Craniosynostoses: Molecular Genetics, Principles of Diagnosis, and Treatment (Monographs in Human Genetics, Vol. 19)

Craniosynostosis - the premature fusion of the cranial sutures of an infant's skull - is a challenging and complex condition that can occur as part of a syndrome or in isolation. In the last two decades increased knowledge about the structure and function of the human genome has enabled the discovery of the molecular etiologies of most forms of syndromic craniosynostosis, which in turn has allowed for the analysis of normal and abnormal sutural biology from the atomic to the population-based level. In parallel with the increase in basic biological understanding, advances in clinical diagnosis and treatment have been achieved including improved prenatal imaging technology and craniofacial surgical techniques as well as condition-specific care in specialized hospitals and clinical units. This book represents a comprehensive overview on the subject of craniosynostosis. Its 19 excellent chapters were written by the foremost authorities in the field for a wide range of readers. They cover topics including a historical review, basic biological and molecular studies, the various common and uncommon syndromes, nonsyndromic craniosynostoses, genetic testing, prenatal ultrasonography, and recent methods of neurosurgical and maxillofacial treatment. Both investigators at the bench and clinicians at the operating table will appreciate this timely book which will be the definitive volume on craniosynostosis for many years to come. Contents 6 Editorial 8 Preface 9 Foreword 10 Chapter 1: Craniosynostosis: A Historical Overview 12 Abstract 12 General History 12 Syndromic Craniosynostosis and GeneticDiscoveries 13 History of Treatment Aspects ofCraniosynostosis 16 Concluding Remarks 17 Acknowledgements 17 References 17 Chapter 2: Discovery of MSX2 Mutation in Craniosynostosis: A Retrospective View 19 Abstract 19 Family Identification 19 Discovery of the Causative Mutation 21 Functional Analyses of the Mutation 21 Conclusion 22 Acknowledgement 22 References 23 Chapter 3: Regulation of Calvarial Bone Growth by Molecules Involved in the Craniosynostoses 24 Abstract 24 Anatomy and Origins of the Cranial Vault 25 Calvarial Sutures as Intramembranous Bone Growth Sites 26 Transcriptional Control of Osteoblast Commitment and Differentiation 27 Ephrins, Boundary Formation, and Directed Bone Growth 28 Fibroblast Growth Factor Receptors in Cranial Osteoblast Proliferation and Differentiation 30 Transforming Growth Factor Beta, Osteoblast Function, and Suture Maintenance 35 Integration of Signaling and Concluding Remarks 36 References 36 Chapter 4: Signal Transduction Pathways and Their Impairment in Syndromic Craniosynostosis 39 Abstract 39 Suture Anatomy 40 Dura Mater 41 Pericranium 43 Osteogenic Fronts and Suture Mesenchyme 43 Genes Associated with Syndromic Craniosynostosis 45 Fibroblast Growth Factor (FGF) Receptors 45 TWIST1 47 MSX2 47 Eph/Ephrin Signaling 47 TGFβ Signaling 48 Integration of Pathways and Mechanisms of Craniosynostosis 48 References 53 Chapter 5: The Molecular Bases for FGF Receptor Activation in Craniosynostosis and Dwarfism Syndromes 56 Abstract 56 Structural and Biochemical Analysis of Mutations Leading to Ligand- Dependent Gain of Function 58 Structural and Biochemical Analysis of Mutations Leading to Ligand- Independent Gain of Function 65 Conclusion 65 Acknowledgements 66 References 66 Chapter 6: Recurrent Germline Mutations in the FGFR2/3 Genes, High Mutation Frequency, Paternal Skewing and Age- Dependence 69 Abstract 69 Specific Human Germline Nucleotide Substitutions Predominantly Come from Men and Increase with Age 69 Models to Explain Male Bias and the Paternal Age Effect 69 Human Germline Nucleotide Substitution Mutations Vary Markedly in Frequency 70 Confirmation of High Nucleotide Substitution Germline Mutation Frequencies, Mutation Hot Spot versus Germline Selection Model 70 Testing the Mutation Hot Spot versus Germline Selection Model 71 Experimental Analysis 71 Apert Syndrome Mutation Frequencies in Young Testis Donors 73 Testis Distribution of a C to G Transversion Mutation at a Control CpG Site 73 By Including Selection, Computational Analysis Explains