title: Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency.
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.
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Omar K
authors.initials: OK
authors.lastname: Alkhairy
authors.affiliation: Centre for Child and Adolescent Health, HELIOS Clinic Krefeld, Krefeld, Germany.
authors.forename: Ruy
authors.initials: R
authors.lastname: Perez-Becker
authors.affiliation: Erasmus MC, Department of Pediatrics, Subdepartment of Pediatric Infectious Disease and Immunology, Rotterdam, The Netherlands.
authors.forename: Gertjan J
authors.initials: GJ
authors.lastname: Driessen
authors.affiliation: 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.
authors.forename: Hassan
authors.initials: H
authors.lastname: Abolhassani
authors.affiliation: Departments of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital/University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: van Montfrans
authors.affiliation: 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.
authors.forename: Stephan
authors.initials: S
authors.lastname: Borte
authors.affiliation: Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Sharon
authors.initials: S
authors.lastname: Choo
authors.affiliation: Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Departments of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital/University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kiki
authors.initials: K
authors.lastname: Tesselaar
authors.affiliation: BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, China.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Fang
authors.affiliation: Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Bienemann
authors.affiliation: 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.
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
authors.affiliation: Erasmus MC, Department of Pediatrics, Subdepartment of Pediatric Infectious Disease and Immunology, Rotterdam, The Netherlands.
authors.forename: Ana
authors.initials: A
authors.lastname: Daneva
authors.affiliation: Children's Cancer Centre, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Francoise
authors.initials: F
authors.lastname: Mechinaud
authors.affiliation: Children's Hospital, Vestische Youth Hospital, University of Witten/Herdecke, Datteln, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiesel
authors.affiliation: Institute for Hygiene and Laboratory Medicine, HELIOS Clinic Krefeld, Krefeld, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.affiliation: Centre for Child and Adolescent Health, HELIOS Clinic Krefeld, Krefeld, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Dückers
authors.affiliation: Centre for Child and Adolescent Health, HELIOS Clinic Krefeld, Krefeld, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Siepermann
authors.affiliation: Erasmus MC, Department of Immunology, Rotterdam, The Netherlands.
authors.forename: Menno C
authors.initials: MC
authors.lastname: van Zelm
authors.affiliation: 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.
authors.forename: Nima
authors.initials: N
authors.lastname: Rezaei
authors.affiliation: Erasmus MC, Department of Immunology, Rotterdam, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.affiliation: Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Asghar
authors.initials: A
authors.lastname: Aghamohammadi
authors.affiliation: 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.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Seidel
authors.affiliation: Centre for Child and Adolescent Health, HELIOS Clinic Krefeld, Krefeld, Germany. Electronic address: tim.niehues@helios-kliniken.de.
authors.forename: Tim
authors.initials: T
authors.lastname: Niehues
authors.affiliation: Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. Electronic address: lennart.hammarstrom@ki.se.
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
mesh_terms: D000293:Adolescent; D002675:Child, Preschool; D020031:Epstein-Barr Virus Infections / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D059472:Exome; D005260:Female; D005434:Flow Cytometry; D006579:Heterozygote; D006689:Hodgkin Disease / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006720:Homozygote; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D009154:Mutation; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D014605:Uveitis / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D055815:Young Adult
chemical_list: D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
keywords: CD27 deficiency; EBV-induced lymphoproliferation; Hodgkin lymphoma; hemophagocytic lymphohistiocytosis; hypogammaglobulinemia