| Monographs in Human Genetics Vol. 19 | 3 |
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| Craniosynostoses | 4 |
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| Molecular Genetics, Principles of Diagnosis, and Treatment | 4 |
| Contents | 6 |
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| Editorial | 8 |
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| Preface | 9 |
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| Foreword | 10 |
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| Chapter 1 | 12 |
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| 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 | 19 |
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| 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 | 24 |
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| Regulation of Calvarial Bone Growth by MoleculesInvolved in the Craniosynostoses | 24 |
| Abstract | 24 |
| Anatomy and Origins of the Cranial Vault | 25 |
| Calvarial Sutures as Intramembranous BoneGrowth Sites | 26 |
| Transcriptional Control of OsteoblastCommitment and Differentiation | 27 |
| Ephrins, Boundary Formation, and DirectedBone Growth | 28 |
| Fibroblast Growth Factor Receptors in CranialOsteoblast Proliferation and Differentiation | 30 |
| Transforming Growth Factor Beta, OsteoblastFunction, and Suture Maintenance | 35 |
| Integration of Signaling and ConcludingRemarks | 36 |
| References | 36 |
| Chapter 4 | 39 |
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| Signal Transduction Pathways and TheirImpairment in Syndromic Craniosynostosis | 39 |
| Abstract | 39 |
| Suture Anatomy | 40 |
| Dura Mater | 41 |
| Pericranium | 43 |
| Osteogenic Fronts and Suture Mesenchyme | 43 |
| Genes Associated with SyndromicCraniosynostosis | 45 |
| Fibroblast Growth Factor (FGF) Receptors | 45 |
| TWIST1 | 47 |
| MSX2 | 47 |
| Eph/Ephrin Signaling | 47 |
| TGFß Signaling | 48 |
| Integration of Pathways and Mechanisms ofCraniosynostosis | 48 |
| References | 53 |
| Chapter 5 | 56 |
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| The Molecular Bases for FGF Receptor Activation inCraniosynostosis and Dwarfism Syndromes | 56 |
| Abstract | 56 |
| Structural and Biochemical Analysis ofMutations Leading to Ligand- Dependent Gainof Function | 58 |
| Structural and Biochemical Analysis ofMutations Leading to Ligand- IndependentGain of Function | 65 |
| Conclusion | 65 |
| Acknowledgements | 66 |
| References | 66 |
| Chapter 6 | 69 |
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| Recurrent Germline Mutations in the FGFR2/3Genes, High Mutation Frequency, Paternal Skewingand Age- Dependence | 69 |
| Abstract | 69 |
| Specific Human Germline NucleotideSubstitutions Predominantly Come from Menand Increase with Age | 69 |
| Models to Explain Male Bias and the PaternalAge Effect | 69 |
| Human Germline Nucleotide SubstitutionMutations Vary Markedly in Frequency | 70 |
| Confirmation of High Nucleotide SubstitutionGermline Mutation Frequencies, Mutation HotSpot versus Germline Selection Model | 70 |
| Testing the Mutation Hot Spot versusGermline Selection Model | 71 |
| Experimental Analysis | 71 |
| Apert Syndrome Mutation Frequencies inYoung Testis Donors | 73 |
| Testis Distribution of a C to G TransversionMutation at a Control CpG Site | 73 |
| By Including Selection, ComputationalAnalysis Explains the Testis Data | 73 |
| The Parental Age Effect of Apert SyndromeOccurrence Revisited | 74 |
| Why Does the Sperm Mutation Frequency Goup with Age? | 76 |
| References | 76 |
| Chapter 7 | 78 |
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| Apert, Crouzon, and Pfeiffer Syndromes | 78 |
| Abstract | 78 |
| Apert Syndrome | 78 |
| Crouzon Syndrome | 92 |
| Pfeiffer Syndrome | 94 |
| Acknowledgement | 98 |
| References | 98 |
| Chapter 8 | 100 |
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| 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 | 109 |
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| Saethre- Chotzen Syndrome: Clinical and MolecularGenetic 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 | 118 |
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| Craniofrontonasal Syndrome: Molecular Genetics,EFNB1 Mutations and the Concept of CellularInterference | 118 |
| Abstract | 118 |
| Clinical Features | 118 |
| Pattern of Inheritance | 120 |
| The CFNS Causing Gene EFNB1 | 121 |
| EFNB1 Mutation Spectrum | 122 |
| Sex- Dependent Manifestation and ProposedPathomechanism in CFNS | 125 |
| Genetic Mouse Models for CFNS | 127 |
| Acknowledgements | 127 |
| References | 127 |
| Chapter 11 | 130 |
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| Uncommon Craniosynostosis Syndromes: A Reviewof 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 |