CD70 deficiency due to a novel mutation in a patient with severe chronic EBV infection presenting as a periodic fever

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Abstract

Primary immunodeficiencies with selective susceptibility to EBV infection are rare conditions associated with severe lymphoproliferation. We followed a patient, son of consanguineous parents, referred to our center for recurrent periodic episodes of fever associated with tonsillitis and adenitis started after an infectious mononucleosis and responsive to oral steroid. An initial diagnosis of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome was done. In the following months, recurrent respiratory infections and episodes of keratitis were also observed, together with a progressive reduction of immunoglobulin levels and an increase of CD20+ cells. Cell sorting and EBV PCR showed 25,000 copies for 100,000 leukocytes with predominant infection of B lymphocytes. Lymph node's biopsy revealed reactive lymphadenopathy with paracortical involvement consistent with a chronic EBV infection. Molecular analysis of XIAP, SHA2D1A, ITK, and CD27 genes did not detect any pathogenic mutation. The patients underwent repeated courses of anti-CD20 therapy with only a partial control of the disease, followed by stem cell transplantation with a complete normalization of clinical and immunological features. Whole exome sequencing of the trio was performed. Among the variants identified, a novel loss of function homozygous c.163-2A > G mutation of the CD70 gene, affecting the exon 2 AG-acceptor splice site, fit the expected recessive model of inheritance. Indeed, deficiency of both CD27, and, more recently, of its ligand CD70, has been reported as a cause of EBV-driven lymphoproliferation and hypogammaglobulinemia. Cell surface analysis of patient-derived PHA-T cell blasts and EBV-transformed lymphoblastoid cell lines confirmed absence of CD70 expression. In conclusion, we describe a case of severe chronic EBV infection caused by a novel mutation of CD70 presenting with recurrent periodic fever.

Original languageEnglish
Article number2015
JournalFrontiers in Immunology
Volume8
Issue numberJAN
DOIs
Publication statusPublished - Jan 29 2018

Fingerprint

Epstein-Barr Virus Infections
Human Herpesvirus 4
Lymphadenitis
Fever
Mutation
Exome
Aphthous Stomatitis
Agammaglobulinemia
Tonsillitis
Infectious Mononucleosis
Transformed Cell Line
RNA Splice Sites
Pharyngitis
Keratitis
Stem Cell Transplantation
Nuclear Family
Respiratory Tract Infections
Genes
Immunoglobulins
Exons

Keywords

  • Aphthous stomatitis
  • CD70 deficiency
  • Cervical adenitis syndrome
  • Ebstein-Barr virus
  • Hematopoietic stem cell transplantation
  • Periodic fever
  • Pharyngitis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

@article{646c04fd3ba64936a1fdc59e23f12ad3,
title = "CD70 deficiency due to a novel mutation in a patient with severe chronic EBV infection presenting as a periodic fever",
abstract = "Primary immunodeficiencies with selective susceptibility to EBV infection are rare conditions associated with severe lymphoproliferation. We followed a patient, son of consanguineous parents, referred to our center for recurrent periodic episodes of fever associated with tonsillitis and adenitis started after an infectious mononucleosis and responsive to oral steroid. An initial diagnosis of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome was done. In the following months, recurrent respiratory infections and episodes of keratitis were also observed, together with a progressive reduction of immunoglobulin levels and an increase of CD20+ cells. Cell sorting and EBV PCR showed 25,000 copies for 100,000 leukocytes with predominant infection of B lymphocytes. Lymph node's biopsy revealed reactive lymphadenopathy with paracortical involvement consistent with a chronic EBV infection. Molecular analysis of XIAP, SHA2D1A, ITK, and CD27 genes did not detect any pathogenic mutation. The patients underwent repeated courses of anti-CD20 therapy with only a partial control of the disease, followed by stem cell transplantation with a complete normalization of clinical and immunological features. Whole exome sequencing of the trio was performed. Among the variants identified, a novel loss of function homozygous c.163-2A > G mutation of the CD70 gene, affecting the exon 2 AG-acceptor splice site, fit the expected recessive model of inheritance. Indeed, deficiency of both CD27, and, more recently, of its ligand CD70, has been reported as a cause of EBV-driven lymphoproliferation and hypogammaglobulinemia. Cell surface analysis of patient-derived PHA-T cell blasts and EBV-transformed lymphoblastoid cell lines confirmed absence of CD70 expression. In conclusion, we describe a case of severe chronic EBV infection caused by a novel mutation of CD70 presenting with recurrent periodic fever.",
keywords = "Aphthous stomatitis, CD70 deficiency, Cervical adenitis syndrome, Ebstein-Barr virus, Hematopoietic stem cell transplantation, Periodic fever, Pharyngitis",
author = "Roberta Caorsi and Marta Rusmini and Stefano Volpi and Sabrina Chiesa and Claudia Pastorino and Sementa, {Angela Rita} and Paolo Uva and Alice Grossi and Edoardo Lanino and Maura Faraci and Francesca Minoia and Sara Signa and Paolo Picco and Alberto Martini and Isabella Ceccherini and Marco Gattorno",
year = "2018",
month = "1",
day = "29",
doi = "10.3389/fimmu.2017.02015",
language = "English",
volume = "8",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media S.A.",
number = "JAN",

