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

Omar K. Alkhairy; Ruy Perez-Becker; Gertjan J. Driessen; Hassan Abolhassani; JM van Montfrans; Stephan Borte; Sharon Choo; Ning Wang; Kiki Tesselaar; Mingyan Fang; Kirsten Bienemann; Kaan Boztug; Ana Daneva; Francoise Mechinaud; Thomas Wiesel; Christian Becker; Gregor Duckers; Kathrin Siepermann; Menno C. van Zelm; Nima Rezaei; Mirjam van der Burg; Asghar Aghamohammadi; Markus G. Seidel; Tim Niehues; Lennart Hammarstrom

doi:10.1016/j.jaci.2015.02.022

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

Omar K. Alkhairy, Ruy Perez-Becker, Gertjan J. Driessen, Hassan Abolhassani, JM van Montfrans, Stephan Borte, Sharon Choo, Ning Wang, Kiki Tesselaar, Mingyan Fang, Kirsten Bienemann, Kaan Boztug, Ana Daneva, Francoise Mechinaud, Thomas Wiesel, Christian Becker, Gregor Duckers, Kathrin Siepermann, Menno C. van Zelm, Nima RezaeiMirjam van der Burg, Asghar Aghamohammadi, Markus G. Seidel, Tim Niehues, Lennart Hammarstrom^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 solubleCD27 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.

Original language	English
Pages (from-to)	703-+
Number of pages	20
Journal	Journal of Allergy and Clinical Immunology
Volume	136
Issue number	3
DOIs	https://doi.org/10.1016/j.jaci.2015.02.022
Publication status	Published - Sept 2015

Keywords

CD27 deficiency
EBV-induced lymphoproliferation
Hodgkin lymphoma
hypogammaglobulinemia
hemophagocytic lymphohistiocytosis
EPSTEIN-BARR-VIRUS
COMMON VARIABLE IMMUNODEFICIENCY
NATURAL-KILLER-CELLS
T-CELLS
LYMPHOPROLIFERATIVE DISORDER
CD27-CD70 INTERACTIONS
READ ALIGNMENT
EBV INFECTION
SCID MICE
NK CELLS

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Alkhairy, O. K., Perez-Becker, R., Driessen, G. J., Abolhassani, H., van Montfrans, JM., Borte, S., Choo, S., Wang, N., Tesselaar, K., Fang, M., Bienemann, K., Boztug, K., Daneva, A., Mechinaud, F., Wiesel, T., Becker, C., Duckers, G., Siepermann, K., van Zelm, M. C., ... Hammarstrom, L. (2015). Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency. Journal of Allergy and Clinical Immunology, 136(3), 703-+. https://doi.org/10.1016/j.jaci.2015.02.022

@article{102d7645ad8f4bfcb88091a05c536f72,

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 solubleCD27 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.",

keywords = "CD27 deficiency, EBV-induced lymphoproliferation, Hodgkin lymphoma, hypogammaglobulinemia, hemophagocytic lymphohistiocytosis, EPSTEIN-BARR-VIRUS, COMMON VARIABLE IMMUNODEFICIENCY, NATURAL-KILLER-CELLS, T-CELLS, LYMPHOPROLIFERATIVE DISORDER, CD27-CD70 INTERACTIONS, READ ALIGNMENT, EBV INFECTION, SCID MICE, NK CELLS",

author = "Alkhairy, {Omar K.} and Ruy Perez-Becker and Driessen, {Gertjan J.} and Hassan Abolhassani and {van Montfrans}, JM and Stephan Borte and Sharon Choo and Ning Wang and Kiki Tesselaar and Mingyan Fang and Kirsten Bienemann and Kaan Boztug and Ana Daneva and Francoise Mechinaud and Thomas Wiesel and Christian Becker and Gregor Duckers and Kathrin Siepermann and {van Zelm}, {Menno C.} and Nima Rezaei and {van der Burg}, Mirjam and Asghar Aghamohammadi and Seidel, {Markus G.} and Tim Niehues and Lennart Hammarstrom",

year = "2015",

month = sep,

doi = "10.1016/j.jaci.2015.02.022",

language = "English",

volume = "136",

pages = "703--+",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "3",

}

Alkhairy, OK, Perez-Becker, R, Driessen, GJ, Abolhassani, H, van Montfrans, JM, Borte, S, Choo, S, Wang, N, Tesselaar, K, Fang, M, Bienemann, K, Boztug, K, Daneva, A, Mechinaud, F, Wiesel, T, Becker, C, Duckers, G, Siepermann, K, van Zelm, MC, Rezaei, N, van der Burg, M, Aghamohammadi, A, Seidel, MG, Niehues, T & Hammarstrom, L 2015, 'Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency', Journal of Allergy and Clinical Immunology, vol. 136, no. 3, pp. 703-+. https://doi.org/10.1016/j.jaci.2015.02.022

TY - JOUR

T1 - Novel mutations in TNFRSF7/CD27

T2 - Clinical, immunologic, and genetic characterization of human CD27 deficiency

AU - Alkhairy, Omar K.

AU - Perez-Becker, Ruy

AU - Driessen, Gertjan J.

AU - Abolhassani, Hassan

AU - van Montfrans, JM

AU - Borte, Stephan

AU - Choo, Sharon

AU - Wang, Ning

AU - Tesselaar, Kiki

AU - Fang, Mingyan

AU - Bienemann, Kirsten

AU - Boztug, Kaan

AU - Daneva, Ana

AU - Mechinaud, Francoise

AU - Wiesel, Thomas

AU - Becker, Christian

AU - Duckers, Gregor

AU - Siepermann, Kathrin

AU - van Zelm, Menno C.

AU - Rezaei, Nima

AU - van der Burg, Mirjam

AU - Aghamohammadi, Asghar

AU - Seidel, Markus G.

AU - Niehues, Tim

AU - Hammarstrom, Lennart

PY - 2015/9

Y1 - 2015/9

N2 - 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 solubleCD27 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.

AB - 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 solubleCD27 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.

KW - CD27 deficiency

KW - EBV-induced lymphoproliferation

KW - Hodgkin lymphoma

KW - hypogammaglobulinemia

KW - hemophagocytic lymphohistiocytosis

KW - EPSTEIN-BARR-VIRUS

KW - COMMON VARIABLE IMMUNODEFICIENCY

KW - NATURAL-KILLER-CELLS

KW - T-CELLS

KW - LYMPHOPROLIFERATIVE DISORDER

KW - CD27-CD70 INTERACTIONS

KW - READ ALIGNMENT

KW - EBV INFECTION

KW - SCID MICE

KW - NK CELLS

U2 - 10.1016/j.jaci.2015.02.022

DO - 10.1016/j.jaci.2015.02.022

M3 - Article

C2 - 25843314

SN - 0091-6749

VL - 136

SP - 703-+

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 3

ER -

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

Abstract

Keywords

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