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Case Report: Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, including vasculitis, immunodeficiency, and hematologic manifestations, potentially progressing over time. The present study describes the long-term evolution of the...

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Autores principales: Barzaghi, Federica, Cicalese, Maria Pia, Zoccolillo, Matteo, Brigida, Immacolata, Barcella, Matteo, Merelli, Ivan, Sartirana, Claudia, Zanussi, Monica, Calbi, Valeria, Bernardo, Maria Ester, Tucci, Francesca, Migliavacca, Maddalena, Giglio, Fabio, Doglio, Matteo, Canarutto, Daniele, Ferrua, Francesca, Consiglieri, Giulia, Prunotto, Giulia, Saettini, Francesco, Bonanomi, Sonia, Rovere-Querini, Patrizia, Di Colo, Giulia, Jofra, Tatiana, Fousteri, Georgia, Penco, Federica, Gattorno, Marco, Hershfield, Michael S., Bongiovanni, Lucia, Ponzoni, Maurilio, Marktel, Sarah, Milani, Raffaella, Peccatori, Jacopo, Ciceri, Fabio, Mortellaro, Alessandra, Aiuti, Alessandro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9557171/
https://www.ncbi.nlm.nih.gov/pubmed/36248833
http://dx.doi.org/10.3389/fimmu.2022.910021
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author Barzaghi, Federica
Cicalese, Maria Pia
Zoccolillo, Matteo
Brigida, Immacolata
Barcella, Matteo
Merelli, Ivan
Sartirana, Claudia
Zanussi, Monica
Calbi, Valeria
Bernardo, Maria Ester
Tucci, Francesca
Migliavacca, Maddalena
Giglio, Fabio
Doglio, Matteo
Canarutto, Daniele
Ferrua, Francesca
Consiglieri, Giulia
Prunotto, Giulia
Saettini, Francesco
Bonanomi, Sonia
Rovere-Querini, Patrizia
Di Colo, Giulia
Jofra, Tatiana
Fousteri, Georgia
Penco, Federica
Gattorno, Marco
Hershfield, Michael S.
Bongiovanni, Lucia
Ponzoni, Maurilio
Marktel, Sarah
Milani, Raffaella
Peccatori, Jacopo
Ciceri, Fabio
Mortellaro, Alessandra
Aiuti, Alessandro
author_facet Barzaghi, Federica
Cicalese, Maria Pia
Zoccolillo, Matteo
Brigida, Immacolata
Barcella, Matteo
Merelli, Ivan
Sartirana, Claudia
Zanussi, Monica
Calbi, Valeria
Bernardo, Maria Ester
Tucci, Francesca
Migliavacca, Maddalena
Giglio, Fabio
Doglio, Matteo
Canarutto, Daniele
Ferrua, Francesca
Consiglieri, Giulia
Prunotto, Giulia
Saettini, Francesco
Bonanomi, Sonia
Rovere-Querini, Patrizia
Di Colo, Giulia
Jofra, Tatiana
Fousteri, Georgia
Penco, Federica
Gattorno, Marco
Hershfield, Michael S.
Bongiovanni, Lucia
Ponzoni, Maurilio
Marktel, Sarah
Milani, Raffaella
Peccatori, Jacopo
Ciceri, Fabio
Mortellaro, Alessandra
Aiuti, Alessandro
author_sort Barzaghi, Federica
collection PubMed
description Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, including vasculitis, immunodeficiency, and hematologic manifestations, potentially progressing over time. The present study describes the long-term evolution of the immuno-hematological features and therapeutic challenge of two identical adult twin sisters affected by DADA2. The absence of plasmatic adenosine deaminase 2 (ADA2) activity in both twins suggested the diagnosis of DADA2, then confirmed by genetic analysis. Exon sequencing revealed a missense (p.Leu188Pro) mutation on the paternal ADA2 allele. While, whole genome sequencing identified an unreported deletion (IVS6_IVS7del*) on the maternal allele predicted to produce a transcript missing exon 7. The patients experienced the disease onset during childhood with early strokes (Patient 1 at two years, Patient 2 at eight years of age), subsequently followed by other shared DADA2-associated features, including neutropenia, hypogammaglobulinemia, reduced switched memory B cells, inverted CD4:CD8 ratio, increased naïve T cells, reduced follicular regulatory T cells, the almost complete absence of NK cells, T-large granular cell leukemia, and osteoporosis. Disease evolution differed: clinical manifestations presented several years earlier and were more pronounced in Patient 1 than in Patient 2. Due to G-CSF refractory life-threatening neutropenia, Patient 1 successfully underwent an urgent hematopoietic stem cell transplantation (HSCT) from a 9/10 matched unrelated donor. Patient 2 experienced a similar, although delayed, disease evolution and is currently on anti-TNF therapy and anti-infectious prophylaxis. The unique cases confirmed that heterozygous patients with null ADA2 activity deserve deep investigation for possible structural variants on a single allele. Moreover, this report emphasizes the importance of timely recognizing DADA2 at the onset to allow adequate follow-up and detection of disease progression. Finally, the therapeutic management in these identical twins raises significant concerns as they share a similar phenotype, with a delayed but almost predictable disease evolution in one of them, who could benefit from a prompt definitive treatment like elective allogeneic HSCT. Additional data are required to assess whether the absence of enzymatic activity at diagnosis is associated with hematological involvement and is also predictive of bone marrow dysfunction, encouraging early HSCT to improve functional outcomes.