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TY - JOUR

T1 - CD70 deficiency due to a novel mutation in a patient with severe chronic EBV infection presenting as a periodic fever

AU - Caorsi, Roberta

AU - Rusmini, Marta

AU - Volpi, Stefano

AU - Chiesa, Sabrina

AU - Pastorino, Claudia

AU - Sementa, Angela Rita

AU - Uva, Paolo

AU - Grossi, Alice

AU - Lanino, Edoardo

AU - Faraci, Maura

AU - Minoia, Francesca

AU - Signa, Sara

AU - Picco, Paolo

AU - Martini, Alberto

AU - Ceccherini, Isabella

AU - Gattorno, Marco

PY - 2018/1/29

Y1 - 2018/1/29

N2 - Primary immunodeficiencies with selective susceptibility to EBV infection are rare conditions associated with severe lymphoproliferation. We followed a patient, son of consanguineous parents, referred to our center for recurrent periodic episodes of fever associated with tonsillitis and adenitis started after an infectious mononucleosis and responsive to oral steroid. An initial diagnosis of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome was done. In the following months, recurrent respiratory infections and episodes of keratitis were also observed, together with a progressive reduction of immunoglobulin levels and an increase of CD20+ cells. Cell sorting and EBV PCR showed 25,000 copies for 100,000 leukocytes with predominant infection of B lymphocytes. Lymph node's biopsy revealed reactive lymphadenopathy with paracortical involvement consistent with a chronic EBV infection. Molecular analysis of XIAP, SHA2D1A, ITK, and CD27 genes did not detect any pathogenic mutation. The patients underwent repeated courses of anti-CD20 therapy with only a partial control of the disease, followed by stem cell transplantation with a complete normalization of clinical and immunological features. Whole exome sequencing of the trio was performed. Among the variants identified, a novel loss of function homozygous c.163-2A > G mutation of the CD70 gene, affecting the exon 2 AG-acceptor splice site, fit the expected recessive model of inheritance. Indeed, deficiency of both CD27, and, more recently, of its ligand CD70, has been reported as a cause of EBV-driven lymphoproliferation and hypogammaglobulinemia. Cell surface analysis of patient-derived PHA-T cell blasts and EBV-transformed lymphoblastoid cell lines confirmed absence of CD70 expression. In conclusion, we describe a case of severe chronic EBV infection caused by a novel mutation of CD70 presenting with recurrent periodic fever.

AB - Primary immunodeficiencies with selective susceptibility to EBV infection are rare conditions associated with severe lymphoproliferation. We followed a patient, son of consanguineous parents, referred to our center for recurrent periodic episodes of fever associated with tonsillitis and adenitis started after an infectious mononucleosis and responsive to oral steroid. An initial diagnosis of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome was done. In the following months, recurrent respiratory infections and episodes of keratitis were also observed, together with a progressive reduction of immunoglobulin levels and an increase of CD20+ cells. Cell sorting and EBV PCR showed 25,000 copies for 100,000 leukocytes with predominant infection of B lymphocytes. Lymph node's biopsy revealed reactive lymphadenopathy with paracortical involvement consistent with a chronic EBV infection. Molecular analysis of XIAP, SHA2D1A, ITK, and CD27 genes did not detect any pathogenic mutation. The patients underwent repeated courses of anti-CD20 therapy with only a partial control of the disease, followed by stem cell transplantation with a complete normalization of clinical and immunological features. Whole exome sequencing of the trio was performed. Among the variants identified, a novel loss of function homozygous c.163-2A > G mutation of the CD70 gene, affecting the exon 2 AG-acceptor splice site, fit the expected recessive model of inheritance. Indeed, deficiency of both CD27, and, more recently, of its ligand CD70, has been reported as a cause of EBV-driven lymphoproliferation and hypogammaglobulinemia. Cell surface analysis of patient-derived PHA-T cell blasts and EBV-transformed lymphoblastoid cell lines confirmed absence of CD70 expression. In conclusion, we describe a case of severe chronic EBV infection caused by a novel mutation of CD70 presenting with recurrent periodic fever.

KW - Aphthous stomatitis

KW - CD70 deficiency

KW - Cervical adenitis syndrome

KW - Ebstein-Barr virus

KW - Hematopoietic stem cell transplantation

KW - Periodic fever

KW - Pharyngitis

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DO - 10.3389/fimmu.2017.02015

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JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

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