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Monozygotic twins with GATA2 deficiency: same haploidentical-related donor, different severity of GvHD

Bone Marrow Transplantation volume 52, pages 1580–1582 (2017)Cite this article

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Twin studies, especially those involving monozygotic twins, are one of the oldest and most powerful methods for separating heritable from non-heritable traits. Recently, monozygotic twin studies have been used to study the frequencies of major immune cell populations.1, 2 However, even monozygotic twins can diverge somatically, genetically, epigenetically and environmentally. Here we describe monozygotic twins with GATA2 deficiency3, 4, 5 who both had nearly complete absence of NK cells and B-cells, monocytopenia (20 K/μL) and CD3 counts <300/μL prior to transplant, who underwent allogeneic hematopoietic stem cell transplant (HSCT) from the same haploidentical 8/10 HLA-matched sibling donor using the identical conditioning regimen and identical GvHD prophylaxis. The first twin developed acute grade II GvHD (skin and gastrointestinal involvement) requiring systemic corticosteroids for 6 months, oral budesonide for 2 months and tacrolimus for 1 and 1.5 years post transplant. In contrast, the second twin developed only grade I aGvHD (stage 1 skin), never required systemic steroids, and stopped tacrolimus 6 months following HSCT. This difference in GvHD highlights the complex role of host genetic and other factors in determining the incidence and severity of GvHD.

Twin 1: A 27-year-old female monozygotic twin with a heterozygous (c.988 C>T, p.R330X) mutation in GATA2 in the blood and skin fibroblasts presented for allogeneic HSCT. The GATA2 mutation was not present in either parent or an older sister, consistent with a de novo germline mutation. Her pre-transplant clinical course, HSCT regimen, and post-transplant course are described (Table 1). Her day 28 donor chimerisms were all 100% including myeloid, CD3 and natural killer (NK) subsets. On day +28, she developed a skin rash comprising 25–50% of her body surface area, nausea, vomiting and diarrhea. She underwent upper and lower gastrointestinal endoscopy for evaluation of GvHD. Biopsies from the upper GI tract were unremarkable; however, lower GI tract biopsies from the rectum were consistent with acute GvHD, which in conjunction with the clinical manifestations was considered grade II. Although the maximum aGvHD grade was limited to grade II, in addition to tacrolimus she required both systemic and topical steroids to control her skin and GI symptoms (oral budesonide). Steroids were required for 6 months and tacrolimus for 18 months post transplant. Bone marrow studies on day +100 demonstrated 96% donor chimerism with complete eradication of the trisomy eight cytogenetic abnormality present prior to transplant. Day 100 immune reconstitution studies (performed while on prednisone 20 mg daily and tacrolimus) demonstrated CD3+ cells of 285/μL, NK cells of 139/μL, CD19+ cells of 21/μL and resolution of monocytopenia to a count of 440 K/μL.

Table 1 Patient, transplant and GvHD characteristics
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Acknowledgements

We gratefully acknowledge the study participants and their families, referring medical care teams, the faculty and staff of the NIH. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.

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Authors and Affiliations

  1. Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    N N Shah & K Baird

  2. Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., NCI Campus at Frederick, Frederick, MD, USA

    M Parta

  3. Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

    K Baird

  4. George Washington School of Medicine and Health Sciences, Washington, DC, USA

    H Rafei

  5. Office of the Clinical Director, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    K Cole

  6. Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    S M Holland

  7. Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    D D Hickstein

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Correspondence to N N Shah.

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Shah, N., Parta, M., Baird, K. et al. Monozygotic twins with GATA2 deficiency: same haploidentical-related donor, different severity of GvHD. Bone Marrow Transplant 52, 1580–1582 (2017). https://doi.org/10.1038/bmt.2017.180

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