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

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Abstract

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.

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Abbreviations

ACIP:

Advisory Committee on Immunization Practices

CMV:

Cytomegalovirus

Con A:

Concanavalin A

CVID:

Common variable immune deficiency

D:

Diversity

hCD4:

Human CD4

HSCT:

Hematopoietic stem cell transplantation

IVIG:

Intravenous immunoglobulin

J:

Joining

PHA:

Phytohemagglutinin

RAG:

Recombination-activating gene

SCID:

Severe combined immune deficiency

SD:

Standard deviation

TLR:

Toll-like receptor

TREC:

T cell receptor excision circle

V:

Variable

VZV:

Varicella zoster virus

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Author information

Authors and Affiliations

  1. Department of Pediatrics, National Jewish Health, 1400 Jackson Street, K801, Denver, CO, 80206-2761, USA

    Cullen M. Dutmer & Erwin W. Gelfand

  2. Department of Pediatric Infectious Diseases, University of Colorado School of Medicine, Aurora, CO, USA

    Edwin J. Asturias & Christiana Smith

  3. Center for Global Health, Colorado School of Public Health, Aurora, CO, USA

    Edwin J. Asturias

  4. Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA

    Megan K. Dishop

  5. Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA

    D. Scott Schmid & William J. Bellini

  6. Division of Immunology, Boston Children’s Hospital, Boston, MA, USA

    Irit Tirosh, Yu Nee Lee & Luigi D. Notarangelo

Authors
  1. Cullen M. Dutmer
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  2. Edwin J. Asturias
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  3. Christiana Smith
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  4. Megan K. Dishop
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  5. D. Scott Schmid
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  6. William J. Bellini
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  7. Irit Tirosh
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  8. Yu Nee Lee
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  9. Luigi D. Notarangelo
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  10. Erwin W. Gelfand
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Corresponding author

Correspondence to Erwin W. Gelfand.

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Declaration of all Sources of Funding

C.D. was supported by a fellowship from Grifols. This work was partially supported by a grant from the National Institutes of Health (grant 5R01AI100887 to L.D.N.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI or the NIH.

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Dutmer, C.M., Asturias, E.J., Smith, C. et al. Late Onset Hypomorphic RAG2 Deficiency Presentation with Fatal Vaccine-Strain VZV Infection. J Clin Immunol 35, 754–760 (2015). https://doi.org/10.1007/s10875-015-0207-8

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  • DOI: https://doi.org/10.1007/s10875-015-0207-8

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