the Testis Data 73 The Parental Age Effect of Apert Syndrome Occurrence Revisited 74 Why Does the Sperm Mutation Frequency Goup with Age? 76 References 76 Chapter 7: Apert, Crouzon, and Pfeiffer Syndromes 78 Abstract 78 Apert Syndrome 78 Crouzon Syndrome 92 Pfeiffer Syndrome 94 Acknowledgement 98 References 98 Chapter 8: Muenke Syndrome 100 Abstract 100 Gene Discovery 101 Inheritance and Genetic Counseling 101 Clinical Findings and Diagnosis 102 Management 104 Molecular Pathogenesis 104 Conclusions 106 Acknowledgements 106 References 107 Chapter 9: Saethre- Chotzen Syndrome: Clinical and Molecular Genetic Aspects 109 Abstract 109 Phenotypic Features 109 The SCS Causing Gene TWIST1 113 TWIST1 Mutational Spectrum 115 Mouse Model 116 Treatment 116 References 116 Chapter 10: Craniofrontonasal Syndrome: Molecular Genetics, EFNB1 Mutations and the Concept of Cellular Interference 118 Abstract 118 Clinical Features 118 Pattern of Inheritance 120 The CFNS Causing Gene EFNB1 121 EFNB1 Mutation Spectrum 122 Sex- Dependent Manifestation and Proposed Pathomechanism in CFNS 125 Genetic Mouse Models for CFNS 127 Acknowledgements 127 References 127 Chapter 11: Uncommon Craniosynostosis Syndromes: A Review of Thirteen Conditions 130 Abstract 130 Antley- Bixler Syndrome (MIM #207410) P450 Oxidoreductase (POR) Deficiency (MIM#201750) 134 Baller- Gerold Syndrome (MIM #218600) 137 Beare- Stevenson Cutis Gyrata Syndrome (MIM#123790) 138 C (Opitz Trigonocephaly) Syndrome (MIM#211750) Bohring- Opitz Syndrome (MIM #605039) 139 Carpenter Syndrome (MIM #201000) 140 Crouzon Syndrome with Acanthosis Nigricans (MIM #612247) 141 Jackson- Weiss Syndrome (MIM #123150) 142 Jacobsen Syndrome (MIM #147791) 143 Osteoglophonic Dysplasia (MIM #166250) 145 Shprintzen- Goldberg Syndrome (MIM#182212) Loeys- Dietz Syndrome, Types IA and IB (MIM #609192, MIM #610168) 147 Acknowledgements 149 References 149 Chapter 12: Metopic Craniosynostosis Syndrome Due to Mutations in GLI3 154 Abstract 154 Case Reports 155 GLI3 Pathogenesis and Mutation Spectrum 159 Genetic Mouse Models for GLI3 Disorders 160 Conclusion and Implications 161 Acknowledgements 161 References 161 Chapter 13: Craniosynostosis and Chromosomal Alterations 163 Abstract 163 Chromosomal Alterations 164 Craniosynostosis Syndromes Due to Chromosomal Deletions: 9p and 11q 168 Chromosomal Rearrangements and Their Contribution to the Identification of Craniosynostotic Candidate Genes 169 Submicroscopic Rearrangements: An Important Cause of Craniosynostosis? 170 Conclusions 170 References 171 Chapter 14: Nonsyndromic Craniosynostoses 176 Abstract 176 Scaphocephaly 177 Trigonocephaly 179 Anterior Plagiocephaly 180 Brachycephaly 181 Posterior Plagiocephaly 182 Bisutural Synostosis 183 Oxycephaly 184 Acknowledgements 185 References 185 Chapter 15: Molecular Genetic Testing of Patients with Craniosynostosis 188 Abstract 188 First Step: Clinical Evaluation 189 Second Step: Genetic Workup of Craniosynostosis 189 Third Step: Interpretation of Test Results and Genetic Counseling 192 References 194 Chapter 16: Prenatal Sonographic Diagnosis of Craniosynostosis 195 Abstract 195 Ultrasound Examination of the Normal Fetal Skull 195 Ultrasound in Craniosynostosis 197 Conclusion 209 References 209 Chapter 17: Clinical Approach to Craniosynostosis 210 Abstract 210 Abnormal Head Shape in the Absence of Craniosynostosis 210 Abnormal Head Shape Due to Craniosynostosis 211 Imaging Studies to Confirm Synostosis 213 Underlying Etiology Varies by Affected Suture or Sutures 214 Clinical Evaluation: Family History 215 Clinical Evaluation: Past Medical History 215 Clinical Evaluation: Physical Examination 217 Evaluation of Specific Organ Systems and Their Function: Central Nervous System and Neurodevelopment 219 Evaluation of Specific Organ Systems and Their Function: Ophthalmologic Considerations 221 Evaluation of Specific Organ Systems and Their Function: Otolaryngologic Considerations 221 Evaluation of Specific Organ Systems and Their Function: Growth and Feeding 222 Evaluation of Specific Organ Systems and Their Function: Internal Organs 222 Evaluation of Specific Organ Systems and Their Function: Musculoskeletal Considerations 222 Differential Diagnosis and Laboratory Testing 223 