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1. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study.

Author

Barzaghi, Federica, Amaya Hernandez, Laura Cristina, Neven, Benedicte, Ricci, Silvia, Kucuk, Zeynep Yesim, Bleesing, Jack J, Nademi, Zohreh, Slatter, Mary Anne, Ulloa, Erlinda Rose, Shcherbina, Anna, Roppelt, Anna, Worth, Austen, Silva, Juliana, Aiuti, Alessandro, Murguia-Favela, Luis, Speckmann, Carsten, Carneiro-Sampaio, Magda, Fernandes, Juliana Folloni, Baris, Safa, Ozen, Ahmet, Karakoc-Aydiner, Elif, Kiykim, Ayca, Schulz, Ansgar, Steinmann, Sandra, Notarangelo, Lucia Dora, Gambineri, Eleonora, Lionetti, Paolo, Shearer, William Thomas, Forbes, Lisa R, Martinez, Caridad, Moshous, Despina, Blanche, Stephane, Fisher, Alain, Ruemmele, Frank M, Tissandier, Come, Ouachee-Chardin, Marie, Rieux-Laucat, Frédéric, Cavazzana, Marina, Qasim, Waseem, Lucarelli, Barbarella, Albert, Michael H, Kobayashi, Ichiro, Alonso, Laura, Diaz De Heredia, Cristina, Kanegane, Hirokazu, Lawitschka, Anita, Seo, Jong Jin, Gonzalez-Vicent, Marta, Diaz, Miguel Angel, Goyal, Rakesh Kumar, Sauer, Martin G, Yesilipek, Akif, Kim, Minsoo, Yilmaz-Demirdag, Yesim, Bhatia, Monica, Khlevner, Julie, Richmond Padilla, Erick J, Martino, Silvana, Montin, Davide, Neth, Olaf, Molinos-Quintana, Agueda, Valverde-Fernandez, Justo, Broides, Arnon, Pinsk, Vered, Ballauf, Antje, Haerynck, Filomeen, Bordon, Victoria, Dhooge, Catharina, Garcia-Lloret, Maria Laura, Bredius, Robbert G, Kałwak, Krzysztof, Haddad, Elie, Seidel, Markus Gerhard, Duckers, Gregor, Pai, Sung-Yun, Dvorak, Christopher C, Ehl, Stephan, Locatelli, Franco, Goldman, Frederick, Gennery, Andrew Richard, Cowan, Mort J, Roncarolo, Maria-Grazia, Bacchetta, Rosa, and Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Subjects
Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation, Humans, Genetic Diseases, X-Linked, Diabetes Mellitus, Type 1, Immune System Diseases, Diarrhea, Disease-Free Survival, Hematopoietic Stem Cell Transplantation, Survival Rate, Retrospective Studies, Follow-Up Studies, Mutation, Adolescent, Adult, Child, Child, Preschool, Infant, Female, Male, Forkhead Transcription Factors, Allografts, Immunosuppression Therapy, FOXP3, IPEX, Treg cells, enteropathy, genetic autoimmunity, hematopoietic stem cell transplantation, immunosuppression, neonatal diabetes, primary immune deficiency, rapamycin, Clinical Research, Stem Cell Research, Regenerative Medicine, Pediatric, Genetics, Transplantation, Aetiology, 2.1 Biological and endogenous factors, Immunology, Allergy
Abstract

BackgroundImmunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined.ObjectiveThis analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors.MethodsClinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed.ResultsWe confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS.ConclusionsPatients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

Published
2018

2. B-cell development and functions and therapeutic options in adenosine deaminase–deficient patients

Author

Brigida, Immacolata, Sauer, Aisha V, Ferrua, Francesca, Giannelli, Stefania, Scaramuzza, Samantha, Pistoia, Valentina, Castiello, Maria Carmina, Barendregt, Barbara H, Cicalese, Maria Pia, Casiraghi, Miriam, Brombin, Chiara, Puck, Jennifer, Müller, Klaus, Notarangelo, Lucia Dora, Montin, Davide, van Montfrans, Joris M, Roncarolo, Maria Grazia, Traggiai, Elisabetta, van Dongen, Jacques JM, van der Burg, Mirjam, and Aiuti, Alessandro

Subjects
Regenerative Medicine, Genetics, Pediatric, Stem Cell Research, Transplantation, Stem Cell Research - Nonembryonic - Non-Human, Gene Therapy, 2.1 Biological and endogenous factors, 5.2 Cellular and gene therapies, Aetiology, Development of treatments and therapeutic interventions, Inflammatory and immune system, Adenosine Deaminase, Adolescent, B-Cell Activating Factor, B-Lymphocytes, Child, Child, Preschool, Enzyme Replacement Therapy, Genetic Therapy, Hematopoietic Stem Cell Transplantation, Humans, Infant, Gene therapy, adenosine deaminase-deficient severe combined immunodeficiency, B-cell development, antibodies, adenosine deaminase–deficient severe combined immunodeficiency, Immunology, Allergy
Abstract

BackgroundAdenosine deaminase (ADA) deficiency causes severe cellular and humoral immune defects and dysregulation because of metabolic toxicity. Alterations in B-cell development and function have been poorly studied. Enzyme replacement therapy (ERT) and hematopoietic stem cell (HSC) gene therapy (GT) are therapeutic options for patients lacking a suitable bone marrow (BM) transplant donor.ObjectiveWe sought to study alterations in B-cell development in ADA-deficient patients and investigate the ability of ERT and HSC-GT to restore normal B-cell differentiation and function.MethodsFlow cytometry was used to characterize B-cell development in BM and the periphery. The percentage of gene-corrected B cells was measured by using quantitative PCR. B cells were assessed for their capacity to proliferate and release IgM after stimulation.ResultsDespite the severe peripheral B-cell lymphopenia, patients with ADA-deficient severe combined immunodeficiency showed a partial block in central BM development. Treatment with ERT or HSC-GT reverted most BM alterations, but ERT led to immature B-cell expansion. In the periphery transitional B cells accumulated under ERT, and the defect in maturation persisted long-term. HSC-GT led to a progressive improvement in B-cell numbers and development, along with increased levels of gene correction. The strongest selective advantage for ADA-transduced cells occurred at the transition from immature to naive cells. B-cell proliferative responses and differentiation to immunoglobulin secreting IgM after B-cell receptor and Toll-like receptor triggering were severely impaired after ERT and improved significantly after HSC-GT.ConclusionsADA-deficient patients show specific defects in B-cell development and functions that are differently corrected after ERT and HSC-GT.

