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Blood. 2017 Sep 21;130(12):1456-1467. doi: 10.1182/blood-2017-03-771600. Epub 2017 Jul 5.

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations.

Author information

1
Study Center for Immunodeficiencies, Assistance Publique-Hopitaux de Paris, Necker Hospital for Sick Children, Paris, France.
2
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
3
Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
4
Division of Pediatric Dermatology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
5
Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL.
6
Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
7
Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
8
Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
9
Pediatric Onco-Hemato-Immunology Unit, University Hospital, Angers, France.
10
Hospices Civils de Lyon, Genetic Unit, School of Medicine, University Lyon 1, Bron, France.
11
Division of Bone Marrow Transplant, Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University, Atlanta, GA.
12
Division of Immunology and.
13
Division of Stem Cell Transplantation, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
14
Department of Biochemistry and Genetics, University Hospital, Angers, France.
15
Clinical Immunology Department and Program of Hematopoietic Stem Cell Transplantation, National Institute of Pediatrics, Mexico City, Mexico.
16
University College London Great Ormond Street Institute of Child Health, London, United Kingdom.
17
Immunodeficiency Diagnosis and Treatment Program, Department of Pediatrics, National Jewish Health, Denver, CO.
18
Department of Pediatric Dermatology, Oregon Health & Science University, Portland, OR.
19
Paediatric Haematology, Starship Blood and Cancer Centre, Starship Hospital, Auckland, New Zealand.
20
Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom.
21
Center for Chronic Immunodeficiency, University of Freiburg, Freiburg, Germany.
22
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
23
Paediatric Immunology Department, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
24
Department of Pediatrics and.
25
Department of Immunology, Institute of Biomedical Sciences, Federal University of São Paulo, São Paulo, Brazil.
26
Blood and Marrow Transplant Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
27
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
28
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
29
Imagine Institute, Paris Descartes University, Paris, France.
30
Pediatric Hematology-Immunology and Rheumatology Unit, Assistance Publique-Hopitaux de Paris, Necker Hospital for Sick Children, Paris, France.
31
National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
32
Oxford University Hospitals NHS Foundation Trust, National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.
33
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France.
34
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.
35
Howard Hughes Medical Institute, New York, NY; and.
36
Center for Human Immunobiology, Section of Immunology, Allergy and Rheumatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX.

Abstract

X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.

PMID:
28679735
PMCID:
PMC5609334
DOI:
10.1182/blood-2017-03-771600
[Indexed for MEDLINE]
Free PMC Article

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