Multidisciplinary Treatment Approach 224 References 224 Chapter 18: Imaging Studies and Neurosurgical Treatment 227 Abstract 227 Technical Aids of Examination 227 Principles of Treatment 233 Surgical Risks 235 Postoperative Surveillance and Strategies 237 Management of Specific Types of Craniosynostosis 238 References 241 Chapter 19: Maxillofacial Examination and Treatment 243 Abstract 243 Development of the Midface 243 Abnormalities of the Viscerocranium in Craniosynostosis 244 Principles of Maxillofacial Treatment in Patients with Craniosynostosis 246 References 253 Author Index 255 Subject Index 256 ISBN,9783805595940,(hard,cover,:,alk.,paper),--,ISBN,9783805595957,(e-ISBN) Karger Contents......Page 6 Editorial......Page 8 Preface......Page 9 Foreword......Page 10 General History......Page 12 Syndromic Craniosynostosis and GeneticDiscoveries......Page 13 History of Treatment Aspects ofCraniosynostosis......Page 16 References......Page 17 Family Identification......Page 19 Functional Analyses of the Mutation......Page 21 Acknowledgement......Page 22 References......Page 23 Abstract......Page 24 Anatomy and Origins of the Cranial Vault......Page 25 Calvarial Sutures as Intramembranous Bone Growth Sites......Page 26 Transcriptional Control of Osteoblast Commitment and Differentiation......Page 27 Ephrins, Boundary Formation, and Directed Bone Growth......Page 28 Fibroblast Growth Factor Receptors in Cranial Osteoblast Proliferation and Differentiation......Page 30 Transforming Growth Factor Beta, Osteoblast Function, and Suture Maintenance......Page 35 References......Page 36 Abstract......Page 39 Suture Anatomy......Page 40 Dura Mater......Page 41 Osteogenic Fronts and Suture Mesenchyme......Page 43 Fibroblast Growth Factor (FGF) Receptors......Page 45 Eph/Ephrin Signaling......Page 47 Integration of Pathways and Mechanisms of Craniosynostosis......Page 48 References......Page 53 Abstract......Page 56 Structural and Biochemical Analysis of Mutations Leading to Ligand- Dependent Gain of Function......Page 58 Conclusion......Page 65 References......Page 66 Models to Explain Male Bias and the Paternal Age Effect......Page 69 Confirmation of High Nucleotide Substitution Germline Mutation Frequencies, Mutation Hot Spot versus Germline Selection Model......Page 70 Experimental Analysis......Page 71 By Including Selection, Computational Analysis Explains the Testis Data......Page 73 The Parental Age Effect of Apert Syndrome Occurrence Revisited......Page 74 References......Page 76 Apert Syndrome......Page 78 Crouzon Syndrome......Page 92 Pfeiffer Syndrome......Page 94 References......Page 98 Abstract......Page 100 Inheritance and Genetic Counseling......Page 101 Clinical Findings and Diagnosis......Page 102 Molecular Pathogenesis......Page 104 Acknowledgements......Page 106 References......Page 107 Phenotypic Features......Page 109 The SCS Causing Gene TWIST1......Page 113 TWIST1 Mutational Spectrum......Page 115 References......Page 116 Clinical Features......Page 118 Pattern of Inheritance......Page 120 The CFNS Causing Gene EFNB1......Page 121 EFNB1 Mutation Spectrum......Page 122 Sex- Dependent Manifestation and Proposed Pathomechanism in CFNS......Page 125 References......Page 127 Abstract......Page 130 Antley- Bixler Syndrome (MIM #207410) P450 Oxidoreductase (POR) Deficiency (MIM#201750)......Page 134 Baller- Gerold Syndrome (MIM #218600)......Page 137 Beare- Stevenson Cutis Gyrata Syndrome (MIM#123790)......Page 138 C (Opitz Trigonocephaly) Syndrome (MIM#211750) Bohring- Opitz Syndrome (MIM #605039)......Page 139 Carpenter Syndrome (MIM #201000)......Page 140 Crouzon Syndrome with Acanthosis Nigricans (MIM #612247)......Page 141 Jackson- Weiss Syndrome (MIM #123150)......Page 142 Jacobsen Syndrome (MIM #147791)......Page 143 Osteoglophonic Dysplasia (MIM #166250)......Page 145 Shprintzen- Goldberg Syndrome (MIM#182212) Loeys- Dietz Syndrome, Types IA and IB (MIM #609192, MIM #610168)......Page 147 References......Page 149 Abstract......Page 154 Case Reports......Page 155 GLI3 Pathogenesis and Mutation Spectrum......Page 159 Genetic Mouse Models for GLI3 Disorders......Page 160 References......Page 161 Abstract......Page 163 Chromosomal Alterations......Page 164 Craniosynostosis