Published
2014

3. Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

Author

Cristina Cifaldi, Immacolata Brigida, Federica Barzaghi, Matteo Zoccolillo, Valentina Ferradini, Davide Petricone, Maria Pia Cicalese, Dejan Lazarevic, Davide Cittaro, Maryam Omrani, Enrico Attardi, Francesca Conti, Alessia Scarselli, Maria Chiriaco, Silvia Di Cesare, Francesco Licciardi, Montin Davide, Francesca Ferrua, Clementina Canessa, Claudio Pignata, Silvia Giliani, Simona Ferrari, Georgia Fousteri, Graziano Barera, Pietro Merli, Paolo Palma, Simone Cesaro, Marco Gattorno, Antonio Trizzino, Viviana Moschese, Loredana Chini, Anna Villa, Chiara Azzari, Andrea Finocchi, Franco Locatelli, Paolo Rossi, Federica Sangiuolo, Alessandro Aiuti, Caterina Cancrini, Gigliola Di Matteo, Cifaldi, Cristina, Brigida, Immacolata, Barzaghi, Federica, Zoccolillo, Matteo, Ferradini, Valentina, Petricone, Davide, Cicalese, MARIA PIA, Lazarevic, Dejan, Cittaro, Davide, Omrani, Maryam, Attardi, Enrico, Conti, Francesca, Scarselli, Alessia, Chiriaco, Maria, Di Cesare, Silvia, Licciardi, Francesco, Davide, Montin, Ferrua, Francesca, Canessa, Clementina, Pignata, Claudio, Giliani, Silvia, Ferrari, Simona, Fousteri, Georgia, Barera, Graziano, Merli, Pietro, Palma, Paolo, Cesaro, Simone, Gattorno, Marco, Trizzino, Antonio, Moschese, Viviana, Chini, Loredana, Villa, Anna, Azzari, Chiara, Finocchi, Andrea, Locatelli, Franco, Rossi, Paolo, Sangiuolo, Federica, Aiuti, Alessandro, Cancrini and Gigliola Di Matteo, Caterina, Cifaldi, C., Brigida, I., Barzaghi, F., Zoccolillo, M., Ferradini, V., Petricone, D., Cicalese, M. P., Lazarevic, D., Cittaro, D., Omrani, M., Attardi, E., Conti, F., Scarselli, A., Chiriaco, M., Di Cesare, S., Licciardi, F., Montin, D., Ferrua, F., Canessa, C., Pignata, C., Giliani, S., Ferrari, S., Fousteri, G., Barera, G., Merli, P., Palma, P., Cesaro, S., Gattorno, M., Trizzino, A., Moschese, V., Chini, L., Villa, A., Azzari, C., Finocchi, A., Locatelli, F., Rossi, P., Sangiuolo, F., Aiuti, A., Cancrini, C., and Di Matteo, G.

Subjects
Haloplex, Ion Torrent, Next Generation Sequencing, gene panels, primary immunodeficiencies, Adolescent, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Genetic Testing, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Italy, Male, Phenotype, Primary Immunodeficiency Diseases, 0301 basic medicine, Gene panel, Primary immunodeficiencies, Candidate gene, 0302 clinical medicine, Targeted ngs, NGS, primary immunodeficiencies, child, genetic, Medicine, Immunology and Allergy, Technology Report, Exome, primary immunodeficiencies, Next Generation Sequencing, gene panels, Ion Torrent, Haloplex, lcsh:Immunologic diseases. Allergy, Immunology, Computational biology, DNA sequencing, 03 medical and health sciences, Preschool, Gene, Settore MED/38 - Pediatria Generale e Specialistica, business.industry, Correction, Ion semiconductor sequencing, Newborn, 030104 developmental biology, lcsh:RC581-607, business, Gene Discovery, 030215 immunology
Abstract

Background: Primary Immunodeficiencies (PIDs) are a heterogeneous group of genetic immune disorders. While some PIDs can manifest with more than one phenotype, signs, and symptoms of various PIDs overlap considerably. Recently, novel defects in immune-related genes and additional variants in previously reported genes responsible for PIDs have been successfully identified by Next Generation Sequencing (NGS), allowing the recognition of a broad spectrum of disorders. Objective: To evaluate the strength and weakness of targeted NGS sequencing using custom-made Ion Torrent and Haloplex (Agilent) panels for diagnostics and research purposes. Methods: Five different panels including known and candidate genes were used to screen 105 patients with distinct PID features divided in three main PID categories: T cell defects, Humoral defects and Other PIDs. The Ion Torrent sequencing platform was used in 73 patients. Among these, 18 selected patients without a molecular diagnosis and 32 additional patients were analyzed by Haloplex enrichment technology. Results: The complementary use of the two custom-made targeted sequencing approaches allowed the identification of causative variants in 28.6% (n = 30) of patients. Twenty-two out of 73 (34.6%) patients were diagnosed by Ion Torrent. In this group 20 were included in the SCID/CID category. Eight out of 50 (16%) patients were diagnosed by Haloplex workflow. Ion Torrent method was highly successful for those cases with well-defined phenotypes for immunological and clinical presentation. The Haloplex approach was able to diagnose 4 SCID/CID patients and 4 additional patients with complex and extended phenotypes, embracing all three PID categories in which this approach was more efficient. Both technologies showed good gene coverage. Conclusions: NGS technology represents a powerful approach in the complex field of rare disorders but its different application should be weighted. A relatively small NGS target panel can be successfully applied for a robust diagnostic suspicion, while when the spectrum of clinical phenotypes overlaps more than one PID an in-depth NGS analysis is required, including also whole exome/genome sequencing to identify the causative gene.

Published
2019

4. Low synovial double negative T and γδ T cells predict longer free-disease survival in oligoarticular JIA

Author

Licciardi, Francesco, Ceci, Maria, Toppino, Claudia, Turco, Marco, Martino, Silvana, Ricotti, Emanuela, Ferro, Francesca, and Montin, Davide

Subjects
Male, B-Lymphocytes, CD19, DNT, Arthritis, Antigens, CD19, Juvenile, Flow Cytometry, JIA, prognostic factor, γδ T cells, Arthritis, Juvenile, Child, Child, Preschool, Disease-Free Survival, Female, Humans, Synovial Fluid, T-Lymphocyte Subsets, Antigens, Preschool
Abstract

Oligoarticular juvenile idiopathic arthritis (oJIA) is the most frequent form of chronic arthritis in children; the clinical course is extremely variable. In this study we have characterized by flow cytometry synovial B and T cells subsets in patients with oJIA in order to identify any parameters that could predict a more aggressive course of disease.B and T cells from synovial fluid (SF) of 39 patients with oJIA were characterized by flow cytometry. In 22 patients SF was analysed at the onset of the disease (GroupA), in 17 SF was analysed at articular relapse (Group B). All patients in Group A were followed up for at least for 2 years after SF analysis: 13 patients relapsed during the follow-up period.Comparison of SF from Group A and Group B demonstrated an activated phenotype in relapsed patients, with higher Switched Memory B cells (58.53 vs 36.07% of CD19+, P-value 0.004) and lower Naïve B cells (8.53 vs 25.9 of CD19+, P-value 0.002) in Group B. Furthermore, patients from Group A who did not relapse showed lower percentages of synovial DNT (2.38 vs 1.50% of CD3 + TCRalpha/beta+, P-value 0.025) and γδ T cells (19.1 vs 15.0% of CD3+ cells, P-value 0.004) at the onset, if compared with other Group A patients.In oJIA relapse SF present an activated B phenotype. Patients at disease onset with DNTs1.8% and/or γδ T cells16% of CD3+ in synovial fluid have longer free-disease survival. © 2017 International Clinical Cytometry Society.

