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01-07-2015 | Astute Clinician Report

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

Authors: Amy P. Hsu, Stefania Pittaluga, Bianca Martinez, Amy P. Rump, Mark Raffeld, Gulbu Uzel, Jennifer M. Puck, Alexandra F. Freeman, Steven M. Holland

Published in: Journal of Clinical Immunology | Issue 5/2015

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.

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

Title: IL2RG Reversion Event in a Common Lymphoid Progenitor Leads to Delayed Diagnosis and Milder Phenotype
Authors: Amy P. Hsu
Stefania Pittaluga
Bianca Martinez
Amy P. Rump
Mark Raffeld
Gulbu Uzel
Jennifer M. Puck
Alexandra F. Freeman
Steven M. Holland
Publication date: 01-07-2015
Publisher: Springer US
Published in: Journal of Clinical Immunology / Issue 5/2015
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-015-0174-0

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