Frontiers in Immunology (Sep 2022)
Case Report: Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency
- Federica Barzaghi,
- Maria Pia Cicalese,
- Maria Pia Cicalese,
- Maria Pia Cicalese,
- Matteo Zoccolillo,
- Immacolata Brigida,
- Matteo Barcella,
- Matteo Barcella,
- Ivan Merelli,
- Claudia Sartirana,
- Monica Zanussi,
- Valeria Calbi,
- Maria Ester Bernardo,
- Maria Ester Bernardo,
- Maria Ester Bernardo,
- Francesca Tucci,
- Maddalena Migliavacca,
- Fabio Giglio,
- Matteo Doglio,
- Daniele Canarutto,
- Daniele Canarutto,
- Daniele Canarutto,
- Francesca Ferrua,
- Giulia Consiglieri,
- Giulia Consiglieri,
- Giulia Prunotto,
- Giulia Prunotto,
- Francesco Saettini,
- Sonia Bonanomi,
- Patrizia Rovere-Querini,
- Patrizia Rovere-Querini,
- Giulia Di Colo,
- Giulia Di Colo,
- Tatiana Jofra,
- Georgia Fousteri,
- Federica Penco,
- Marco Gattorno,
- Michael S. Hershfield,
- Lucia Bongiovanni,
- Maurilio Ponzoni,
- Maurilio Ponzoni,
- Sarah Marktel,
- Raffaella Milani,
- Jacopo Peccatori,
- Fabio Ciceri,
- Fabio Ciceri,
- Alessandra Mortellaro,
- Alessandro Aiuti,
- Alessandro Aiuti,
- Alessandro Aiuti
Affiliations
- Federica Barzaghi
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Maria Pia Cicalese
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Maria Pia Cicalese
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Maria Pia Cicalese
- Vita-Salute San Raffaele University, Milan, Italy
- Matteo Zoccolillo
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Immacolata Brigida
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Matteo Barcella
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Matteo Barcella
- Institute for Biomedical Technologies, National Research Council, Segrate, Italy
- Ivan Merelli
- Institute for Biomedical Technologies, National Research Council, Segrate, Italy
- Claudia Sartirana
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Monica Zanussi
- Clinical Genomics-Molecular Genetics Service, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Donato, San Raffaele Hospital, Milan, Italy
- Valeria Calbi
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Maria Ester Bernardo
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Maria Ester Bernardo
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Maria Ester Bernardo
- Vita-Salute San Raffaele University, Milan, Italy
- Francesca Tucci
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Maddalena Migliavacca
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Fabio Giglio
- Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy
- Matteo Doglio
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Daniele Canarutto
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Daniele Canarutto
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Daniele Canarutto
- Vita-Salute San Raffaele University, Milan, Italy
- Francesca Ferrua
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Giulia Consiglieri
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Giulia Consiglieri
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Giulia Prunotto
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Giulia Prunotto
- Bone Marrow Transplantation Unit, Pediatric Department of Milano-Bicocca University, Monza e Brianza per il Bambino e la sua Mamma Foundation, Monza, Italy
- Francesco Saettini
- Bone Marrow Transplantation Unit, Pediatric Department of Milano-Bicocca University, Monza e Brianza per il Bambino e la sua Mamma Foundation, Monza, Italy
- Sonia Bonanomi
- Bone Marrow Transplantation Unit, Pediatric Department of Milano-Bicocca University, Monza e Brianza per il Bambino e la sua Mamma Foundation, Monza, Italy
- Patrizia Rovere-Querini
- Vita-Salute San Raffaele University, Milan, Italy
- Patrizia Rovere-Querini
- Internal Medicine, Diabetes, and Endocrinology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Giulia Di Colo
- Vita-Salute San Raffaele University, Milan, Italy
- Giulia Di Colo
- Immunology, Rheumatology, Allergy and Rare Disease Unit, IRCCS San Rafaelle Hospital, Milan, Italy
- Tatiana Jofra
- 0Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Georgia Fousteri
- 0Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Federica Penco
- 1Clinica Pediatrica – Reumatologia e Centro Malattie Autoinfiammatorie, IRCCS Giannina Gaslini, Genova, Italy
- Marco Gattorno
- 1Clinica Pediatrica – Reumatologia e Centro Malattie Autoinfiammatorie, IRCCS Giannina Gaslini, Genova, Italy
- Michael S. Hershfield
- 2Department of Medicine and Biochemistry, Duke University Medical Center, Durham, NC, United States
- Lucia Bongiovanni
- 3Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Maurilio Ponzoni
- Vita-Salute San Raffaele University, Milan, Italy
- Maurilio Ponzoni
- 3Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Sarah Marktel
- Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy
- Raffaella Milani
- 4Immunohematology and Transfusion Medicine Unit, IRCCS Ospedale San Raffaele, Milan, Italy
- Jacopo Peccatori
- Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy
- Fabio Ciceri
- Vita-Salute San Raffaele University, Milan, Italy
- Fabio Ciceri
- Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy
- Alessandra Mortellaro
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Alessandro Aiuti
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Alessandro Aiuti
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Alessandro Aiuti
- Vita-Salute San Raffaele University, Milan, Italy
- DOI
- https://doi.org/10.3389/fimmu.2022.910021
- Journal volume & issue
-
Vol. 13
Abstract
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.
Keywords