov 2015
Externally publishedYes


  • RAG2
  • T cell lymphopenia
  • immunosuppression
  • vaccine-strain virus infection


Dive into the research topics of 'Late Onset Hypomorphic RAG2 Deficiency Presentation with Fatal Vaccine-Strain VZV Infection'. Together they form a unique fingerprint.

Cite this