Published
2017

5. Role of Colchicine Treatment in Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS): Real-Life Data from the AIDA Network

Author

Bruno Frediani, Laura Obici, Alessandra Renieri, Jurgen Sota, Valeria Caggiano, Francesco Licciardi, José Hernández-Rodríguez, Roberto Giacomelli, Piero Ruscitti, Antonio Vitale, Nicola Ricco, Lorenzo Dagna, Carlo Salvarani, Maria Cristina Maggio, Davide Montin, Giacomo Emmi, Alessandra Soriano, Marco Cattalini, Luca Cantarini, Ombretta Viapiana, Vittoria Lamacchia, Francesco Caso, Raffaele Manna, Antonella Insalaco, Vitale, Antonio, Sota, Jurgen, Obici, Laura, Ricco, Nicola, Maggio, Maria Cristina, Cattalini, Marco, Ruscitti, Piero, Caso, Francesco, Manna, Raffaele, Viapiana, Ombretta, Caggiano, Valeria, Emmi, Giacomo, Insalaco, Antonella, Montin, Davide, Licciardi, Francesco, Soriano, Alessandra, Dagna, Lorenzo, Salvarani, Carlo, Lamacchia, Vittoria, Hernández-Rodríguez, José, Giacomelli, Roberto, Frediani, Bruno, Renieri, Alessandra, Cantarini, Luca, Vitale, A., Sota, J., Obici, L., Ricco, N., Maggio, M. C., Cattalini, M., Ruscitti, P., Caso, F., Manna, R., Viapiana, O., Caggiano, V., Emmi, G., Insalaco, A., Montin, D., Licciardi, F., Soriano, A., Dagna, L., Salvarani, C., Lamacchia, V., Hernandez-Rodriguez, J., Giacomelli, R., Frediani, B., Renieri, A., and Cantarini, L.

Subjects
Male, 0301 basic medicine, Eye Diseases, TRAPS,Colchicine,AIDA Network, Gene mutation, Gastroenterology, Receptors, Tumor Necrosis Factor, chemistry.chemical_compound, Settore MED/38 - Pediatria Generale E Specialistica, 0302 clinical medicine, Receptors, Pathology, RB1-214, Colchicine, Age of Onset, Young adult, Child, Amyloidosis, Syndrome, Middle Aged, Colchicine, tumor necrosis factor, TRAPS, Inflamació, Penetrance, Phenotype, Child, Preschool, Female, Joint Diseases, Research Article, Adult, Risk, medicine.medical_specialty, Adolescent, Fever, Article Subject, Immunology, Exanthema, Humans, Mutation, Myalgia, Retrospective Studies, Young Adult, Lower risk, 03 medical and health sciences, Internal medicine, medicine, Preschool, Inflammation, 030203 arthritis & rheumatology, business.industry, TRAPS, Retrospective cohort study, Cell Biology, medicine.disease, 030104 developmental biology, chemistry, Age of onset, Tumor Necrosis Factor, business
Abstract

Objective. To analyze the potential role of colchicine monotherapy in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) in terms of control of clinical and laboratory manifestations. Methods. Patients with TRAPS treated with colchicine monotherapy were retrospectively enrolled; demographic, clinical and therapeutic data were collected and statistically analysed after having clustered patients according to different times at disease onset, penetrance of mutations, dosage of colchicine, and different disease manifestations. Results. 24 patients (14 males; 15 with pediatric disease onset) treated with colchicine monotherapy were enrolled. Colchicine resulted in a complete response in 3 (12.5%) cases, partial response in 14 (58.3%) patients, and lack of response in 7 (29.2%) patients. There were not significant differences in colchicine response between pediatric and adult disease onset (p=0.42), between low- and high-penetrance mutations (p=0.62), and according to different dosages (p=0.66). No significant differences were identified in the frequency of specific disease manifestations between patients experiencing any response to colchicine and patients with lack of response. Conclusions. Colchicine monotherapy is useful in a low percentage of TRAPS patients; nevertheless, it could be attempted in patients with milder phenotypes and at a lower risk of developing reactive amyloidosis.

Published
2020
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6. Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey

