Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency

• Published in: Journal of allergy and clinical immunology Vol. 136; no. 3; pp. 703 - 712.e10
• Main Authors: Alkhairy, Omar K., Perez-Becker, Ruy, Driessen, Gertjan J., Abolhassani, Hassan, van Montfrans, Joris, Borte, Stephan, Choo, Sharon, Wang, Ning, Tesselaar, Kiki, Fang, Mingyan, Bienemann, Kirsten, Boztug, Kaan, Daneva, Ana, Mechinaud, Francoise, Wiesel, Thomas, Becker, Christian, Dückers, Gregor, Siepermann, Kathrin, van Zelm, Menno C., Rezaei, Nima, van der Burg, Mirjam, Aghamohammadi, Asghar, Seidel, Markus G., Niehues, Tim, Hammarström, Lennart
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2015; Elsevier Limited
• Subjects: Adolescent; Allergy and Immunology; Antigens; CD27 deficiency; Child, Preschool; Cytotoxicity; Deoxyribonucleic acid; DNA; EBV-induced lymphoproliferation; Epstein-Barr virus; Epstein-Barr Virus Infections - diagnosis; Epstein-Barr Virus Infections - genetics; Epstein-Barr Virus Infections - immunology; Epstein-Barr Virus Infections - pathology; Exome; Families & family life; Female; Flow Cytometry; Genomes; hemophagocytic lymphohistiocytosis; Heterozygote; Hodgkin Disease - diagnosis; Hodgkin Disease - genetics; Hodgkin Disease - immunology; Hodgkin Disease - pathology; Hodgkin lymphoma; Homozygote; Human subjects; Humans; hypogammaglobulinemia; Immunophenotyping; Infant; Kinases; Lymphocytes; Lymphohistiocytosis, Hemophagocytic - diagnosis; Lymphohistiocytosis, Hemophagocytic - genetics; Lymphohistiocytosis, Hemophagocytic - immunology; Lymphohistiocytosis, Hemophagocytic - pathology; Lymphoproliferative Disorders - diagnosis; Lymphoproliferative Disorders - genetics; Lymphoproliferative Disorders - immunology; Lymphoproliferative Disorders - pathology; Male; Mutation; Proteins; Quality; T cell receptors; Tumor Necrosis Factor Receptor Superfamily, Member 7 - deficiency; Tumor Necrosis Factor Receptor Superfamily, Member 7 - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 7 - immunology; Uveitis - diagnosis; Uveitis - genetics; Uveitis - immunology; Uveitis - pathology; Young Adult; LPD; IM; TBS; WES; EBV-induced lymphoproliferation; HLH; CD27 deficiency; hemophagocytic lymphohistiocytosis; IVIG; hypogammaglobulinemia; WB; CVID; SNP; HLH-2004 protocol; ADCC; HSCT; NK; Hodgkin lymphoma; Common variable immunodeficiency; Western blotting; Tris-buffered saline; Dexamethasone, etoposide, and cyclosporine A; Hematopoietic stem cell transplantation; Antibody-dependent cell-mediated cytotoxicity; Lymphoproliferative disease; Whole-exome sequencing; Intravenous immunoglobulin; Infectious mononucleosis; Natural killer; Single nucleotide polymorphism
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2015.02.022

The clinical and immunologic features of CD27 deficiency remain obscure because only a few patients have been identified to date. 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. 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. 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. 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.