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1. 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

2. All that glisters is not COVID: Low prevalence of seroconversion against SARS-CoV-2 in a pediatric cohort of patients with chilblain-like lesions.

Author

Denina M, Pellegrino F, Morotti F, Coppo P, Bonsignori IM, Garazzino S, Ravanini P, Avolio M, Cavallo R, Bertolotti L, Felici E, Acucella G, Montin D, Rabbone I, and Licciardi F

Subjects
Adolescent, Antibodies, Viral blood, Betacoronavirus immunology, COVID-19, COVID-19 Testing, Chilblains blood, Chilblains diagnosis, Child, Child, Preschool, Coronavirus Infections blood, Coronavirus Infections complications, Coronavirus Infections epidemiology, Female, Humans, Infant, Italy epidemiology, Male, Pandemics, Pneumonia, Viral blood, Pneumonia, Viral complications, Pneumonia, Viral epidemiology, Prevalence, SARS-CoV-2, Seroconversion, Betacoronavirus isolation & purification, Chilblains etiology, Clinical Laboratory Techniques statistics & numerical data, Coronavirus Infections diagnosis, Pneumonia, Viral diagnosis
Published
2020
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3. Consensus of the Italian Primary Immunodeficiency Network on transition management from pediatric to adult care in patients affected with childhood-onset inborn errors of immunity.

Author

Cirillo E, Giardino G, Ricci S, Moschese V, Lougaris V, Conti F, Azzari C, Barzaghi F, Canessa C, Martire B, Badolato R, Dotta L, Soresina A, Cancrini C, Finocchi A, Montin D, Romano R, Amodio D, Ferrua F, Tommasini A, Baselli LA, Dellepiane RM, Polizzi A, Chessa L, Marzollo A, Cicalese MP, Putti MC, Pession A, Aiuti A, Locatelli F, Plebani A, and Pignata C

Subjects
Adult, Age of Onset, Child, Consensus, Humans, Information Services, Italy epidemiology, Practice Guidelines as Topic, Primary Immunodeficiency Diseases diagnosis, Primary Immunodeficiency Diseases therapy, Transition to Adult Care standards
Abstract

Medical advances have dramatically improved the long-term prognosis of children and adolescents with inborn errors of immunity (IEIs). Transfer of the medical care of individuals with pediatric IEIs to adult facilities is also a complex task because of the large number of distinct disorders, which requires involvement of patients and both pediatric and adult care providers. To date, there is no consensus on the optimal pathway of the transitional care process and no specific data are available in the literature regarding patients with IEIs. We aimed to develop a consensus statement on the transition process to adult health care services for patients with IEIs. Physicians from major Italian Primary Immunodeficiency Network centers formulated and answered questions after examining the currently published literature on the transition from childhood to adulthood. The authors voted on each recommendation. The most frequent IEIs sharing common main clinical problems requiring full attention during the transitional phase were categorized into different groups of clinically related disorders. For each group of clinically related disorders, physicians from major Italian Primary Immunodeficiency Network institutions focused on selected clinical issues representing the clinical hallmark during early adulthood., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Published
2020
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4. Long-term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality.

Author

Lougaris V, Soresina A, Baronio M, Montin D, Martino S, Signa S, Volpi S, Zecca M, Marinoni M, Baselli LA, Dellepiane RM, Carrabba M, Fabio G, Putti MC, Cinetto F, Lunardi C, Gazzurelli L, Benvenuto A, Bertolini P, Conti F, Consolini R, Ricci S, Azzari C, Leonardi L, Duse M, Pulvirenti F, Milito C, Quinti I, Cancrini C, Finocchi A, Moschese V, Cirillo E, Crescenzi L, Spadaro G, Marasco C, Vacca A, Cardinale F, Martire B, Trizzino A, Licciardello M, Cossu F, Di Matteo G, Badolato R, Ferrari S, Giliani S, Pession A, Ugazio A, Pignata C, and Plebani A

Subjects
Adolescent, Adult, Agammaglobulinemia mortality, Child, Child, Preschool, Follow-Up Studies, Genetic Diseases, X-Linked mortality, Humans, Infant, Infant, Newborn, Italy epidemiology, Male, Middle Aged, Survival Analysis, Young Adult, Agammaglobulinemia epidemiology, Genetic Diseases, X-Linked epidemiology, Infections epidemiology, Lung Diseases epidemiology, Sinusitis epidemiology
Abstract

Background: X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce., Objective: Our aim was to describe the natural history of XLA., Methods: A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients' laboratory, clinical, and imaging data were recorded on an annual base., Results: Data on the patients (N = 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean follow-up of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 23 months after). Respiratory, skin, and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared with that for the healthy male Italian population, and it further deteriorated in the presence of chronic lung disease., Conclusions: This is the first detailed long-term follow-up study for patients with XLA, revealing that although immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. The overall survival of affected patients is reduced. Further studies are warranted to improve patients' clinical management and increase awareness among physicians., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Published
2020
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5. Epidemiologic Impact of the New Guidelines for the Diagnosis of Acute Rheumatic Fever.