Author

Cattalini M, Della Paolera S, Zunica F, Bracaglia C, Giangreco M, Verdoni L, Meini A, Sottile R, Caorsi R, Zuccotti G, Fabi M, Montin D, Meneghel A, Consolaro A, Dellepiane RM, Maggio MC, La Torre F, Marchesi A, Simonini G, Villani A, Cimaz R, Ravelli A, Taddio A Maria Concetta Alberelli: UOC Pediatria, Marche-Nord, Clotilde Alizzi: Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialities 'G. D’Alessandro', University of Palermo, Palermo Italy, Patrizia Barone: Unità Operativa Complessa di Broncopneumologia Pediatrica AOU 'Policlinico - Vittorio Emanuele Via Santa Sofia 78 Catania, Lucia Augusta Baselli: Pediatric Intermediate Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan Italy, Veronica Bennato: U. O. Pediatria, Ospedale A, Manzoni Lecco, Francesca Biscaro: UOC Pediatria, Ospedale Ca’ Foncello, Treviso, Grazia Bossi: UOC Pediatria, Fondazione IRCCS Policlinico San Matteo, Pavia Italy, Andrea Campana: Bambino Gesù Children’s Hospital, Rome Italy, Maurizio Carone: UO Malattie Infettive, Ospedale Pediatrico ‘Giovanni XXIII’, Bari Italy, Adele Civino: U. O. C. Pediatria P. O. Vito Fazzi, Lecce, Giovanni Conti: Nefrologia e Reumatologia Pediatrica con Dialisi, Azienda Ospedaliero-Universitario 'G. Martino', Eleonora Dei Rossi: University of Trieste, Trieste Italy, Emanuela Del Giudice: Department of Maternal Infantile and Urological Sciences, Sapeinza University of Rome, Polo Pontini, Alice Dell’Anna: U. O. C. Pediatria P. O. Vito Fazzi Lecce, Maia De Luca: Bambino Gesù Children’s Hospital, Piazza S. Onofrio n. 4, 00165 Rome, Italy, Enrico Felici: Pediatric and Pediatric Emergency Unit, The Children Hospital, AO SS Antonio e Biago e C. Arrigo, Alessandria Italy, Giovanni Filocamo: Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milano, Ilenia Floretta: Pediatria, Ospedale Santa Chiara, Trento Italy, Maria Loreta Foschini: SC Pediatria, PO SAN MICHELE AOBrotzu, Cagliari Italy, Marcello Lanari: Department of Pediatrics, University of Bologna, IRCCS S. Orsola-Malpighi Hospital, Bologna Italy, Bianca Lattanzi: SOD Pediatria, Ospedali Riuniti, Ancona Italy, Alessandra Lazzerotti: Clinica Pediatrica, Università Milano Bicocca, Fondazione MBBM - onlus c/o Ospedale San Gerardo, Monza Italy, Francesco Licciardi: Department of Pediatrics and Public Health, University of Turin, Turin Italy, Alessandra Manerba: Child Cardiology, ASST Spedali Civili di Brescia and University of Brescia, Brescia Italy, Savina Mannarino: Division of Cardiology, Children’s Hospital V Buzzi, ASST FBF Sacco, Achille Marino: Department of Pediatrics, Desio Hospital, ASST Monza, Desio Italy, Agostina Marolda: Pediatrics and Neonatology Dipartment, ASST Ovest Milanese, 'G. Fornaroli' Hospital, Magenta Milan, Laura Martelli: Paediatric Department, Hospital Papa Giovanni XXIII, Bergamo Italy, Giorgia Martini, Department of Woman’s and Child’s Health, University of Padova, Padua Italy, Angela Mauro: Department of Paediatrics, Emergency Department, Santobono-Pausilipon Children’s Hospital, Naples, Italy. Maria Vincenza Mastrolia: Pediatric Rheumatology Unit, AOU Meyer, University of Florence, Florence, Italy. Angelo Mazza: Paediatric Department, Angela Miniaci: Clinica Pediatrica, Reumatologia, Azienda Ospedaliero-Universitaria di Bologna, Francesca Minoia: Fondazione IRCCS Cà Granda, Alma Olivieri: Dipartimento della donna, del bambino e di chirurgia generale e specialistica, Università della Campania, 'L Vanvitelli, Napoli, Guido Pennoni: Dipartimento Materno-Infantile, Gubbio-Gualdo Tadino, Italy, Rossana Pignataro: UOC Pediatria e Neonatologia, ASST Lodi, Lodi, Francesca Ricci, Clinica Pediatrica, ASST Spedali Civili di Brescia e Università degli Studi di Brescia, Donato Rigante: Department of Pediatrics, Univarsità Cattolica Sacro Cuore, Matilde Rossi: UOC di Pediatrai e Neonatologia, Ospedale di Macerata, Macerata, Claudia Santagati: Dipartimento di Pediatria, Ospedale di Rovigo, Rovigo, Martina Soliani: Pediatria ASST Cremona, Italy, Silvia Sonego: University of Trieste, Domenico Sperlì: UOC di Pediatria, S. O. 'Annunziata' - A. O. di Cosenza, Sara Stucchi: Maternal and Child Health, Division of Paediatrics, ASST Grande Ospedale Metropolitano Niguarda, Milano Italy, Barbara Teruzzi: Maternal and Child Health, Elpidio Tierno: UOC di Pediatria, Dipartimento della Salute della Donna e del Bambin, AORN 'Sant’Anna e San Sebastiano'- Caserta, Tatiana Utytatnikova: Dipartimento Materno-Infantile, Pediatria, ASST Bergamo-EST, Seriate Bergamo, Piero Valentini, Department of Pediatrics, Gianluca Vergine, UOC Pediatria Rimini, Ospedale Infermi, ASL Romagna, Rimini Italy., Cattalini, Marco, Della Paolera, Sara, Zunica, Fiammetta, Bracaglia, Claudia, Giangreco, Manuela, Verdoni, Lucio, Meini, Antonella, Sottile, Rita, Caorsi, Roberta, Zuccotti, Gianvincenzo, Fabi, Marianna, Montin, Davide, Meneghel, Alessandra, Consolaro, Alessandro, Dellepiane, Rosa Maria, Maggio, Maria Cristina, La Torre, Francesco, Marchesi, Alessandra, Simonini, Gabriele, Villani, Alberto, Cimaz, Rolando, Ravelli, Angelo, Taddio, Andrea, Cattalini, M, Della Paolera, S, Zunica, F, Bracaglia, C, Giangreco, M, Verdoni, L, Meini, A, Sottile, R, Caorsi, R, Zuccotti, G, Fabi, M, Montin, D, Meneghel, A, Consolaro, A, Dellepiane, Rm, Maggio, Mc, La Torre, F, Marchesi, A, Simonini, G, Villani, A, Cimaz, R, Ravelli, A, Taddio, A Maria Concetta Alberelli: UOC Pediatria, Marche-Nord, Clotilde Alizzi: Department of Health Promotion Sciences Maternal and Infantile, Care, Internal Medicine and Medical Specialities 'G., D’Alessandro', University of, Palermo, Palermo, Italy, Patrizia Barone: Unità Operativa Complessa di Broncopneumologia Pediatrica AOU 'Policlinico, - Vittorio Emanuele Via Santa Sofia 78 Catania, Lucia Augusta Baselli: Pediatric Intermediate Care, Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore, Policlinico, Milan, Italy, Veronica Bennato: U. O., Pediatria, Ospedale, A, Manzoni, Lecco, Francesca Biscaro: UOC, Pediatria, Ospedale Ca’, Foncello, Treviso, Grazia Bossi: UOC, Pediatria, Fondazione IRCCS Policlinico San, Matteo, Pavia, Italy, Andrea Campana: Bambino Gesù Children’s, Hospital, Rome, Italy, Maurizio Carone: UO Malattie, Infettive, Ospedale Pediatrico ‘Giovanni, Xxiii’, Bari, Italy, Adele Civino: U. O. C. Pediatria P. O. Vito Fazzi, Lecce, Giovanni Conti: Nefrologia e Reumatologia Pediatrica con Dialisi, Azienda Ospedaliero-Universitario 'G. Martino', Eleonora Dei Rossi: University of, Trieste, Trieste, Italy, Emanuela Del Giudice: Department of Maternal Infantile and Urological, Science, Sapeinza University of, Rome, Polo, Pontini, Alice Dell’Anna: U. O. C. Pediatria P. O., Vito Fazzi Lecce, Maia De Luca: Bambino Gesù Children’s, Hospital, Piazza, S. Onofrio n. 4., 00165, Rome, Italy, Enrico Felici: Pediatric and Pediatric Emergency, Unit, The Children, Hospital, AO SS Antonio e Biago e C., Arrigo, Alessandria, Italy, Giovanni Filocamo: Fondazione IRCCS Cà, Granda, Ospedale Maggiore, Policlinico, Milano, Ilenia Floretta:, Pediatria, Ospedale Santa, Chiara, Trento, Italy, Maria Loreta Foschini: SC, Pediatria, PO SAN MICHELE, Aobrotzu, Cagliari, Italy, Marcello Lanari: Department of, Pediatric, University of, Bologna, IRCCS S., Orsola-Malpighi Hospital, Bologna, Italy, Bianca Lattanzi: SOD, Pediatria, Ospedali, Riuniti, Ancona, Italy, Alessandra Lazzerotti: Clinica, Pediatrica, Università Milano, Bicocca, Fondazione MBBM, - onlus c/o Ospedale San Gerardo, Monza, Italy, Francesco Licciardi: Department of Pediatrics and Public, Health, University of, Turin, Turin, Italy, Alessandra Manerba: Child, Cardiology, ASST Spedali Civili di Brescia and University of, Brescia, Brescia, Italy, Savina Mannarino: Division of, Cardiology, Children’s Hospital, V Buzzi, ASST FBF, Sacco, Achille Marino: Department of, Pediatric, Desio, Hospital, Asst, Monza, Desio, Italy, Agostina Marolda: Pediatrics and Neonatology, Dipartment, ASST Ovest, Milanese, 'G., Fornaroli' Hospital, Magenta, Milan, Laura Martelli: Paediatric, Department, Hospital Papa Giovanni, Xxiii, Bergamo, Italy, Giorgia, Martini, Department of Woman’s and Child’s, Health, University of, Padova, Padua, Italy, Angela Mauro: Department of, Paediatric, Emergency, Department, Santobono-Pausilipon Children’s, Hospital, Naples, Italy., Maria Vincenza Mastrolia: Pediatric Rheumatology Unit, Aou, Meyer, University of, Florence, Florence, Italy., Angelo Mazza: Paediatric Department, Angela Miniaci: Clinica, Pediatrica, Reumatologia, Azienda Ospedaliero-Universitaria di, Bologna, Francesca Minoia: Fondazione IRCCS Cà, Granda, Alma Olivieri: Dipartimento della, Donna, del bambino e di chirurgia generale, e specialistica, Università della, Campania, 'L, Vanvitelli, Napoli, Claudio, Guido Pennoni: Dipartimento, Materno-Infantile, Gubbio-Gualdo Tadino, Italy, Rossana Pignataro: UOC Pediatria, e Neonatologia, Asst, Lodi, Lodi, Francesca, Ricci, Clinica, Pediatrica, ASST Spedali Civili di Brescia, e Università degli Studi di Brescia, Donato Rigante: Department of, Pediatric, Univarsità Cattolica Sacro, Cuore, Matilde Rossi: UOC di Pediatrai, e Neonatologia, Ospedale di, Macerata, Macerata, Claudia Santagati: Dipartimento di, Pediatria, Ospedale di, Rovigo, Rovigo, Martina Soliani: Pediatria ASST Cremona, Italy, Silvia Sonego: University of, Trieste, Domenico Sperlì: UOC di Pediatria, S. O. 'Annunziata' - A. O. di Cosenza, Sara Stucchi: Maternal and Child, Health, Division of, Paediatric, ASST Grande Ospedale Metropolitano, Niguarda, Milano, Italy, Barbara Teruzzi: Maternal and Child, Health, Elpidio Tierno: UOC di, Pediatria, Dipartimento della Salute della Donna, e del Bambin, AORN 'Sant’Anna, e San Sebastiano'- Caserta, Tatiana Utytatnikova: Dipartimento, Materno-Infantile, Pediatria, Asst, Bergamo-EST, Seriate, Bergamo, Piero, Valentini, Department of, Pediatric, Gianluca, Vergine, UOC Pediatria, Rimini, Ospedale, Infermi, Asl, Romagna, Rimini, Italy., Cattalini M., Della Paolera S., Zunica F., Bracaglia C., Giangreco M., Verdoni L., Meini A., Sottile R., Caorsi R., Zuccotti G., Fabi M., Montin D., Meneghel A., Consolaro A., Dellepiane R.M., Maggio M.C., La Torre F., Marchesi A., Simonini G., Villani A., Cimaz R., Ravelli A., Taddio A., Adamoli P., Alberelli M.C., Alizzi C., Barone P., Bennato V., Biscaro F., Bossi G., Campana A., Carone M., Civino A., Conti G., Rossi E.D., Del Giudice E., Dell'Anna A., De Luca M., Felici E., Filocamo G., Floretta I., Foschini M.L., Lanari M., Lattanzi B., Lazzerotti A., Licciardi F., Manerba A., Mannarino S., Marino A., Marolda A., Martelli L., Martini G., Mauro A., Mastrolia M.V., Mazza A., Miniaci A., Minoia F., Olivieri A., Pennoni G., Pignataro R., Ricci F., Rigante D., Rossi M., Santagati C., Soliani M., Sonego S., Sperli D., Stucchi S., Teruzzi B., Tierno E., Utytatnikova T., Valentini P., and Vergine G.

