title: Unrelated Hematopoietic Cell Transplantation in a Patient with Combined Immunodeficiency with Granulomatous Disease and Autoimmunity Secondary to RAG Deficiency.
abstract: The use of HLA-identical hematopoietic stem cell transplantation (HSCT) demonstrates overall survival rates greater than 75 % for T-B-NK+ severe combined immunodeficiency secondary to pathogenic mutation of recombinase activating genes 1 and 2 (RAG1/2). Limited data exist regarding the use of HSCT in patients with hypomorphic RAG variants marked by greater preservation of RAG activity and associated phenotypes such as granulomatous disease in combination with autoimmunity. We describe a 17-year-old with combined immunodeficiency and immune dysregulation characterized by granulomatous lung disease and autoimmunity secondary to compound heterozygous RAG mutations. A myeloablative reduced toxicity HSCT was completed using an unrelated bone marrow donor. With the increasing cases of immune dysregulation being discovered with hypomorphic RAG variants, the use of HSCT may advance to the forefront of treatment. This case serves to discuss indications of HSCT, approaches to preparative therapy, and the potential complications in this growing cohort of patients with immune dysregulation and RAG deficiency.
authors.affiliation: Division of Hematology/Oncology, CHOC Children's Hospital, 1201 W. La Veta Avenue, Orange, CA, 92868, USA. tamidjohn@gmail.com.
authors.forename: Tami
authors.initials: T
authors.lastname: John
authors.affiliation: Division of Immunology, MassGeneral Hospital for Children, 55 Fruit Street, Boston, MA, 02114, USA.
authors.forename: Jolan E
authors.initials: JE
authors.lastname: Walter
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
authors.forename: Catherina
authors.initials: C
authors.lastname: Schuetz
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Utah School of Medicine, 81 Mario Capecchi Drive, Salt Lake City, UT, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Chen
authors.affiliation: Allergy and Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Roshini S
authors.initials: RS
authors.lastname: Abraham
authors.affiliation: Bone Marrow Transplantation Unit, Federal University of Paraná, Rua XV de Novembro, 1299 - Centro, Curitiba, PR, 80060-000, Brazil.
authors.forename: Carmem
authors.initials: C
authors.lastname: Bonfim
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Boyce
authors.affiliation: Allergy and Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Avni Y
authors.initials: AY
authors.lastname: Joshi
authors.affiliation: NIAID, National Institutes of Health, Building 10CRC, Room 5-3940, 10 Center Drive, MSC 1456, Bethesda, MD, 20892-9806, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kang
authors.affiliation: Disciplina de Alergia, Imunologia Clínica e Reumatologia - UNIFESP, Sao Paulo, Brazil.
authors.forename: Beatriz Tavares Costa
authors.initials: BT
authors.lastname: Carvalho
authors.affiliation: Division of Hematology, CHOC Children's Hospital, 1201 W. La Veta Avenue, Orange, CA, 92868, USA.
authors.forename: Arash
authors.initials: A
authors.lastname: Mahajerin
authors.affiliation: Division of Hematology, CHOC Children's Hospital, 1201 W. La Veta Avenue, Orange, CA, 92868, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Nugent
authors.affiliation: Division of Hematology, CHOC Children's Hospital, 1201 W. La Veta Avenue, Orange, CA, 92868, USA.
authors.forename: Geetha
authors.initials: G
authors.lastname: Puthenveetil
authors.affiliation: Division of Hematology, CHOC Children's Hospital, 1201 W. La Veta Avenue, Orange, CA, 92868, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Soni
authors.affiliation: NIAID, National Institutes of Health, Building 10CRC, Room 5-3940, 10 Center Drive, MSC 1456, Bethesda, MD, 20892-9806, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Pediatrics, University of California, San Francisco, Box 1278, UCSF, San Francisco, CA, 94143, USA.
authors.forename: Morton J
authors.initials: MJ
authors.lastname: Cowan
authors.affiliation: Division of Immunology, Children's Hospital Boston, Karp Building, Room 10217, 1 Blackfan Circle, Boston, MA, 02115, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Notarangelo
authors.affiliation: Division of Hematology, CHOC Children's Hospital, 1201 W. La Veta Avenue, Orange, CA, 92868, USA.
authors.forename: David
authors.initials: D
authors.lastname: Buchbinder
mesh_terms: D000293:Adolescent; D000483:Alleles; D001327:Autoimmune Diseases / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D015415:Biomarkers; D006105:Granulomatous Disease, Chronic / Q000150:complications* / Q000175:diagnosis; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D016130:Immunophenotyping; D007239:Infections / Q000175:diagnosis / Q000209:etiology / Q000628:therapy; D018655:Lymphocyte Count; D009154:Mutation; D016511:Severe Combined Immunodeficiency / Q000150:complications* / Q000175:diagnosis / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D018398:Homeodomain Proteins; D016756:Immunoglobulins, Intravenous; C064658:RAG-1 protein
keywords: RAG deficiency; autoimmunity; bone marrow transplantation; immune dysregulation; primary immunodeficiency