Author

Licciardi F, Scaioli G, Mulatero R, Marolda A, Delle Piane M, Martino S, Montin D, and Tovo PA

Subjects
Adolescent, Child, Child, Preschool, Female, Humans, Incidence, Italy epidemiology, Male, Practice Guidelines as Topic, Retrospective Studies, Seasons, Sex Distribution, Rheumatic Fever diagnosis, Rheumatic Fever epidemiology
Abstract

Objectives: To estimate the incidence of acute rheumatic fever (ARF) in a metropolitan area of Northern Italy and study how the introduction of the 2015 revised Jones criteria affects the epidemiology in a region with moderate to high incidence of ARF., Study Design: The incidence of ARF in children 5-14 years old living in the Province of Turin was estimated using low-risk criteria in a 10-year period (group A patients). The proportion of patients fulfilling only high-risk (HR) criteria (group B patients) was also calculated both prospectively (from July 2015 through December 2016) and retrospectively (from January 2007 through June 2015)., Results: One hundred thirty-five group A patients were identified for an annual incidence of 3.2-9.6 out of 100 000 children. The use of HR criteria identified an additional 28 patients (group B), resulting in a 20.7% increase in the incidence of ARF. Age, sex annual incidence, and seasonal distribution pattern were comparable between group A and group B patients., Conclusions: HR criteria should be used for the diagnosis ARF in our region. The application of these criteria led to a 20% increase in patients with the diagnosis of ARF. The characteristics of patients fulfilling only HR criteria are similar to the remaining patients, suggesting that these criteria are sensitive and specific., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Published
2018
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6. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study.

Author

Barzaghi F, Amaya Hernandez LC, Neven B, Ricci S, Kucuk ZY, Bleesing JJ, Nademi Z, Slatter MA, Ulloa ER, Shcherbina A, Roppelt A, Worth A, Silva J, Aiuti A, Murguia-Favela L, Speckmann C, Carneiro-Sampaio M, Fernandes JF, Baris S, Ozen A, Karakoc-Aydiner E, Kiykim A, Schulz A, Steinmann S, Notarangelo LD, Gambineri E, Lionetti P, Shearer WT, Forbes LR, Martinez C, Moshous D, Blanche S, Fisher A, Ruemmele FM, Tissandier C, Ouachee-Chardin M, Rieux-Laucat F, Cavazzana M, Qasim W, Lucarelli B, Albert MH, Kobayashi I, Alonso L, Diaz De Heredia C, Kanegane H, Lawitschka A, Seo JJ, Gonzalez-Vicent M, Diaz MA, Goyal RK, Sauer MG, Yesilipek A, Kim M, Yilmaz-Demirdag Y, Bhatia M, Khlevner J, Richmond Padilla EJ, 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 ML, Bredius RG, Kałwak K, Haddad E, Seidel MG, Duckers G, Pai SY, Dvorak CC, Ehl S, Locatelli F, Goldman F, Gennery AR, Cowan MJ, Roncarolo MG, and Bacchetta R

Subjects
Adolescent, Adult, Allografts, Child, Child, Preschool, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 mortality, Diabetes Mellitus, Type 1 therapy, Disease-Free Survival, Female, Follow-Up Studies, Humans, Immune System Diseases genetics, Immune System Diseases immunology, Immune System Diseases mortality, Immune System Diseases therapy, Infant, Male, Retrospective Studies, Survival Rate, Diabetes Mellitus, Type 1 congenital, Diarrhea genetics, Diarrhea immunology, Diarrhea mortality, Diarrhea therapy, Forkhead Transcription Factors genetics, Forkhead Transcription Factors immunology, Genetic Diseases, X-Linked genetics, Genetic Diseases, X-Linked immunology, Genetic Diseases, X-Linked mortality, Genetic Diseases, X-Linked therapy, Hematopoietic Stem Cell Transplantation, Immune System Diseases congenital, Immunosuppression Therapy, Mutation
Abstract

Background: Immunodysregulation 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., 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., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2018
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7. Diagnosing XLP1 in patients with hemophagocytic lymphohistiocytosis.

Author

Meazza R, Tuberosa C, Cetica V, Falco M, Parolini S, Grieve S, Griffiths GM, Sieni E, Marcenaro S, Micalizzi C, Montin D, Fagioli F, Moretta A, Mingari MC, Moretta L, Notarangelo LD, Bottino C, Aricò M, and Pende D

Subjects
Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Intracellular Signaling Peptides and Proteins genetics, Killer Cells, Natural immunology, Leukocytes, Mononuclear immunology, Lymphohistiocytosis, Hemophagocytic genetics, Lymphohistiocytosis, Hemophagocytic immunology, Lymphoproliferative Disorders genetics, Lymphoproliferative Disorders immunology, Male, Mutation, Signaling Lymphocytic Activation Molecule Associated Protein, Signaling Lymphocytic Activation Molecule Family, Young Adult, Antigens, CD immunology, Intracellular Signaling Peptides and Proteins immunology, Lymphohistiocytosis, Hemophagocytic diagnosis, Lymphoproliferative Disorders diagnosis, Receptors, Immunologic immunology
Abstract