Syndromes Due to Chromosomal Deletions: 9p and 11q......Page 168 Chromosomal Rearrangements and Their Contribution to the Identification of Craniosynostotic Candidate Genes......Page 169 Conclusions......Page 170 References......Page 171 Abstract......Page 176 Scaphocephaly......Page 177 Trigonocephaly......Page 179 Anterior Plagiocephaly......Page 180 Brachycephaly......Page 181 Posterior Plagiocephaly......Page 182 Bisutural Synostosis......Page 183 Oxycephaly......Page 184 References......Page 185 Abstract......Page 188 Second Step: Genetic Workup of Craniosynostosis......Page 189 Third Step: Interpretation of Test Results and Genetic Counseling......Page 192 References......Page 194 Ultrasound Examination of the Normal Fetal Skull......Page 195 Ultrasound in Craniosynostosis......Page 197 References......Page 209 Abnormal Head Shape in the Absence of Craniosynostosis......Page 210 Abnormal Head Shape Due to Craniosynostosis......Page 211 Imaging Studies to Confirm Synostosis......Page 213 Underlying Etiology Varies by Affected Suture or Sutures......Page 214 Clinical Evaluation: Past Medical History......Page 215 Clinical Evaluation: Physical Examination......Page 217 Evaluation of Specific Organ Systems and Their Function: Central Nervous System and Neurodevelopment......Page 219 Evaluation of Specific Organ Systems and Their Function: Otolaryngologic Considerations......Page 221 Evaluation of Specific Organ Systems and Their Function: Musculoskeletal Considerations......Page 222 Differential Diagnosis and Laboratory Testing......Page 223 References......Page 224 Technical Aids of Examination......Page 227 Principles of Treatment......Page 233 Surgical Risks......Page 235 Postoperative Surveillance and Strategies......Page 237 Management of Specific Types of Craniosynostosis......Page 238 References......Page 241 Development of the Midface......Page 243 Abnormalities of the Viscerocranium in Craniosynostosis......Page 244 Principles of Maxillofacial Treatment in Patients with Craniosynostosis......Page 246 References......Page 253 Author Index......Page 255 Subject Index......Page 256 Craniosynostosis : a historical overview / Solomon, B.D. (Bethesda, Md.); Collmann, H.; Kress, W. (Würzburg); Muenke, M. (Bethesda, Md.) Discovery of MSX2 mutation in craniosynostosis : a retrospective view / Müller, U. (Giessen) Regulation of calvarial bone growth by molecules involved in the craniosynostoses / Benson, M.D.; Opperman, L.A. (Dallas Tex.) Signal transduction pathways and their impairment in syndromic craniosynostosis / Connerney, J.J. (Boston, Mass.); Spicer, D.B. (Scarborough, Me.) The molecular bases for FGF receptor activation in craniosynostosis and dwarfism syndromes / Beenken, A.; Mohammadi, M. (New York, N.Y.) Recurrent germline mutations in the FGFR2/3 genes, high mutation frequency, paternal skewing and age-dependence / Arnheim, N.; Calabrese, P. (Los Angeles, Calif.) Apert, Crouzon, and Pfeiffer syndromes / Cohen Jr., M.M. (Halifax, N.S.) Muenke syndrome / Solomon, B.D.; Muenke, M. (Bethesda, Md.) Saethre-Chotzen syndrome : clinical and molecular genetic aspects / Kress, W.; Collmann, H. (Würzburg) Craniofrontonasal syndrome : molecular genetics, EFNB1 mutations and the concept of cellular interference / Wieland, I. (Magdeburg) Uncommon craniosynostosis syndromes : a review of thirteen conditions / Raam, M.S. (Bethesda, Md./Chevy Chase, Md.); Muenke, M. (Bethesda, Md.) Metopic craniosynostosis syndrome due to mutations in GLI3 / McDonald-McGinn, D.M.; Feret, H.; Nah, H.-D.; Zackai, E.H. (Philadelphia, Pa.) Craniosynostosis and chromosomal alterations / Passos-Bueno, M.R.; Fanganiello, R.D.; Jehee, F.S. (Sao Paulo) Nonsyndromic craniosynostoses / Collmann, H. (Würzburg); Solomon, B.D. (Bethesda, Md.); Schweitzer, T.; Kress, W. (Würzburg); Muenke, M. (Bethesda, Md.) Molecular genetic testing of patients with craniosynostosis / Hehr, U. (Regensburg) Prenatal sonographic diagnosis of craniosynostosis / Schramm, T. (Munich) Clinical approach to craniosynostosis / Gripp, K.W. (Wilmington, Del.) Imaging studies and neurosurgical treatment / Collmann, H.; Schweitzer, T.; Bohm, H. (Würzburg) Maxillofacial examination and treatment / Bohm, H.; Schweitzer, T.; Kübler, A. (Würzburg).