Subjects
Coronary artery abnormalities, Hypotension, Kawasaki disease, Multisystem inflammatory syndrome associated with coronavirus disease, Myocarditis, Pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection, SARS-CoV-2, Age Distribution, Antirheumatic Agents, Aspirin, C-Reactive Protein, COVID-19, Child, Child, Preschool, Coronary Artery Disease, Cough, Diarrhea, Dyspnea, Female, Glucocorticoids, Heart Failure, Humans, Hyperferritinemia, Immunoglobulins, Intravenous, Immunologic Factors, Infant, Intensive Care Units, Pediatric, Interleukin 1 Receptor Antagonist Protein, Italy, Lymphopenia, Male, Mucocutaneous Lymph Node Syndrome, Platelet Aggregation Inhibitors, Shock, Systemic Inflammatory Response Syndrome, Tachypnea, Troponin T, Vomiting, lcsh:Diseases of the musculoskeletal system, coronary artery abnormalities, hypotension, kawasaki disease, multisystem inflammatory syndrome associated with coronavirus disease, myocarditis, pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection, age distribution, antirheumatic agents, aspirin, C-reactive protein, child, preschool, coronary artery disease, cough, diarrhea, yspnea, female, glucocorticoids, heart failure, humans, hyperferritinemia, immunoglobulins, intravenous, immunologic factors, infant, intensive care units, pediatric, interleukin 1 receptor antagonist protein, italy, lymphopenia, male, mucocutaneous lymph node syndrome, platelet aggregation inhibitors, shock, systemic inflammatory response syndrome, tachypnea, troponin T, vomiting, Myocarditi, 030204 cardiovascular system & hematology, SARS-CoV-2, Kawasaki disease, Pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection, Myocarditis, Hypotension, Multisystem inflammatory syndrome associated with coronavirus disease, Coronary artery abnormalities, Coronary artery disease, Settore MED/38 - Pediatria Generale E Specialistica, 0302 clinical medicine, Glucocorticoid, Immunologic Factor, Immunology and Allergy, Coronary artery abnormalitie, Fisher's exact test, Pediatric, biology, lcsh:RJ1-570, Antirheumatic Agent, Settore MED/38, Intensive Care Units, Cohort, symbols, Platelet aggregation inhibitor, Intravenous, Human, Research Article, medicine.medical_specialty, Immunoglobulins, 03 medical and health sciences, symbols.namesake, Rheumatology, Internal medicine, medicine, Preschool, 030203 arthritis & rheumatology, business.industry, Platelet Aggregation Inhibitor, lcsh:Pediatrics, medicine.disease, Systemic inflammatory response syndrome, Immunoglobulins, Intravenou, Pediatrics, Perinatology and Child Health, biology.protein, lcsh:RC925-935, business
Abstract

Background There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities. Methods The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group – KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients’ outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups. Results One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%; p = 0.04 and 71,9% vs 43,4%; p = 0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%; p Conclusion Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths.

Published
2020

7. Immunophenotype anomalies predict the development of autoimmune cytopenia in 22q11.2 deletion syndrome

Author

Stefano Volpi, Francesca Conti, Baldassarre Martire, Emanuela Ricotti, Silvia Ricci, Ugo Ramenghi, Francesco Licciardi, Donato Amodio, Carmela Giancotta, Grazia Bossi, Chiara Azzari, Agostina Marolda, Marco Gattorno, Francesca Robasto, Giuliana Giardino, Caterina Cancrini, Claudio Pignata, Marzia Duse, Alessandro Plebani, Lucia Leonardi, Rosa Maria Dellepiane, Annarosa Soresina, Rita Consolini, Silvana Martino, Maria Caterina Putti, Francesca Ferro, Davide Montin, Giacomo Scaioli, Lucia Augusta Baselli, Silvia Di Cesare, Montin, Davide, Marolda, Agostina, Licciardi, Francesco, Robasto, Francesca, Di Cesare, Silvia, Ricotti, Emanuela, Ferro, Francesca, Scaioli, Giacomo, Giancotta, Carmela, Amodio, Donato, Conti, Francesca, Giardino, Giuliana, Leonardi, Lucia, Ricci, Silvia, Volpi, Stefano, Baselli, Lucia Augusta, Azzari, Chiara, Bossi, Grazia, Consolini, Rita, Dellepiane, Rosa Maria, Duse, Marzia, Gattorno, Marco, Martire, Baldassarre, Caterina Putti, Maria, Soresina, Annarosa, Plebani, Alessandro, Ramenghi, Ugo, Martino, Silvana, Pignata, Claudio, and Cancrini, Caterina

