Omar K Alkhairy1, Ruy Perez-Becker2, Gertjan J Driessen3, Hassan Abolhassani4, Joris van Montfrans5, Stephan Borte6, Sharon Choo7, Ning Wang8, Kiki Tesselaar5, Mingyan Fang9, Kirsten Bienemann10, Kaan Boztug11, Ana Daneva3, Francoise Mechinaud12, Thomas Wiesel13, Christian Becker14, Gregor Dückers2, Kathrin Siepermann2, Menno C van Zelm15, Nima Rezaei16, Mirjam van der Burg15, Asghar Aghamohammadi17, Markus G Seidel18, Tim Niehues19, Lennart Hammarström20. 1. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia. 2. Centre for Child and Adolescent Health, HELIOS Clinic Krefeld, Krefeld, Germany. 3. Erasmus MC, Department of Pediatrics, Subdepartment of Pediatric Infectious Disease and Immunology, Rotterdam, The Netherlands. 4. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. 5. Departments of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital/University Medical Center Utrecht, Utrecht, The Netherlands. 6. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Leipzig, Germany. 7. Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia. 8. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. 9. BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, China. 10. Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany. 11. CeMM Research Center of Molecular Medicine, Austrian Academy of Sciences, and Division of Neonatal Medicine and Intensive Care, Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria. 12. Children's Cancer Centre, Royal Children's Hospital, Melbourne, Australia. 13. Children's Hospital, Vestische Youth Hospital, University of Witten/Herdecke, Datteln, Germany. 14. Institute for Hygiene and Laboratory Medicine, HELIOS Clinic Krefeld, Krefeld, Germany. 15. Erasmus MC, Department of Immunology, Rotterdam, The Netherlands. 16. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, and Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran. 17. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. 18. St Anna Children's Hospital, Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria; Division of Pediatric Hematology Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria. Electronic address: markus.seidel@medunigraz.at. 19. Centre for Child and Adolescent Health, HELIOS Clinic Krefeld, Krefeld, Germany. Electronic address: tim.niehues@helios-kliniken.de. 20. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. Electronic address: lennart.hammarstrom@ki.se.
Abstract
BACKGROUND: The clinical and immunologic features of CD27 deficiency remain obscure because only a few patients have been identified to date. OBJECTIVE: We sought to identify novel mutations in TNFRSF7/CD27 and to provide an overview of clinical, immunologic, and laboratory phenotypes in patients with CD27 deficiency. METHODS: Review of the medical records and molecular, genetic, and flow cytometric analyses of the patients and family members were performed. Treatment outcomes of previously described patients were followed up. RESULTS: In addition to the previously reported homozygous mutations c.G24A/p.W8X (n = 2) and c.G158A/p.C53Y (n = 8), 4 novel mutations were identified: homozygous missense c.G287A/p.C96Y (n = 4), homozygous missense c.C232T/p.R78W (n = 1), heterozygous nonsense c.C30A/p.C10X (n = 1), and compound heterozygous c.C319T/p.R107C-c.G24A/p.W8X (n = 1). EBV-associated lymphoproliferative disease/hemophagocytic lymphohistiocytosis, Hodgkin lymphoma, uveitis, and recurrent infections were the predominant clinical features. Expression of cell-surface and soluble CD27 was significantly reduced in patients and heterozygous family members. Immunoglobulin substitution therapy was administered in 5 of the newly diagnosed cases. CONCLUSION: CD27 deficiency is potentially fatal and should be excluded in all cases of severe EBV infections to minimize diagnostic delay. Flow cytometric immunophenotyping offers a reliable initial test for CD27 deficiency. Determining the precise role of CD27 in immunity against EBV might provide a framework for new therapeutic concepts.
BACKGROUND: The clinical and immunologic features of CD27 deficiency remain obscure because only a few patients have been identified to date. OBJECTIVE: We sought to identify novel mutations in TNFRSF7/CD27 and to provide an overview of clinical, immunologic, and laboratory phenotypes in patients with CD27 deficiency. METHODS: Review of the medical records and molecular, genetic, and flow cytometric analyses of the patients and family members were performed. Treatment outcomes of previously described patients were followed up. RESULTS: In addition to the previously reported homozygous mutations c.G24A/p.W8X (n = 2) and c.G158A/p.C53Y (n = 8), 4 novel mutations were identified: homozygous missense c.G287A/p.C96Y (n = 4), homozygous missense c.C232T/p.R78W (n = 1), heterozygous nonsense c.C30A/p.C10X (n = 1), and compound heterozygous c.C319T/p.R107C-c.G24A/p.W8X (n = 1). EBV-associated lymphoproliferative disease/hemophagocytic lymphohistiocytosis, Hodgkin lymphoma, uveitis, and recurrent infections were the predominant clinical features. Expression of cell-surface and soluble CD27 was significantly reduced in patients and heterozygous family members. Immunoglobulin substitution therapy was administered in 5 of the newly diagnosed cases. CONCLUSION:CD27 deficiency is potentially fatal and should be excluded in all cases of severe EBV infections to minimize diagnostic delay. Flow cytometric immunophenotyping offers a reliable initial test for CD27 deficiency. Determining the precise role of CD27 in immunity against EBV might provide a framework for new therapeutic concepts.
Authors: Carole Le Coz; Bertram Bengsch; Caroline Khanna; Melissa Trofa; Takuya Ohtani; Brian E Nolan; Sarah E Henrickson; Michele P Lambert; Taylor Olmsted Kim; Jenny M Despotovic; Scott Feldman; Olajumoke O Fadugba; Patricia Takach; Melanie Ruffner; Soma Jyonouchi; Jennifer Heimall; Kathleen E Sullivan; E John Wherry; Neil Romberg Journal: J Allergy Clin Immunol Date: 2019-08-22 Impact factor: 10.793