VELO-CARDIO-FACIAL SYNDROME: A MODEL FOR UNDERSTANDING MICRODELETION DISORDERS; ED. BY KIERAN C. MURPHY

Velo-cardio-facial Syndrome (VCFS) is a genetic disorder caused by the deletion of part of chromosome 22. It occurs in approximately one in 4000 births and there are now more than 100 physical phenotypic features reported. VCFS affects every major system in the body and this is the first book to describe its full clinical impact. It has been authored by leading international VCFS clinicians/researchers. The focus is on clinical issues with chapters devoted to psychiatric disorders (with the sufferer showing very high levels of schizophrenia), neuroimaging, speech and language disorders, as well as cardiac, ENT, gastrointestinal, ophthalmic and urological manifestations. Molecular genetics, immunodeficiency and genetic counselling are also covered, and practical approaches to diagnosis and treatment described. As VCFS is seen as a paradigm for other microdeletion disorders, this book will not just appeal to clinicians seeing VCFS patients, but also to those with interests in other genetic disorders. Cover 1 Half-title 3 Title 5 Copyright 6 Contents 7 Abbreviations 9 Contributors 10 Foreword 13 1 Historical overview 15 Speech disorders and VCFS 17 Immune and endocrine disorders 18 Congenital heart anomalies 19 Development of interest in the 1990s 21 Psychiatric manifestations 22 Secondary sequences 23 Other syndromes associated with 22q11.2 deletions 26 Nosology in the historical context 27 Spreading information 29 References 30 2 Molecular genetics of velo-cardio-facial syndrome 33 Introduction 33 Prenatal diagnosis of the 22q11 deletion 33 Embryology of main structures affected in 22q11DS 34 A molecular genetic approach 34 Genes mapping within the TDR 35 DGCR6 35 PRODH 36 DGCR5 36 DGCR2 (aliases IDD, LAN, Sez 12) 36 TSK 37 DGSI (alias Es2) 37 GSCL 37 SCL25A1 (alias CTP) 37 CLTCL1 37 HIRA (alias TUPLE1, DGCR1) 38 NLVCF 38 UFD1l 38 CDC45L 39 CLDN5 (alias TMVCF) 39 PNUTL1 (alias CDCREL1) 39 GP1Bbeta 39 GNB1L (alias WDR14) 40 TRXR2 40 COMT 40 ARVCF 40 T10 41 DGCR8 41 RANBP1 41 ZNF74 41 RTN4R 41 USP18 (UBP43) 41 SREC2 42 PCQAP 42 PIK4CA 42 HC-II 42 SNAP 29 42 CRKL 42 LZTR1 (alias TCFL2) 43 P2X6 43 SLC7A4 43 Mechanism of deletion 43 Testing candidate genes 45 Mouse models 45 Developmental genetics 47 Neural crest involvement 47 Df1 mice and behavior 49 Other models 49 TBX1 mutations are rare in non-deletion VCFS/DGS 49 Chromosome 10p deletion syndromes 50 The future 51 References 52 3 Congenital cardiovascular disease and velocharater-cardio-facial syndrome 61 Types of cardiac defects 63 Tetralogy of Fallot 63 Pulmonary atresia with ventricular septal defect 64 Persistent truncus arteriosus 67 Interrupted aortic arch 68 Isolated aortic arch anomalies 72 Ventricular septal defect 72 Other cardiovascular defects 76 Common findings 77 Clinical implications 79 Surgical implications 80 General issues 81 Tetralogy of Fallot 81 Pulmonary atresia with ventricular septal defect 82 Truncus arteriosus 83 Interrupted aortic arch 84 Isolated aortic arch anomalies 84 Ventricular septal defect 85 Perioperative policy 85 References 86 4 Palatal anomalies and velopharyngeal dysfunction associated with velo-cardio-facial syndrome 97 Cleft palate and VCFS 97 Defining the palatal phenotype in VCFS 97 Surgical management of cleft palate: timing 101 Surgical management of cleft palate: technique 102 Velopharyngeal insufficiency and VCFS 105 Anatomy and physiology of the velopharyngeal valve 105 Nature of velopharyngeal dysfunction in VCFS 107 Assessment of velopharyngeal function 108 Nonsurgical management of velopharyngeal insufficiency 111 Surgical management of velopharyngeal insufficiency 111 Summary 115 References 115 5 Nephro-urologic, gastrointestinal, and ophthalmic findings 119 Nephro-urological anomalies in VCFS 119 Pathogenesis of congenital nephro-urological malformations 120 Clinical manifestations of congenital uropathies 122 Prenatal presentation of uropathies 122 Other renal and urological manifestations 123 Gastrointestinal findings 123 Congenital malformations of the gastrointestinal system 124 Feeding and swallowing difficulties 124 Oral preparatory phase 124 Normal development 124 VCFS 125 Oral phase 125 Normal development 125 VCFS 125 Pharyngeal phase 126 Normal development 126 VCFS 127 Esophageal phase 128 Normal development 128 VCFS 128 Developmental influence 129 Breastfeeding in VCFS 129 Conclusions 130 Ophthalmic findings 130 Acknowledgements 132 References 133 6 Immunodeficiency in velo-cardio-facial syndrome 137 Overview 137 A multidisciplinary approach 138 Overview of the immunodeficiency 139 The immunodeficiency is independent of other phenotypic features 141 Natural history of the immunodeficiency 142 Specifics of the immunodeficiency 143 Consequences of the immunodeficiency 143 Management 144 Summary 146 References 146 7 Behavioral and psychiatric disorder in velo-cardio-facial syndrome 149 Behavioral and psychiatric disorder in children with VCFS 149 Psychiatric disorder in adults with VCFS 150 VCFS and schizophrenia – a valid association? 