Large granular lymphocyte proliferation and revertant mosaicism: two rare events in a Wiskott-Aldrich syndrome patient

K. Boztug; U. Baumann; M. Ballmaier; D. Webster; I. Sandrock; R. Jacobs; T. Lion; S. Preuner; M. Germeshausen; G. Hansen; K. Welte; C. Klein

doi:10.3324/haematol.11222

Open access journal of the Ferrata-Storti Foundation, a non-profit organization

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Large granular lymphocyte proliferation and revertant mosaicism: two rare events in a Wiskott-Aldrich syndrome patient

K. Boztug
U. Baumann
M. Ballmaier
D. Webster
I. Sandrock
R. Jacobs
T. Lion
S. Preuner
M. Germeshausen
G. Hansen
K. Welte
C. Klein

Vol. 92 No. 3 (2007): March, 2007 https://doi.org/10.3324/haematol.11222

Abstract

We report on a 6 year old patient with an unusual clinical presentation of WAS and oligoclonal proliferation of TCRγδ ⁺ large granular lymphocytes (LGL). Flow cytometry demonstrated two distinct populations of lymphocytes with strongly decreased (WASP⁻) or normal expression levels of WASP (WASP⁺), respectively. Molecular analysis confirmed a splice site mutation in intron 2 of the WASP gene in the WASP- cells but not in WASP⁺ cells. LGL cells were WASP⁺, suggesting that two independent rare events, somatic revertant mosaicism and LGL expansion, have occurred in a child with WAS. Our report points to diagnostic difficulties in the presence of partial WASP reversions and LGL.

References

Lamy T, Loughran TPJ. Clinical features of large granular lymphocyte leukemia. Semin Hematol. 2003; 40:185-95. PubMed https://doi.org/10.1016/S0037-1963(03)00133-1 Google Scholar
Thrasher AJ. WASp in immune-system organization and function. Nat Rev Immunol. 2002; 2:635-46. PubMed https://doi.org/10.1038/nri884 Google Scholar
Ariga T, Kondoh T, Yamaguchi K, Yamada M, Sasaki S, Nelson DL. Spontaneous in vivo reversion of an inherited mutation in the Wiskott-Aldrich syndrome. J Immunol. 2001; 166:5245-9. PubMed https://doi.org/10.4049/jimmunol.166.8.5245 Google Scholar
Lutskiy MI, Beardsley DS, Rosen FS, Remold-O’Donnell E. Mosaicism of NK cells in a patient with Wiskott-Aldrich syndrome. Blood. 2005; 106:2815-7. PubMed https://doi.org/10.1182/blood-2004-12-4724 Google Scholar
Wada T, Schurman SH, Otsu M, Garabedian EK, Ochs HD, Nelson DL. Somatic mosaicism in Wiskott-Aldrich syndrome suggests in vivo reversion by a DNA slippage mechanism. Proc Natl Acad Sci U S A. 2001; 98:8697-702. PubMed https://doi.org/10.1073/pnas.151260498 Google Scholar
Wada T, Konno A, Schurman SH, Garabedian EK, Anderson SM, Kirby M. Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings. J Clin Invest. 2003; 111:1389-97. PubMed https://doi.org/10.1172/JCI200315485 Google Scholar
Raeiszadeh M, Kopycinski J, Paston SJ, Diss T, Lowdell M, Hardy GA. The T cell response to persistent herpes virus infections in common variable immunodeficiency. Clin Exp Immunol. 2006; 146:234-42. PubMed https://doi.org/10.1111/j.1365-2249.2006.03209.x Google Scholar
Lion T, Watzinger F. Chimerism analysis following nonmyeloablative stem cell transplantation. Methods Mol Med. 2006; 125:275-95. PubMed Google Scholar
Ariga T, Yamada M, Pudua FR, Sakiyama Y. Detection of a novel splice-site mutation that results in skipping exon 3 of the WASP gene in a patient with Wiskott-Aldrich syndrome. Biochim Biophys Acta. 1996; 1317:158-60. PubMed Google Scholar
Klein C, Nguyen D, Lui C-H, Mizoguchi A, Bhan AK, Miki H. Gene therapy for Wiskott-Aldrich syndrome: rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice. Blood. 2003; 101:2159-66. PubMed https://doi.org/10.1182/blood-2002-05-1423 Google Scholar
Wong KF, Yip SF, So CC, Lau GT, Yeung YM. Cytomegalovirus infection associated with clonal proliferation of T-cell large granular lymphocytes: causal or casual?. Cancer Genet Cytogenet. 2003; 142:77-9. PubMed https://doi.org/10.1016/S0165-4608(02)00739-2 Google Scholar
Tanaka Y, Matsui K, Yamashita K, Matsuda K, Shinohara K, Matsutani A. T-gamma delta large granular lymphocyte leukemia preceded by pure red cell aplasia and complicated with hemophagocytic syndrome caused by Epstein-Barr virus infection. Intern Med. 2006; 45:631-5. PubMed https://doi.org/10.2169/internalmedicine.45.1594 Google Scholar
Boztug K, Dewey RA, Klein C. Development of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome. Curr Opin Mol Ther. 2006; 8:390-5. PubMed Google Scholar
Kitchen BJ, Boxer LA. Large granular lymphocyte leukemia (LGL) in a child with Hyper IgM syndrome and autoimmune hemolytic anemia. Pediatr Blood Cancer. 2006. Google Scholar
Holm AM, Tjonnfjord G, Yndestad A, Beiske K, Muller F, Aukrust P. Polyclonal expansion of large granular lymphocytes in common variable immunodeficiency - association with neutropenia. Clin Exp Immunol. 2006; 2006:418-24. Google Scholar
Dechanet J, Merville P, Lim A, Retiere C, Pitard V, Lafarge X. Implication of gammadelta T cells in the human reponse to cytomegalovirus. J Clin Invest. 1999; 103:1437-49. PubMed https://doi.org/10.1172/JCI5409 Google Scholar