Subjects
Male, Hemolytic anemia, T-Lymphocytes, Lymphocyte, NK cells, Gastroenterology, 0302 clinical medicine, Immunophenotyping, Immunology and Allergy, 030212 general & internal medicine, CD4 naïve cell, Child, hemolytic anemia, B-Lymphocytes, thrombocytopenic purpura, 22q11.2 deletion syndrome, Autoimmune cytopenia, B immunophenotype, CD4 naïve cells, DiGeorge syndrome, Switched memory B cells, T immunophenotype, Thrombocytopenic purpura, Middle Aged, diGeorge syndrome, medicine.anatomical_structure, Child, Preschool, Female, Switched memory B cell, autoimmune cytopenia, switched memory B cells, Autoimmune hemolytic anemia, Adolescent, Adult, Autoimmune Diseases, Case-Control Studies, DiGeorge Syndrome, Humans, Lymphopenia, Young Adult, medicine.medical_specialty, Naive B cell, 03 medical and health sciences, Internal medicine, medicine, NK cell, Preschool, Survival rate, Settore MED/38 - Pediatria Generale e Specialistica, Cytopenia, business.industry, medicine.disease, 030228 respiratory system, business
Abstract

Background Patients with 22q11.2 deletion syndrome (22q11.2DS) may develop severe thrombocytopenic purpura and hemolytic anemia. There are no reliable predictors for the development of hematologic autoimmunity (HA) in these patients. Objective To describe the peculiar B and T subpopulation defects in patients with 22q11DS who have developed HA and test if these defects precede the development of HA. Methods We performed a case-control multicenter study. Patients with HA were compared with a control population of 22q11.2DS without HA (non-HA). A complete immunological evaluation was performed at diagnosis and at the last follow-up including extensive T and B phenotypes. Results Immunophenotype at the last follow-up was available in 23 HA and 45 non-HA patients. HA patients had significantly decreased percentage of naive CD4+ cells (26.8% vs 43.2%, P = .003) and recent thymic emigrants (48.6% vs 80.5%, P = .046); decreased class-switched B cells (2.0% vs 5.9%, P = .04) and increased naive B cells (83.5% vs 71.4%, P = .02); increased CD16+/56+ both in absolute number (312 vs 199, P = .009) and percentage (20.0% vs 13.0%, P = .03). Immunophenotype was performed in 36 patients (11 HA and 25 non-HA) at diagnosis. Odds ratio (OR) of immune cytopenia were estimated for both CD4 naive ≤30% (OR 14.0, P = .002) and switched memory B cells ≤2% (OR 44.0, P = .01). The estimated survival curves reached statistical significance, respectively, P = .0001 and P = .002. Conclusions Among patients with 22q11.2DS, those with HA have characteristic lymphocyte anomalies that appear considerably before HA onset. Systematic immunophenotyping of patients with 22q11.2DS at diagnosis is advisable for early identification of patients at risk for this severe complication.

Published
2019

8. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study

Author

Barzaghi, F., Hernandez, L.C.A., Neven, B., Ricci, S., Kucuk, Z.Y., Bleesing, J.J., Nademi, Z., Slatter, M.A., Ulloa, E.R., Shcherbina, A., Roppelt, A., Worth, A., Silva, J., Aiuti, A., Murguia-Favela, L., Speckmann, C., Carneiro-Sampaio, M., Fernandes, J.F., Baris, S., Ozen, A., Karakoc-Aydiner, E., Kiykim, A., Schulz, A., Steinmann, S., Notarangelo, L.D., Gambineri, E., Lionetti, P., Shearer, W.T., Forbes, L.R., Martinez, C., Moshous, D., Blanche, S., Fisher, A., Ruemmele, F.M., Tissandier, C., Ouachee-Chardin, M., Rieux-Laucat, F., Cavazzana, M., Qasim, W., Lucarelli, B., Albert, M.H., Kobayashi, I., Alonso, L., Heredia, C.D. de, Kanegane, H., Lawitschka, A., Seo, J.J., Gonzalez-Vicent, M., Diaz, M.A., Goyal, R.K., Sauer, M.G., Yesilipek, A., Kim, M., Yilmaz-Demirdag, Y., Bhatia, M., Khlevner, J., Padilla, E.J.R., Martino, S., Montin, D., Neth, O., Molinos-Quintana, A., Valverde-Fernandez, J., Broides, A., Pinsk, V., Ballauf, A., Haerynck, F., Bordon, V., Dhooge, C., Garcia-Lloret, M.L., Bredius, R.G., Kawak, K., Haddad, E., Seidel, M.G., Duckers, G., Pai, S.Y., Dvorak, C.C., Ehl, S., Locatelli, F., Goldman, F., Gennery, A.R., Cowan, M.J., Roncarolo, M.G., Bacchetta, R., PIDTC, IEWP, European Soc Blood Marrow, Barzaghi, Federica, Hernandez, Laura Cristina Amaya, Neven, Benedicte, Ricci, Silvia, Kucuk, Zeynep Yesim, Bleesing, Jack J., Nademi, Zohreh, Slatter, Mary Anne, Ulloa, Erlinda Rose, Shcherbina, Anna, Roppelt, Anna, Worth, Austen, Silva, Juliana, Aiuti, Alessandro, Murguia-Favela, Luis, Speckmann, Carsten, Carneiro-Sampaio, Magda, Fernandes, Juliana Folloni, Baris, Safa, Ozen, Ahmet, Karakoc-Aydiner, Elif, Kiykim, Ayca, Schulz, Ansgar, Steinmann, Sandra, Notarangelo, Lucia Dora, Gambineri, Eleonora, Lionetti, Paolo, Shearer, William Thomas, Forbes, Lisa R., Martinez, Caridad, Moshous, Despina, Blanche, Stephane, Fisher, Alain, Ruemmele, Frank M., Tissandier, Come, Ouachee-Chardin, Marie, Rieux-Laucat, Frederic, Cavazzana, Marina, Qasim, Waseem, Lucarelli, Barbarella, Albert, Michael H., Kobayashi, Ichiro, Alonso, Laura, De Heredia, Cristina Diaz, Kanegane, Hirokazu, Lawitschka, Anita, Seo, Jong Jin, Gonzalez-Vicent, Marta, Diaz, Miguel Angel, Goyal, Rakesh Kumar, Sauer, Martin G., Yesilipek, Akif, Kim, Minsoo, Yilmaz-Demirdag, Yesim, Bhatia, Monica, Khlevner, Julie, Padilla, Erick J. Richmond, Martino, Silvana, Montin, Davide, Neth, Olaf, Molinos-Quintana, Agueda, Valverde-Fernandez, Justo, Broides, Arnon, Pinsk, Vered, Ballauf, Antje, Haerynck, Filomeen, Bordon, Victoria, Dhooge, Catharina, Garcia-Lloret, Maria Laura, Bredius, Robbert G., Kalwak, Krzysztof, Haddad, Elie, Seidel, Markus Gerhard, Duckers, Gregor, Pai, Sung-Yun, Dvorak, Christopher C., Ehl, Stephan, Locatelli, Franco, Goldman, Frederick, Gennery, Andrew Richard, Cowan, Mort J., Roncarolo, Maria-Grazia, Bacchetta, Rosa, Amaya Hernandez, Laura Cristina, Murguia-Favela, Lui, Shearer, William Thoma, Rieux-Laucat, Frédéric, Diaz De Heredia, Cristina, Richmond Padilla, Erick J., and Kałwak, Krzysztof