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spelling pubmed-95571712022-10-14 Case Report: Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency Barzaghi, Federica Cicalese, Maria Pia Zoccolillo, Matteo Brigida, Immacolata Barcella, Matteo Merelli, Ivan Sartirana, Claudia Zanussi, Monica Calbi, Valeria Bernardo, Maria Ester Tucci, Francesca Migliavacca, Maddalena Giglio, Fabio Doglio, Matteo Canarutto, Daniele Ferrua, Francesca Consiglieri, Giulia Prunotto, Giulia Saettini, Francesco Bonanomi, Sonia Rovere-Querini, Patrizia Di Colo, Giulia Jofra, Tatiana Fousteri, Georgia Penco, Federica Gattorno, Marco Hershfield, Michael S. Bongiovanni, Lucia Ponzoni, Maurilio Marktel, Sarah Milani, Raffaella Peccatori, Jacopo Ciceri, Fabio Mortellaro, Alessandra Aiuti, Alessandro Front Immunol Immunology Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, including vasculitis, immunodeficiency, and hematologic manifestations, potentially progressing over time. The present study describes the long-term evolution of the immuno-hematological features and therapeutic challenge of two identical adult twin sisters affected by DADA2. The absence of plasmatic adenosine deaminase 2 (ADA2) activity in both twins suggested the diagnosis of DADA2, then confirmed by genetic analysis. Exon sequencing revealed a missense (p.Leu188Pro) mutation on the paternal ADA2 allele. While, whole genome sequencing identified an unreported deletion (IVS6_IVS7del*) on the maternal allele predicted to produce a transcript missing exon 7. The patients experienced the disease onset during childhood with early strokes (Patient 1 at two years, Patient 2 at eight years of age), subsequently followed by other shared DADA2-associated features, including neutropenia, hypogammaglobulinemia, reduced switched memory B cells, inverted CD4:CD8 ratio, increased naïve T cells, reduced follicular regulatory T cells, the almost complete absence of NK cells, T-large granular cell leukemia, and osteoporosis. Disease evolution differed: clinical manifestations presented several years earlier and were more pronounced in Patient 1 than in Patient 2. Due to G-CSF refractory life-threatening neutropenia, Patient 1 successfully underwent an urgent hematopoietic stem cell transplantation (HSCT) from a 9/10 matched unrelated donor. Patient 2 experienced a similar, although delayed, disease evolution and is currently on anti-TNF therapy and anti-infectious prophylaxis. The unique cases confirmed that heterozygous patients with null ADA2 activity deserve deep investigation for possible structural variants on a single allele. Moreover, this report emphasizes the importance of timely recognizing DADA2 at the onset to allow adequate follow-up and detection of disease progression. Finally, the therapeutic management in these identical twins raises significant concerns as they share a similar phenotype, with a delayed but almost predictable disease evolution in one of them, who could benefit from a prompt definitive treatment like elective allogeneic HSCT. Additional data are required to assess whether the absence of enzymatic activity at diagnosis is associated with hematological involvement and is also predictive of bone marrow dysfunction, encouraging early HSCT to improve functional outcomes. Frontiers Media S.A. 2022-09-29 /pmc/articles/PMC9557171/ /pubmed/36248833 http://dx.doi.org/10.3389/fimmu.2022.910021 Text en Copyright © 2022 Barzaghi, Cicalese, Zoccolillo, Brigida, Barcella, Merelli, Sartirana, Zanussi, Calbi, Bernardo, Tucci, Migliavacca, Giglio, Doglio, Canarutto, Ferrua, Consiglieri, Prunotto, Saettini, Bonanomi, Rovere-Querini, Di Colo, Jofra, Fousteri, Penco, Gattorno, Hershfield, Bongiovanni, Ponzoni, Marktel, Milani, Peccatori, Ciceri, Mortellaro and Aiuti https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Barzaghi, Federica
Cicalese, Maria Pia
Zoccolillo, Matteo
Brigida, Immacolata
Barcella, Matteo
Merelli, Ivan
Sartirana, Claudia
Zanussi, Monica
Calbi, Valeria
Bernardo, Maria Ester
Tucci, Francesca
Migliavacca, Maddalena
Giglio, Fabio
Doglio, Matteo
Canarutto, Daniele
Ferrua, Francesca
Consiglieri, Giulia
Prunotto, Giulia
Saettini, Francesco
Bonanomi, Sonia
Rovere-Querini, Patrizia
Di Colo, Giulia
Jofra, Tatiana
Fousteri, Georgia
Penco, Federica
Gattorno, Marco
Hershfield, Michael S.
Bongiovanni, Lucia
Ponzoni, Maurilio
Marktel, Sarah
Milani, Raffaella
Peccatori, Jacopo
Ciceri, Fabio
Mortellaro, Alessandra
Aiuti, Alessandro
Case Report: Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency
title Case Report: Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency
title_full Case Report: Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency
title_fullStr Case Report: Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency
title_full_unstemmed Case Report: Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency
title_short Case Report: Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency
title_sort case report: consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9557171/
https://www.ncbi.nlm.nih.gov/pubmed/36248833
http://dx.doi.org/10.3389/fimmu.2022.910021
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