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Journal of Clinical Immunology

, Volume 35, Issue 5, pp 449–453 | Cite as

IL2RG Reversion Event in a Common Lymphoid Progenitor Leads to Delayed Diagnosis and Milder Phenotype

  • Amy P. Hsu
  • Stefania Pittaluga
  • Bianca Martinez
  • Amy P. Rump
  • Mark Raffeld
  • Gulbu Uzel
  • Jennifer M. Puck
  • Alexandra F. Freeman
  • Steven M. Holland
Astute Clinician Report

Abstract

Severe combined immunodeficiency (SCID) is most frequently caused by mutations in the cytokine receptor common gamma chain, CD132, encoded by the X-linked gene, IL2RG. Most patients present in the first year of life with failure to thrive, severe, opportunistic infections and absence of CD3+ T cells. We present a patient with pediatric illness and a diagnosis of combined variable immune deficiency (CVID) who was diagnosed at age 23 with an inherited IL2RG mutation causing loss of signal transduction through CD132. His peripheral blood included CD3/CD4 and CD3/CD8 positive cells as well as low levels of CD19+ B cells containing a reversion to the wildtype IL2RG allele. The reversion, which was not present at birth, may account for his mild phenotype and late diagnosis.

Keywords

X-SCID IL2RG Reversion Common gamma chain 

Notes

Publication Disclaimer

The views expressed in this article are those of the authors and do not reflect the official policy of the U.S. Government. This research was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E.

Conflict Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Hsieh MY, Hong WH, Lin JJ, Lee WI, Lin KL, Wang HS, et al. T-cell receptor excision circles and repertoire diversity in children with profound T-cell immunodeficiency. J Microbiol Immunol Infect. 2013;46(5):374–81.PubMedCrossRefGoogle Scholar
  2. 2.
    Puck JM. Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: the winner is T-cell receptor excision circles. J Allergy Clin Immunol. 2012;129:607–16.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Puck JM, Deschenes SM, Porter JC, Dutra AS, Brown CJ, Willard HF, et al. The interleukin-2 receptor g chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum Mol Genet. 1993;2(8):1099–104.PubMedCrossRefGoogle Scholar
  4. 4.
    Noguchi M, Yi Huafang Y, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, et al. Interleukin-2 receptor g chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993;73(1):147–57.PubMedCrossRefGoogle Scholar
  5. 5.
    Russell SM, Keegan AD, Harada N, Nakamura Y, Noguchi M, Leland P, et al. Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor. Science. 1993;262(5141):1880–3.PubMedCrossRefGoogle Scholar
  6. 6.
    Noguchi M, Nakamura Y, Russell SM, Ziegler SF, Tsang M, Cao X, et al. Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor. Science. 1993;262(5141):1877–80.PubMedCrossRefGoogle Scholar
  7. 7.
    Kimura Y, Takeshita T, Kondo M, Ishii N, Nakamura M, Van Snick J, et al. Sharing of the IL-2 receptor gama chain with the functional IL-9 receptor complex. Int Immunol. 1995;7(1):115–20.PubMedCrossRefGoogle Scholar
  8. 8.
    Giri JG, Anderson DM, Kumaki S, Park LS, Grabstein KH, Cosman D. IL-15, a novel T cell growth factor that shares activities and receptor components with IL-2. J Leukoc Biol. 1995;57(5):763–6.PubMedGoogle Scholar
  9. 9.
    Habib T, Senadheera S, Weinberg K, Kaushansky K. The common gamma chain (gamma c) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3. Biochemistry. 2002;41(27):8725–31.PubMedCrossRefGoogle Scholar
  10. 10.
    Recher M, Berglund LJ, Avery DT, Cowan MJ, Gennery AR, Smart J, et al. IL-21 is the primary common g chain-binding cytokine required for human B-cell differentiation in vivo. Blood. 2011;118(26):6824–35.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Vosshenrich CA, Ranson T, Samson SI, Corcuff E, Colucci F, Rosmaraki EE, et al. Roles for common cytokine receptor gamma-chain-dependent cytokines in the generation, differentiation, and maturation nof NK cell precursors and peripheral NK cells in vivo. J Immunol. 2005;174(3):1213–21.PubMedCrossRefGoogle Scholar
  12. 12.
    Volker S, Volker W, Le Deist F, Dirksen U, Broker B, Muller-Fleckenstein I, et al. Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N Engl J Med. 1996;335:1563–7.CrossRefGoogle Scholar
  13. 13.
    Speckmann C, Pannicke U, Wiech E, Schwarz K, Fisch P, Friedrich W, et al. Clinical and immunologic consequences of a somatic reversion in a patient with X-linked severe combined immunodeficiency. Blood. 2008;112(10):4090–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Kawai T, Saito M, Nishikomori R, Yasumi T, Izawa K, Murakami T, et al. Multiple reversions of an IL2RG mutation restore T cell function in an X-linked severe combined immunodeficiency patient. J Clin Immunol. 2012;32(4):690–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Kuijpers TW, van Leeuwen EM, Barendregt BH, Klarenbeek P, Aan de Kerk DJ, Baars PA, et al. A reversion of an IL2RG mutation in combined immunodeficiency providing competititive advantage to the majority of CD8+ T cells. Haematologica. 2013;98(7):1030–8.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Hsu AP, Sowerwine KJ, Lawrence MG, Davis J, Henderson CJ, Zarember KA, et al. Intermediate phenotypes in patients with autosomal dominant hyper-IgE syndrome caused by somatic mosaicism. J Allergy Clin Immunol. 2013;131(6):1586–93.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Uzel G, Tng E, Rosenzweig SD, Hsu AP, Shaw JM, Horwitz ME, et al. Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1). Blood. 2008;111(1):209–18.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Kwan A, Abraham RS, Currier R, Brower A, Andruszewski K, Abbott JK, et al. Newborn screening for SCID in the United States: experience from 11 screening programs. JAMA. 2014;312(7):729–38.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2015

Authors and Affiliations

  • Amy P. Hsu
    • 1
  • Stefania Pittaluga
    • 2
  • Bianca Martinez
    • 1
  • Amy P. Rump
    • 3
  • Mark Raffeld
    • 2
  • Gulbu Uzel
    • 1
  • Jennifer M. Puck
    • 4
  • Alexandra F. Freeman
    • 1
  • Steven M. Holland
    • 1
  1. 1.National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Clinical Infectious DiseasesBethesdaUSA
  2. 2.Laboratory of PathologyNational Cancer Institute, National Institutes of HealthBethesdaUSA
  3. 3.Clinical Research Directorate/Clinical Monitoring Research ProgramLeidos Biomedical Research, Inc., Frederick National Laboratory for Cancer ResearchFrederickUSA
  4. 4.Department of PediatricsUniversity of California, San FranciscoSan FranciscoUSA

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