Subjects
0301 basic medicine, Male, Allergy, medicine.medical_treatment, Medizin, Disease, Hematopoietic stem cell transplantation, SIROLIMUS, Regenerative Medicine, primary immune deficiency, Medicine and Health Sciences, IPEX, Immunology and Allergy, 2.1 Biological and endogenous factors, Enteropathy, Aetiology, POLYENDOCRINOPATHY, Child, Pediatric, CÉLULAS-TRONCO, immunosuppression, Hematopoietic Stem Cell Transplantation, Genetic Diseases, X-Linked, Immunosuppression, Forkhead Transcription Factors, X-LINKED SYNDROME, Allografts, Survival Rate, surgical procedures, operative, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Immune System Diseases, Genetic Diseases, Child, Preschool, hematopoietic stem cell transplantation, Female, hematopoietic stem, neonatal diabetes, FOXP3, Primary Immune Deficiency, Treg cells, enteropathy, genetic autoimmunity, rapamycin, Type 1, Diarrhea, Adult, medicine.medical_specialty, Adolescent, Immunology, Neonatal onset, Article, Disease-Free Survival, 03 medical and health sciences, Neonatal diabete, Clinical Research, Internal medicine, IMMUNODYSREGULATION, medicine, Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation, Diabetes Mellitus, Genetics, Humans, REGULATORY T-CELLS, cell transplantation, Preschool, Retrospective Studies, Immunosuppression Therapy, Transplantation, IMMUNE DYSREGULATION, business.industry, MUTATIONS, Infant, Retrospective cohort study, STEM-CELL TRANSPLANTATION, IPEX syndrome, X-Linked, medicine.disease, Stem Cell Research, BONE-MARROW-TRANSPLANTATION, Treg cell, FOXP3 MUTATIONS, Diabetes Mellitus, Type 1, 030104 developmental biology, ENGRAFTMENT, Mutation, business, Follow-Up Studies
Abstract

Background Immunodysregulation polyendocrinopathy enteropathy x-linked(IPEX) syndromeis a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. Conclusions Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen., GRAPHICAL ABSTRACT

Published
2018

9. Circulating follicular helper and follicular regulatory T cells are severely compromised in human CD40 deficiency: A case report

Author

Maria Pia Cicalese, Jolanda Gerosa, Manuela Baronio, Davide Montin, Francesco Licciardi, Annarosa Soresina, Rosa Maria Dellepiane, Maurizio Miano, Lucia Augusta Baselli, Stefano Volpi, Carlo Dufour, Alessandro Plebani, Alessandro Aiuti, Vassilios Lougaris, Georgia Fousteri, Cicalese, Maria Pia, Gerosa, Jolanda, Baronio, Manuela, Montin, Davide, Licciardi, Francesco, Soresina, Annarosa, Dellepiane, Rosa Maria, Miano, Maurizio, Baselli, Lucia Augusta, Volpi, Stefano, Dufour, Carlo, Plebani, Alessandro, Aiuti, Alessandro, Lougaris, Vassilio, and Fousteri, Georgia

Subjects
Male, 0301 basic medicine, Helper-Inducer, T-Lymphocytes, Case Report, AICDA, Hyper-IgM Immunodeficiency Syndrome, Lymphocyte Activation, T-Lymphocytes, Regulatory, 0302 clinical medicine, Activation-induced (cytidine) deaminase, CD40, Immunology and Allergy, Child, CD40LG, class switch recombination, follicular helper T cells, follicular regulatory T cells, hyper-IgM syndrome, somatic hypermutation, Adolescent, Adult, CD40 Antigens, CD40 Ligand, Child, Preschool, Cytidine Deaminase, Female, Humans, Immunophenotyping, Mutation, T-Lymphocytes, Helper-Inducer, Young Adult, biology, Follicular regulatory T cells, Cytidine deaminase, Regulatory, Class switch recombination, Follicular helper T cells, Hyper-IgM syndrome, Somatic hypermutation, Immunology, lcsh:Immunologic diseases. Allergy, Hyper IgM syndrome, 03 medical and health sciences, Immune system, medicine, Preschool, Follicular helper T cell, AICDA, CD40, CD40LG, Class switch recombination, Follicular helper T cells, Follicular regulatory T cells, Hyper-IgM syndrome, Somatic hypermutation, Immunology and Allergy, Immunology, Follicular regulatory T cell, Germinal center, medicine.disease, 030104 developmental biology, Immunoglobulin class switching, biology.protein, lcsh:RC581-607, 030215 immunology
Abstract

Mutations in genes that control class switch recombination and somatic hypermutation during the germinal center (GC) response can cause diverse immune dysfunctions. In particular, mutations in CD40LG, CD40, AICDA, or UNG cause hyper-IgM (HIGM) syndrome, a heterogeneous group of primary immunodeficiencies. Follicular helper (Tfh) and follicular regulatory (Tfr) T cells play a key role in the formation and regulation of GCs, but their role in HIGM pathogenesis is still limited. Here, we found that compared to CD40 ligand (CD40L)- and activation-induced cytidine deaminase (AICDA)-deficient patients, circulating Tfh and Tfr cells were severely compromised in terms of frequency and activation phenotype in a child with CD40 deficiency. These findings offer useful insight for human Tfh biology, with potential implications for understanding the molecular basis of HIGM syndrome caused by mutations in CD40.