152 Is the frequency of schizophrenia increased in VCFS individuals? 152 Is there increased frequency of VCFS in people with schizophrenia? 153 Is there a susceptibility locus for schizophrenia mapping to 22q11? 154 VCFS and schizophrenia – what is the mechanism? 155 Assessment and treatment of psychiatric disorders in individuals with VCFS 155 Adults 156 Children and adolescents 157 Conclusions 158 References 158 8 The cognitive spectrum in velo-cardio-facial syndrome 161 Introduction 161 Cognition 162 Intelligence 162 Intellectual profile 163 Academic achievement 164 Cognitive functions 165 Mathematics and numerical skills 165 Visual object and spatial cognition 167 Memory 167 Executive functions (EF) 168 Attention 169 Communication skills and language 170 VCFS and non-verbal learning disability (NVLD) 171 Summary 172 Discussion and future directions 172 References 175 9 Neuroimaging in velo-cardio-facial syndrome 179 Introduction 179 Qualitative MRI studies in VCFS 179 Quantitative MRI studies of children and adolescents with VCFS 180 Quantitative MRI studies of VCFS adults 184 Effects of imprinting 187 Discussion 188 References 190 10 Speech and language disorders in velo-cardio-facial syndrome 195 Language 195 Speech 198 Voice 199 Resonance 201 Articulation 206 Summary 209 References 210 11 Genetic counseling 214 Mortality 216 Variability 216 Parent of origin 216 Inheritance 218 Recurrence risk 218 Genetic counseling 220 Guidelines for prenatal diagnosis 223 References 229 12 Family issues 233 Impact of initial diagnosis 233 Why us? 233 The mother 233 The father 234 Siblings 234 The grandparents 234 What happens while the baby is still in hospital? 235 Issues for children and adults with VCFS 235 Social implications 235 Personality 236 Medical 237 Communication and education 237 How physicians can help individuals with VCFS and their families 239 How else might the physician help? 240 Support services 241 Conclusions 242 Index 244 Cover......Page 1 Half-title......Page 3 Title......Page 5 Copyright......Page 6 Contents......Page 7 Abbreviations......Page 9 Contributors......Page 10 Foreword......Page 13 1 Historical overview......Page 15 Speech disorders and VCFS......Page 17 Immune and endocrine disorders......Page 18 Congenital heart anomalies......Page 19 Development of interest in the 1990s......Page 21 Psychiatric manifestations......Page 22 Secondary sequences......Page 23 Other syndromes associated with 22q11.2 deletions......Page 26 Nosology in the historical context......Page 27 Spreading information......Page 29 References......Page 30 Prenatal diagnosis of the 22q11 deletion......Page 33 A molecular genetic approach......Page 34 DGCR6......Page 35 DGCR2 (aliases IDD, LAN, Sez 12)......Page 36 CLTCL1......Page 37 UFD1l......Page 38 GP1Bbeta......Page 39 ARVCF......Page 40 USP18 (UBP43)......Page 41 CRKL......Page 42 Mechanism of deletion......Page 43 Mouse models......Page 45 Neural crest involvement......Page 47 TBX1 mutations are rare in non-deletion VCFS/DGS......Page 49 Chromosome 10p deletion syndromes......Page 50 The future......Page 51 References......Page 52 3 Congenital cardiovascular disease and velocharater-cardio-facial syndrome......Page 61 Tetralogy of Fallot......Page 63 Pulmonary atresia with ventricular septal defect......Page 64 Persistent truncus arteriosus......Page 67 Interrupted aortic arch......Page 68 Ventricular septal defect......Page 72 Other cardiovascular defects......Page 76 Common findings......Page 77 Clinical implications......Page 79 Surgical implications......Page 80 Tetralogy of Fallot......Page 81 Pulmonary atresia with ventricular septal defect......Page 82 Truncus arteriosus......Page 83 Isolated aortic arch anomalies......Page 84 Perioperative policy......Page 85 References......Page 86 Defining the palatal phenotype in VCFS......Page 97 Surgical management of cleft palate: timing......Page 101 Surgical management of cleft palate: technique......Page 102 Anatomy and physiology of the velopharyngeal valve......Page 105 Nature of velopharyngeal dysfunction in VCFS......Page 107 Assessment of velopharyngeal function......Page 108 Surgical management of velopharyngeal insufficiency......Page 111 References......Page 115 Nephro-urological anomalies in VCFS......Page 119 Pathogenesis of congenital nephro-urological malformations......Page 120 Prenatal presentation of uropathies......Page 122 Gastrointestinal findings......Page 123 Normal development......Page 124 VCFS......Page 125 Normal development......Page 126 VCFS......Page 127 VCFS......Page 128 Breastfeeding in VCFS......Page 129 Ophthalmic findings......Page 130 Acknowledgements......Page 132 References......Page 133 Overview......Page 137 A multidisciplinary approach......Page 138 Overview of the immunodeficiency......Page 139 The immunodeficiency is independent of other phenotypic features......Page 141 Natural history of the immunodeficiency......Page 142 Consequences