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Vol. 92 No. 3 (2007): March, 2007 : Online Only Articles

DOI

https://doi.org/10.3324/haematol.11222

Pubmed

17405757

Published

2007-03-01

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Ferrata Storti Foundation, Pavia, Italy

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0390-6078

Online ISSN

1592-8721

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[bib1] Lamy T, Loughran TPJ. Clinical features of large granular lymphocyte leukemia. Semin Hematol. 2003; 40:185-95. PubMed https://doi.org/10.1016/S0037-1963(03)00133-1 Google Scholar

[bib2] Thrasher AJ. WASp in immune-system organization and function. Nat Rev Immunol. 2002; 2:635-46. PubMed https://doi.org/10.1038/nri884 Google Scholar

[bib3] Ariga T, Kondoh T, Yamaguchi K, Yamada M, Sasaki S, Nelson DL. Spontaneous in vivo reversion of an inherited mutation in the Wiskott-Aldrich syndrome. J Immunol. 2001; 166:5245-9. PubMed https://doi.org/10.4049/jimmunol.166.8.5245 Google Scholar

[bib4] Lutskiy MI, Beardsley DS, Rosen FS, Remold-O’Donnell E. Mosaicism of NK cells in a patient with Wiskott-Aldrich syndrome. Blood. 2005; 106:2815-7. PubMed https://doi.org/10.1182/blood-2004-12-4724 Google Scholar

[bib5] Wada T, Schurman SH, Otsu M, Garabedian EK, Ochs HD, Nelson DL. Somatic mosaicism in Wiskott-Aldrich syndrome suggests in vivo reversion by a DNA slippage mechanism. Proc Natl Acad Sci U S A. 2001; 98:8697-702. PubMed https://doi.org/10.1073/pnas.151260498 Google Scholar

[bib6] Wada T, Konno A, Schurman SH, Garabedian EK, Anderson SM, Kirby M. Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings. J Clin Invest. 2003; 111:1389-97. PubMed https://doi.org/10.1172/JCI200315485 Google Scholar

[bib7] Raeiszadeh M, Kopycinski J, Paston SJ, Diss T, Lowdell M, Hardy GA. The T cell response to persistent herpes virus infections in common variable immunodeficiency. Clin Exp Immunol. 2006; 146:234-42. PubMed https://doi.org/10.1111/j.1365-2249.2006.03209.x Google Scholar

[bib8] Lion T, Watzinger F. Chimerism analysis following nonmyeloablative stem cell transplantation. Methods Mol Med. 2006; 125:275-95. PubMed Google Scholar

[bib9] Ariga T, Yamada M, Pudua FR, Sakiyama Y. Detection of a novel splice-site mutation that results in skipping exon 3 of the WASP gene in a patient with Wiskott-Aldrich syndrome. Biochim Biophys Acta. 1996; 1317:158-60. PubMed Google Scholar

[bib10] Klein C, Nguyen D, Lui C-H, Mizoguchi A, Bhan AK, Miki H. Gene therapy for Wiskott-Aldrich syndrome: rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice. Blood. 2003; 101:2159-66. PubMed https://doi.org/10.1182/blood-2002-05-1423 Google Scholar

[bib11] Wong KF, Yip SF, So CC, Lau GT, Yeung YM. Cytomegalovirus infection associated with clonal proliferation of T-cell large granular lymphocytes: causal or casual?. Cancer Genet Cytogenet. 2003; 142:77-9. PubMed https://doi.org/10.1016/S0165-4608(02)00739-2 Google Scholar

[bib12] Tanaka Y, Matsui K, Yamashita K, Matsuda K, Shinohara K, Matsutani A. T-gamma delta large granular lymphocyte leukemia preceded by pure red cell aplasia and complicated with hemophagocytic syndrome caused by Epstein-Barr virus infection. Intern Med. 2006; 45:631-5. PubMed https://doi.org/10.2169/internalmedicine.45.1594 Google Scholar

[bib13] Boztug K, Dewey RA, Klein C. Development of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome. Curr Opin Mol Ther. 2006; 8:390-5. PubMed Google Scholar

[bib14] Kitchen BJ, Boxer LA. Large granular lymphocyte leukemia (LGL) in a child with Hyper IgM syndrome and autoimmune hemolytic anemia. Pediatr Blood Cancer. 2006. Google Scholar

[bib15] Holm AM, Tjonnfjord G, Yndestad A, Beiske K, Muller F, Aukrust P. Polyclonal expansion of large granular lymphocytes in common variable immunodeficiency - association with neutropenia. Clin Exp Immunol. 2006; 2006:418-24. Google Scholar

[bib16] Dechanet J, Merville P, Lim A, Retiere C, Pitard V, Lafarge X. Implication of gammadelta T cells in the human reponse to cytomegalovirus. J Clin Invest. 1999; 103:1437-49. PubMed https://doi.org/10.1172/JCI5409 Google Scholar

Large granular lymphocyte proliferation and revertant mosaicism: two rare events in a Wiskott-Aldrich syndrome patient

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