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, heterogeneous, hyperinflammmatory disorder. Prompt identification of inherited forms resulting from mutation in genes involved in cellular cytotoxicity can be crucial. X-linked lymphoproliferative disease 1 (XLP1), due to mutations in SH2D1A (Xq25) encoding signaling lymphocyte activation molecule-associated protein (SAP), may present with HLH. Defective SAP induces paradoxical inhibitory function of the 2B4 coreceptor and impaired natural killer (NK) (and T) cell response against EBV-infected cells., Objective: To characterize a cohort of patients with HLH and XLP1 for SAP expression and 2B4 function in lymphocytes, proposing a rapid diagnostic screening to direct mutation analysis., Methods: We set up rapid assays for 2B4 function (degranulation or (51)Cr-release) to be combined with intracellular SAP expression in peripheral blood NK cells. We studied 12 patients with confirmed mutation in SH2D1A and some family members., Results: The combined phenotypic/functional assays allowed efficient and complete diagnostic evaluation of all patients with XLP1, thus directing mutation analysis and treatment. Nine cases were SAP(-), 2 expressed SAP with mean relative fluorescence intensity values below the range of healthy controls (SAP(dull)), and 1, carrying the R55L mutation, was SAP(+). NK cells from all patients showed inhibitory 2B4 function and defective killing of B-EBV cells. Carriers with SH2D1A mutations abolishing SAP expression and low percentage of SAP(+) cells showed neutral 2B4 function at the polyclonal NK cell level. Three novel SH2D1A mutations have been identified., Conclusions: Study of SAP expression is specific but may have insufficient sensitivity for screening XLP1 as a single tool. Combination with 2B4 functional assay allows identification of all cases., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Published
2014
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8. Clinical features and follow-up in patients with 22q11.2 deletion syndrome.

Author

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 A, Pietrogrande MC, Marino B, Ugazio AG, Plebani A, and Rossi P

Subjects
Abnormalities, Multiple epidemiology, Adolescent, Adult, Age Factors, Child, Child, Preschool, Chromosomes, Human, Pair 22 genetics, Delayed Diagnosis, Developmental Disabilities diagnosis, DiGeorge Syndrome genetics, DiGeorge Syndrome therapy, Early Diagnosis, Female, Follow-Up Studies, Genetic Testing, Humans, Infant, Infant, Newborn, Male, Prospective Studies, Retrospective Studies, Risk Assessment, Severity of Illness Index, Sex Factors, Time Factors, Young Adult, Abnormalities, Multiple diagnosis, Developmental Disabilities epidemiology, DiGeorge Syndrome diagnosis, Disease Progression, Monitoring, Physiologic methods
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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Published
2014
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9. B-cell development and functions and therapeutic options in adenosine deaminase-deficient patients.

Author

Brigida I, Sauer AV, Ferrua F, Giannelli S, Scaramuzza S, Pistoia V, Castiello MC, Barendregt BH, Cicalese MP, Casiraghi M, Brombin C, Puck J, Müller K, Notarangelo LD, Montin D, van Montfrans JM, Roncarolo MG, Traggiai E, van Dongen JJ, van der Burg M, and Aiuti A

Subjects
Adenosine Deaminase genetics, Adenosine Deaminase therapeutic use, Adolescent, B-Cell Activating Factor physiology, B-Lymphocytes immunology, Child, Child, Preschool, Humans, Infant, Adenosine Deaminase deficiency, B-Lymphocytes physiology, Enzyme Replacement Therapy, Genetic Therapy, Hematopoietic Stem Cell Transplantation
Abstract

Background: Adenosine 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., Objective: We 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., Methods: Flow 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., Results: Despite 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., Conclusions: ADA-deficient patients show specific defects in B-cell development and functions that are differently corrected after ERT and HSC-GT., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Published
2014
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10. Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias.

Author

Chen R, Giliani S, Lanzi G, Mias GI, Lonardi S, Dobbs K, Manis J, Im H, Gallagher JE, Phanstiel DH, Euskirchen G, Lacroute P, Bettinger K, Moratto D, Weinacht K, Montin D, Gallo E, Mangili G, Porta F, Notarangelo LD, Pedretti S, Al-Herz W, Alfahdli W, Comeau AM, Traister RS, Pai SY, Carella G, Facchetti F, Nadeau KC, Snyder M, and Notarangelo LD

Subjects
Animals, Child, Preschool, Exome genetics, Female, Humans, Infant, Infant, Newborn, Male, Mice, Mutation, Oligonucleotide Array Sequence Analysis, RNA, Messenger metabolism, Thymus Gland metabolism, Tissue Array Analysis, Immunologic Deficiency Syndromes genetics, Intestinal Atresia genetics, Intestines abnormalities, Proteins genetics
Abstract

Background: Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects., Objective: We sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequences of 5 patients and their healthy direct relatives from 5 unrelated families., Methods: We performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene tetratricopeptide repeat domain 7A (TTC7A) on 3 additional patients with CID-MIA., Results: Through analysis and comparison of the exomic sequence of the subjects from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in 2 of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells, as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from 2 patients with CID-MIA., Conclusions: We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Published
2013
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