of the immunodeficiency......Page 143 Management......Page 144 References......Page 146 Behavioral and psychiatric disorder in children with VCFS......Page 149 Psychiatric disorder in adults with VCFS......Page 150 Is the frequency of schizophrenia increased in VCFS individuals?......Page 152 Is there increased frequency of VCFS in people with schizophrenia?......Page 153 Is there a susceptibility locus for schizophrenia mapping to 22q11?......Page 154 Assessment and treatment of psychiatric disorders in individuals with VCFS......Page 155 Adults......Page 156 Children and adolescents......Page 157 References......Page 158 Introduction......Page 161 Intelligence......Page 162 Intellectual profile......Page 163 Academic achievement......Page 164 Mathematics and numerical skills......Page 165 Memory......Page 167 Executive functions (EF)......Page 168 Attention......Page 169 Communication skills and language......Page 170 VCFS and non-verbal learning disability (NVLD)......Page 171 Discussion and future directions......Page 172 References......Page 175 Qualitative MRI studies in VCFS......Page 179 Quantitative MRI studies of children and adolescents with VCFS......Page 180 Quantitative MRI studies of VCFS adults......Page 184 Effects of imprinting......Page 187 Discussion......Page 188 References......Page 190 Language......Page 195 Speech......Page 198 Voice......Page 199 Resonance......Page 201 Articulation......Page 206 Summary......Page 209 References......Page 210 11 Genetic counseling......Page 214 Parent of origin......Page 216 Recurrence risk......Page 218 Genetic counseling......Page 220 Guidelines for prenatal diagnosis......Page 223 References......Page 229 The mother......Page 233 The grandparents......Page 234 Social implications......Page 235 Personality......Page 236 Communication and education......Page 237 How physicians can help individuals with VCFS and their families......Page 239 How else might the physician help?......Page 240 Support services......Page 241 Conclusions......Page 242 Index......Page 244 "Velo-cardio-facial syndrome (VCFS) is a genetic disorder associated with a deletion of the long arm of chromosome 22. It is the most common interstitial deletion disorder found in man and affects every major system in the body with more than 100 physical and behavioural phenotypic features reported. This book, written by leading international VCFS clinicians and scientists, attempts to summarise the rapid progress that has recently been made in understanding and treating people with VCFS. The focus is on clinical issues with chapters devoted to psychiatric disorders (with particular reference to the high rates of schizophrenia reported), neuroimaging, speech and language disorders, as well as cardiac, ENT, gastrointestinal, ophthalmic, and urological manifestations. Molecular genetics, immunodeficiency, and genetic counselling are also covered, and practical approaches to diagnosis and treatment described. As VCFS is seen as a paradigm for other microdeletion disorders, this book will appeal not just to clinicians who see VCFS patients, but also to those with interests in other genetic disorders."--Jacket

Velo-Cardio-Facial Syndrome (VCFS) is a genetic disorder caused by the deletion of part of chromosome 22. It occurs in approximately one in 4000 births and there are now more than 100 physical phenotypic features reported. VCFS affects every major system in the body and this 2005 book was the first to describe its full clinical impact. It has been authored by leading international VCFS clinicians/researchers. The focus is on clinical issues with chapters devoted to psychiatric disorders (with the sufferer showing very high levels of schizophrenia), neuroimaging, speech and language disorders, as well as cardiac, ENT, gastrointestinal, ophthalmic and urological manifestations. Molecular genetics, immunodeficiency and genetic counselling are also covered, and practical approaches to diagnosis and treatment described. As VCFS is seen as a paradigm for other microdeletion disorders, this book will not just appeal to clinicians seeing VCFS patients, but also to those interested in other genetic disorders.

Velo-Cardio-Facial Syndrome (VCFS) is a genetic disorder caused by deletion of part of chromosome 22. The focus is clinical issues with chapters devoted to psychiatric disorders, neuroimaging, speech and language, cardiac, ENT, gastrointestinal, ophthalmic and urological manifestations. This 2005 book has been authored by leading international VCFS clinicians and researchers. Velo-cardio-facial Syndrome (VCFS) is a genetic disorder caused by deletion of part of chromosome 22. The focus is on clinical issues with chapters devoted to psychiatric disorders, neuroimaging, speech and language, cardiac, ENT, gastrointestinal, ophthalmic and urological manifestations. This book has been authored by leading international VCFS clinicians and researchers Edited By Kieran C. Murphy, Peter J. Scambler. Includes Bibliographical References And Index.