Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency - 04/09/15

Doi : 10.1016/j.jaci.2015.02.022

Omar K. Alkhairy, MD ^a,^b,^{^{∗
These authors have contributed equally to this work.}}, Ruy Perez-Becker, MD ^c,^{^{∗
These authors have contributed equally to this work.}}, Gertjan J. Driessen, MD, PhD ^d, Hassan Abolhassani, MD ^a,^e, Joris van Montfrans, MD, PhD ^f, Stephan Borte, MD ^a,^g, Sharon Choo, MD ^h, Ning Wang, PhD ^a, Kiki Tesselaar, PhD ^f, Mingyan Fang, PhD ⁱ, Kirsten Bienemann, MD ^j, Kaan Boztug, MD ^k, Ana Daneva, MSc ^d, Francoise Mechinaud, MD ^l, Thomas Wiesel, MD ^m, Christian Becker, MD ⁿ, Gregor Dückers, MD ^c, Kathrin Siepermann, MD ^c, Menno C. van Zelm, PhD ^o, Nima Rezaei, MD, PhD ^e,^p, Mirjam van der Burg, PhD ^o, Asghar Aghamohammadi, MD, PhD ^e, Markus G. Seidel, MD ^q,^r,^⁎ , Tim Niehues, MD ^c,^⁎ , Lennart Hammarström, MD, PhD ^a,^⁎
^a Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
^b Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia
^c Centre for Child and Adolescent Health, HELIOS Clinic Krefeld, Krefeld, Germany
ⁿ Institute for Hygiene and Laboratory Medicine, HELIOS Clinic Krefeld, Krefeld, Germany
^d Erasmus MC, Department of Pediatrics, Subdepartment of Pediatric Infectious Disease and Immunology, Rotterdam, The Netherlands
^e Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
^p Department of Immunology, School of Medicine, and Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
^f Departments of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital/University Medical Center Utrecht, Utrecht, The Netherlands
^g Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Leipzig, Germany
^h Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia
ⁱ BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, China
^j Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
^k 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
^q St Anna Children's Hospital, Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria
^l Children's Cancer Centre, Royal Children's Hospital, Melbourne, Australia
^m Children's Hospital, Vestische Youth Hospital, University of Witten/Herdecke, Datteln, Germany
^o Erasmus MC, Department of Immunology, Rotterdam, The Netherlands
^r Division of Pediatric Hematology Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria

^∗Corresponding author: Lennart Hammarström, MD, PhD, Department of Laboratory Medicine, Division of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.^∗Markus G. Seidel, MD, Medical University Graz, Auenbruggerpl. 38, A-8036 Graz, Austria.^∗Tim Niehues, MD, Centre for Child and Adolescent Health, HELIOS Klinikum Krefeld, Lutherplatz 40, D-47805 Krefeld, Germany.

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.

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Key words : CD27 deficiency, EBV-induced lymphoproliferation, Hodgkin lymphoma, hypogammaglobulinemia, hemophagocytic lymphohistiocytosis

Abbreviations used : ADCC, CVID, HLH, HLH-2004 protocol, HSCT, IM, IVIG, LPD, NK, SNP, TBS, WB, WES

Plan

Methods

Patients

Genomic DNA extraction

Whole-exome sequencing

Confirmatory sequencing

Flow cytometric immunophenotyping

Soluble CD27 ELISA

Results

Clinical features and mutations

Supported by the Jeffrey Modell Foundation, the Swedish Research Council, the German Federal Ministry of Education and Research (BMBF 1315883), and funds from the Karolinska Institutet.

Disclosure of potential conflict of interest: G. J. Driessen has received research support from Stichting vrienden van Sophia and Baxter. S. Borte has received research support from BMBF (funding no. 1315883) and is employed by St Georg Hospital Leipzig. K. Bienemann has received research support from Deutsche Forschungsgemeinschaft. G. Dückers has received payment for manuscript preparation from Arzneimittelverlag and has received travel support from Novartis. M. C. van Zelm has received research support from Erasmus Medical Center Fellowship and has a patent for IgE-expressing B cells (PCT-NL2001-050781). M. G. Seidel has received payment for development of educational presentations from Octapharma and Biotest and has received travel support from CSL and Baxter. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 136 - N° 3

P. 703 - septembre 2015 Retour au numéro

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Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency - 04/09/15

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