BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

Allergy and Clinical Immunology Department Functional Unit of Immunology SJD Clinic Hospital Sant Joan de Déu Institut de Recerca Pediàtrica Hospital Sant Joan de Déu Esplugues de Llobregat Spain

Center for Chronic Immunodeficiency and Molecular Pathology Department of Pathology University Medical Center University of Freiburg Freiburg Germany

Center for Chronic Immunodeficiency Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Center for Chronic Immunodeficiency Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany; Center for Pediatrics University Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

Center for Chronic Immunodeficiency Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany; Department of Pediatric Pneumology Allergy and Neonatology Hannover Medical School Hannover Germany; Center of Pediatric Surgery Hannover Medical School Hannover Germany

Center for Chronic Immunodeficiency Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany; Institute of Immunology and Transplantation Royal Free Hospital University College London London United Kingdom

Center for Chronic Immunodeficiency Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany; Institute of Medical Biometry and Statistics Faculty of Medicine and Medical Center University of Freiburg Freiburg Germany

Center for Chronic Immunodeficiency Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany; Spemann Graduate School of Biology and Medicine Freiburg University Freiburg Germany

Centre for Molecular Medicine Norway Nordic EMBL Partnership University of Oslo and Institute for Cancer Research University Hospital Oslo Oslo Norway

Children's Hospital of Philadelphia Perelman School of Medicine University of Pennsylvania Philadelphia Pa

Clinical Immunology and Allergy Unit Nottingham University Hospitals Nottingham United Kingdom

CLIP Department of Paediatric Haematology Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Clinical Immunology and Allergology Medical Faculty Masaryk University Brno Czech Republic; Department of Clinical Immunology and Allergology St Anne's University Hospital Brno Czech Republic

Department of Clinical Immunology and Allergy Royal Melbourne Hospital Melbourne Australia

Department of Community Pediatrics Perinatal and Maternal Medicine Tokyo Medical and Dental University Tokyo Japan

Department of Hematology Oslo University Hospital Oslo Norway

Department of Immunology and Histocompatibility Centre for Primary Immunodeficiencies Aghia Sophia Children's Hospital Athens Greece

Department of Immunology University Hospital Motol and 2nd Faculty of Medicine Charles University Prague Prague Czech Republic

Department of Immunology University Hospital Zurich University of Zurich Zurich Switzerland

Department of Infectious Diseases and General Internal Medicine University Hospital of Liège Liege Belgium

Department of Internal Medicine 3 University Hospital Regensburg Regensburg Germany

Department of Internal Medicine Radboudumc Center for Infectious Diseases Nijmegen The Netherlands

Department of Medicine Clinical Immunology and Allergy Division Centre Hospitalier de l'Université de Montréal Université de Montréal Montreal Quebec Canada

Department of Paediatric Gastroenterology Great North Children's Hospital Newcastle United Kingdom

Department of Pathology University Medical Center University of Freiburg Freiburg Germany

Department of Pediatric Immunology and Stem Cell Transplantation Dr von Hauner Children's Hospital Ludwig Maximilians Universität Munich Germany

Department of Pediatrics and Developmental Biology Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University Tokyo Japan

Department of Pediatrics Division of Pediatric Hematology Oncology Weill Cornell Medicine New York NY

Department of Pediatrics Hiroshima University Graduate School of Biomedical and Health Sciences Hiroshima Japan

Department of Pediatrics University Hospital Jena Jena Germany

Department of Pediatrics University Hospital Motol and 2nd Faculty of Medicine Charles University Prague Prague Czech Republic

Department of Pediatrics University Medical Center Ulm Ulm Germany

Department of Radiology Royal Free Hospital University College London London United Kingdom

Division of Bone Marrow Transplantation and Immune Deficiency Cincinnati Children's Hospital Medical Center Cincinnati Ohio

Division of Gastroenterology and Department of Pediatrics Harvard Medical School Boston Mass

Division of Gastroenterology Hepatology and Endoscopy Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston Mass

Division of Gastroenterology Hepatology and Endoscopy Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston Mass; Department of Medicine 1 University Medical Center Dresden Technical University Dresden Dresden Germany; Department of Internal Medicine 1 University Medical Center Schleswig Holstein Kiel Germany

Division of Immunology Boston Children's Hospital and Department of Pediatrics Harvard Medical School Boston Mass

Division of Immunology University Children's Hospital Zurich University of Zurich Zurich Switzerland

Division of Pediatric Gastroenterology Hepatology and Nutrition Department of Medicine Children's Hospital Boston Mass

Division of Rheumatology Department of Internal Medicine 5 University of Heidelberg Heidelberg Germany

Great North Children's Hospital Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine Newcastle University Newcastle United Kingdom

HELIOS Children's Hospital Krefeld Germany

Immunodeficiency Clinic Medical Outpatient Unit and Immunodeficiency Lab Department Biomedicine University Hospital Basel Switzerland

Immunology Team American Insurance Montevideo Uruguay

Institute for Computational Biomedicine Department of Physiology and Biophysics Weill Cornell Medical College New York NY

Institute for Transfusion Medicine and Gene Therapy University Medical Center Freiburg Freiburg Germany

Institute of Clinical Molecular Biology Christian Albrechts University of Kiel Kiel Germany

Institute of Immunology and Transplantation Royal Free Hospital University College London London United Kingdom

Institute of Immunology University Hospital Heidelberg Heidelberg Germany

Molecular Genetics Laboratory Centre for Cardiovascular Surgery and Transplantation Brno Czech Republic; Medical Genomics RG Central European Institute of Technology Masaryk University Brno Czech Republic

Mount Sinai Hospital Mount Sinai St Luke's and Mount Sinai West Department of Medicine Allergy and Immunology New York NY

Pediatrics Clinic and Institute for Molecular Medicine A Nocivelli Department of Clinical and Experimental Sciences University of Brescia ASST Spedali Civili of Brescia Brescia Italy

Sección de Infectología e Inmunopatología Unidad de Pediatría Hospital Virgen del Rocío Instituto de Biomedicina de Sevilla Seville Spain

Section of Allergy and Clinical Immunology Yale University School of Medicine New Haven Conn

Servei de Genòmica Departament de Ciències Experimentals i de la Salut Universitat Pompeu Fabra Parc de Recerca Biomèdica de Barcelona Barcelona Spain

UCL Institute of Immunity and Transplantation Royal Free Hospital London United Kingdom

Unidad de Inmunología Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla Seville Spain

University of Manchester Royal Manchester Children's Hospital Manchester United Kingdom

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J Allergy Clin Immunol. 2018 Dec;142(6):1762-1764.e1. doi: 10.1016/j.jaci.2018.10.006. PubMed

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Do common infections trigger disease-onset or -severity in CTLA-4 insufficiency?

Mutual alteration of NOD2-associated Blau syndrome and IFNγR1 deficiency