Published
2018

10. Clinical features and follow-up in patients with 22q11.2 deletion syndrome

Author

Cancrini, C, Puliafito, P, Digilio, M, Soresina, A, Martino, S, Rondelli, R, Consolini, R, Ruga, E, Cardinale, F, Finocchi, A, Romiti, Ml, Martire, B, Bacchetta, R, Albano, V, Carotti, A, Specchia, F, Montin, D, Cirillo, E, Cocchi, G, Trizzino, A, Bossi, G, Milanesi, O, Azzari, C, Corsello, G, Pignata, C, Aiuti, A, Pietrogrande, M, Marino, B, Ugazio, A, Plebani, A, Rossi, P, Pierani, P, Gabrielli, A, Danieli, M, De Mattia, D, Sisto, C, Dammacco, F, Ranieri, G, Pession, A, Ricci, G, Minelli, P, Lougaris, V, Badolato, R, Cattaneo, R, Airò, P, Mura, R, Cossu, F, Del Giacco, S, Manconi, P, Consarino, C, Dello Russo, A, Miniero, R, Anastasio, E, Marino, S, Russo, G, Paganelli, R, Sperlì, D, Carpino, L, Aricò, M, Gambineri, E, Lippi, F, Canessa, C, Maggi, E, Romagnani, S, Matucci, A, Vultaggio, A, Gattorno, M, Castagnola, E, Nigro, G, Presta, G, Civino, A, Buzi, F, Gambaretto, G, Fasoli, S, Salpietro, C, Gallizzi, R, Dellepiane, R, Panisi, C, Fabio, G, Carrabba, M, Roncarolo, M, Biondi, A, Vallinoto, C, Poggi, V, Menna, G, Di Nardo, R, Sottile, R, Marone, G, Spadaro, G, Carli, M, Basso, G, Putti, C, Semenzato, G, Agostini, C, D'Angelo, P, Izzi, G, Bertolini, P, Zecca, M, Marseglia, G, Maccario, R, Felici, L, Favre, C, Vecchi, V, Sacchini, P, Rinaldi, G, Livadiotti, S, Simonetti, A, Stabile, A, Duse, M, Iacobini, M, Quinti, I, Fiorilli, M, Moschese, V, Cecere, F, D'Ambrosio, A, De Zan, G, Strafella, S, Tamaro, P, Rabusin, M, Tommasini, A, Tovo, P, De Carli, M, De Carli, S, Nespoli, L, Marinoni, M, Porcellini, A, Lunardi, C, Patuzzo, G, Boner, A, Degani, D, Cancrini, C, Puliafito, P, Digilio, Mc, Soresina, A, Martino, S, Rondelli, R, Consolini, R, Ruga, Em, Cardinale, F, Finocchi, A, Romiti, Ml, Martire, B, Bacchetta, R, Albano, V, Carotti, A, Specchia, F, Montin, D, Cirillo, E, Cocchi, G, Trizzino, A, Bossi, G, Milanesi, O, Azzari, C, Corsello, G, Pignata, C, Aiuti, Alessandro, Pietrogrande, Mc, Marino, B, Ugazio, Ag, Plebani, A, Rossi, P., Cancrini, Caterina, Puliafito, Pamela, Digilio, Maria Cristina, Soresina, Annarosa, Martino, Silvana, Rondelli, Roberto, Consolini, Rita, Ruga, Ezia Maria, Cardinale, Fabio, Finocchi, Andrea, Romiti, Maria Luisa, Martire, Baldassarre, Bacchetta, Rosa, Albano, Veronica, Carotti, Adriano, Specchia, Fernando, Montin, Davide, Cirillo, Emilia, Cocchi, Guido, Trizzino, Antonino, Bossi, Grazia, Milanesi, Ornella, Azzari, Chiara, Corsello, Giovanni, Pignata, Claudio, Pietrogrande, Maria Cristina, Marino, Bruno, Ugazio, Alberto Giovanni, Plebani, Alessandro, Rossi, Paolo, Aiuti, A, Rossi, P, Pierani, P, Gabrielli, A, Danieli, Mg, De Mattia, D, Sisto, C, Dammacco, F, Ranieri, G, Pession, A, Ricci, G, Minelli, P, Lougaris, V, Badolato, R, Cattaneo, R, Airò, P, Mura, Rm, Cossu, F, Del Giacco, S, Manconi, Pe, Consarino, C, Dello Russo, Am, Miniero, R, Anastasio, E, Marino, S, Russo, G, Paganelli, R, Sperlì, D, Carpino, L, Aricò, M, Gambineri, E, Lippi, F, Canessa, C, Maggi, E, Romagnani, S, Matucci, A, Vultaggio, A, Gattorno, M, Castagnola, E, Nigro, G, Presta, G, Civino, A, Buzi, F, Gambaretto, G, Fasoli, S, Salpietro, C, Gallizzi, R, Dellepiane, Rm, Panisi, C, Fabio, G, Carrabba, M, Pietrogrande, M, Roncarolo, Mg, Biondi, A, Vallinoto, C, Poggi, V, Menna, G, Di Nardo, R, Sottile, R, Marone, G, Spadaro, G, Carli, M, Basso, G, Putti, C, Semenzato, G, Agostini, C, D'Angelo, P, Izzi, G, Bertolini, P, Zecca, M, Marseglia, G, Maccario, R, Felici, L, Favre, C, Vecchi, V, Sacchini, P, Rinaldi, G, Livadiotti, S, Simonetti, A, Stabile, A, Duse, M, Iacobini, M, Quinti, I, Fiorilli, M, Moschese, V, Cecere, F, D'Ambrosio, A, De Zan, G, Strafella, S, Tamaro, Paolo, Rabusin, M, Tommasini, A, Tovo, P, De Carli, M, De Carli, S, Nespoli, L, Marinoni, M, Porcellini, A, Lunardi, C, Patuzzo, G, Boner, A, Degani, D., Cancrini, C., Pulisfito, P., Digilio, M. C., Soresina, A., Martino, S., Rondelli, R., Consolini, R., Ruga, E. M., C. a. r. d. i. n. a. l. e., F., Finocchi, A., Romiti, M. L., Martire, B., Bacchetta, R., Albano, V., Carotti, A., Specchia, F., Montin, D., Cocchi, G., Trizzino, A., Bossi, G., Milanesi, O., Azzari, C., Corsello, G., Aiuti, A., Pietrogrande, M. C., Marino, B., Ugazio, A. G., Plebani, A., Digilio, MC, Ruga, EM, Romiti, ML, trizzino, A, Aiuti, Pietrogrande, MC, and Ugazio, AG

Subjects
Male, Pediatrics, 22q11.2 deletion, Delayed Diagnosis, Time Factors, Chromosomes, Human, Pair 22, Developmental Disabilities, digeorge syndrome, Sex Factor, Severity of Illness Index, Retrospective Studie, DiGeorge syndrome, Early Diagnosi, Age Factor, Prospective Studies, Neonatal hypocalcemia, Prospective cohort study, Child, medicine.diagnostic_test, Delayed Diagnosi, Primary immune disorders, Age Factors, del 22q, MIM, Abnormalities, Multiple, Adolescent, Adult, Child, Preschool, DiGeorge Syndrome, Early Diagnosis, Female, Follow-Up Studies, Genetic Testing, Humans, Infant, Infant, Newborn, Monitoring, Physiologic, Retrospective Studies, Risk Assessment, Sex Factors, Young Adult, Disease Progression, Cohort, Abnormalities, Multiple, Pediatrics, Perinatology and Child Health, Human, medicine.medical_specialty, Time Factor, Monitoring, Developmental Disabilitie, Italian Association of Pediatric Haematology and Oncology, Context (language use), Chromosomes, Follow-Up Studie, Severity of illness, medicine, 22q11DS, 22q11.2 deletion syndrome, AIEOP, Mendelian Inheritance in Man, Preschool, Physiologic, Genetic testing, Settore MED/38 - Pediatria Generale e Specialistica, business.industry, Retrospective cohort study, medicine.disease, Newborn, Prospective Studie, Pair 22, business
Abstract

Objective To investigate the clinical manifestations at diagnosis and during follow-up in patients with 22q11.2 deletion syndrome to better define the natural history of the disease. Study design A retrospective and prospective multicenter study was conducted with 228 patients in the context of the Italian Network for Primary Immunodeficiencies. Clinical diagnosis was confirmed by cytogenetic or molecular analysis. Results The cohort consisted of 112 males and 116 females; median age at diagnosis was 4 months (range 0 to 36 years 10 months). The diagnosis was made before 2 years of age in 71% of patients, predominantly related to the presence of heart anomalies and neonatal hypocalcemia. In patients diagnosed after 2 years of age, clinical features such as speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features were the main elements leading to diagnosis. During follow-up (available for 172 patients), the frequency of autoimmune manifestations ( P = .015) and speech disorders ( P = .002) increased. After a median follow-up of 43 months, the survival probability was 0.92 at 15 years from diagnosis. Conclusions Our data show a delay in the diagnosis of 22q11.2 deletion syndrome with noncardiac symptoms. This study provides guidelines for pediatricians and specialists for early identification of cases that can be confirmed by genetic testing, which would permit the provision of appropriate clinical management.

Published
2014

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