The Genetics and Development of Scoliosis (eBook)

Kenro Kusumi, Ph.D., is an Associate Professor in the School of Life Sciences at Arizona State University and is a founding faculty member at the new University of Arizona College of Medicine-Phoenix in partnership with Arizona State University. Dr. Kusumi’s current research focuses on early spinal development, axial musculoskeletal regeneration, and their applications to genetic studies of scoliosis and other musculoskeletal disorders. Sally L. Dunwoodie, Ph.D., is an Associate Professor at the University of New South Wales and Laboratory Head in the Developmental Biology Division at the Victor Chang Cardiac Research Institute in Sydney. Dr Dunwoodie's research focuses on development of the spine, heart, kidney and placenta in mouse, and their relevance to the molecular basis of congenital abnormalities.

Preface 5
Contents 7
Contributors 8
1 Genetic Regulation of Somite and Early Spinal Patterning 10
Introduction 10
Formation of Paraxial Mesoderm 11
Segmental Prepatterning in the Presomitic Mesoderm 12
Notch Pathway Genes 13
Wnt Pathway Genes 16
Fibroblast Growth Factor (FGF) Signaling 17
Interactions Between Notch, Wnt, and FGF Pathway Genes 17
Prepatterning at the Wavefront or Determination Front 18
FGF and Wnt Signaling and the Determination Front 19
Retinoic Acid and the Determination Front 20
Comparison with Somitogenesis in Humans 22
References 23
2 Development and Functional Anatomy of the Spine 30
Introduction 30
Embryonic Origins of the Spine 31
Establishing the Intersomitic Boundary 32
Somite Epithelialization 32
Rostral/Caudal Polarity of Somites 34
The Anatomy and Development of the Vertebrae and IV Discs 35
Functional Anatomy of the Vertebrae and IV Discs 36
Development of the Vertebrae 39
Remodeling the Sclerotome into Vertebrae 41
Rostral/Caudal Patterning 41
Formation of the IV Discs 43
The Anatomy and Development of Spinal Muscles 43
Functional Anatomy of the Spinal Muscles 44
Development of Spinal Muscles 46
Tendon Development 47
References 48
3 Environmental Factors and Axial Skeletal Dysmorphogenesis 56
Introduction 56
Vertebral Dysmorphogenesis in Human Congenital Scoliosis 59
Normal Development of the Axial Skeleton 59
Experimental Axial Skeletal Teratology 61
Pathogenesis of Abnormal Axial Development 61
Overview of Agents and Conditions Associated with Axial Skeletal Teratogenesis 64
Non-genetically Linked Conditions Characterized by Axial Skeletal Defects: VATER Association 65
Environmental Factors That Cause Axial Skeletal Dysmorphogenesis 67
Valproic Acid 67
Hypoxia 67
Carbon Monoxide 68
Diabetes 69
Retinoic Acid 71
Hyperthermia 71
Arsenic 72
Ethanol 73
Methanol 74
Conclusion 74
References 75
4 Overview and Comparison of Idiopathic, Neuromuscular, and Congenital Forms of Scoliosis 82
References 87
5 Abnormal Vertebral Segmentation (or Segmentation Defects of the Vertebrae) and the Spondylocostal Dysostoses 89
Introduction 89
The Problem of Nomenclature 91
The Diversity of Phenotypes Manifesting Axial Skeletal Defects 95
Notch Signaling Pathway Genes and Spondylocostal Dysostosis 97
Delta-Like 3 (DLL3) and SCD 98
Mesoderm Posterior 2 (MESP2) and SCD 101
Lunatic Fringe (LFNG) and SCD 103
Hairy and Enhancer of Split (HES7) and SCD 105
Mesoderm Posterior 2 ( MESP2 ) and Spondylothoracic Dysostosis (STD) 107
A New Classification of SDV 108
Concluding Remarks 112
References 112
6 Spondylothoracic Dysostosis in Puerto Rico 117
Introduction 117
Spondylothoracic Dysostosis and Segmentation Defects of the Vertebrae 118
Spondylothoracic Dysostosis in the Puerto Rican population 119
Clinical Features 120
Raising a Child with Spondylothoracic Dysostosis 124
Prenatal Diagnosis 126
Molecular Analysis of MESP2 in Cases of Spondylothoracic Dysostosis 127
MESP2 and Spondylocostal Dysostosis 129
Role of MESP2 in Somitogenesis 129
Clinical Management of Patients with STD 130
Neonatal Period 131
Infancy and Early Childhood 131
Late Childhood and Adulthood 132
References 132
7 Progress in Understanding Genetic Contributions in Syndromic and Non-Syndromic Disorders Associated with Congenital, Neuromuscular, and Idiopathic Scoliosis 135
Introduction 135
Epidemiology of Segmentation Defects of Vertebrae (SDV) 136
Sporadically Occurring SDV Syndromes 136
Alagille Syndrome 136
Klippel--Feil Anomaly 137
Hemifacial Microsomia (Oculo-Auriculo-Vertebral Spectrum) 138
VACTERL Syndrome 139
Currarino Syndrome 139
Teratogens: A Significant Etiologic Factor in the Development of SDV 140
Overview of the Types of Inheritance Patterns Associated with SDVs and Methodologies Used to Identify Mutations in Vertebral Malformation Syndrome Genes 141
Marfan Syndrome 144
EhlersDanlos Syndrome 145
Spondylocarpotarsal Syndrome 147
Stickler Syndrome 147
Fibronectin 148
PraderWilli Syndrome 148
Neuromuscular and Neurogenic Etiologies 149
SmithMagenis Syndrome 150
Concluding Remarks 152
References 153
8 Genetics and Functional Pathology of Idiopathic Scoliosis 161
Introduction 161
Classification and Natural History 161
Overview of Genetic Analysis of Idiopathic Scoliosis 163
Segregation Analysis 164
Heterogeneity and Other Confounding Factors 165
Positional and Candidate Gene Approaches 166
Chromosomal Anomalies Associated with Idiopathic Scoliosis 167
Genome-Wide Linkage Analysis 167
Summary 170
References 171
9 Current Understanding of Genetic Factors in IdiopathicScoliosis 175
Introduction 175
Scoliosis 175
Idiopathic Scoliosis 175
Presentation, Disease Course, and Treatment 176
What Is Expected from This Chapter? 178
Population Studies 178
Familial and Twin Studies 178
Sibling Risk Studies 179
Inheritance of IS Susceptibility 180
Ethnic Patterns 180
Molecular Genetics 180
Cytogenetic Studies 183
Linkage Analyses 183
Genetic Etiology of IS 185
Models Involving Neurologic Tissues 185
Models Involving Other Spinal Tissues 187
Discovering New Genetic Factors in Idiopathic Scoliosis 187
Discovering Genetic Risk Factors for IS Susceptibility 188
Discovering Risk Factors for Disease Course 189
Understanding Discovered IS Genes in the Context of Adolescent Spinal Development 189
Clinical Implications 191
References 191
10 Conclusion: Trends and Predictions for Geneticand Developmental Biological Research on Scoliosis 199
Introduction 199
Summary 205
References 205
Index 207