EtiologyBased Dental and Craniofacial Diagnostics

Etiology-Based Dental and Craniofacial Diagnostics

It is a great pleasure for me to dedicate this book to dentists and other professionals working in the community dental clinics in Denmark. I would like to take the opportunity to express my admiration for this public dental institution which serves nearly all of the children in the country. A hearty thanks for: • Mutual collaboration and inspiration regarding diagnostics and treatment of patients in the clinic • The helpfulness and confidence that I have received over many years • Interest and support in this project for the benefit of our future patients. Inger Kjær

Etiology-Based Dental and Craniofacial Diagnostics Inger Kjær

This edition first published 2017  2017 by John Wiley & Sons Limited. Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices:: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 1606 Golden Aspen Drive, Suites 103 and 104, Ames, Iowa 50010, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by health science practitioners for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Names: Kjær, Inger, author. Title: Etiology-based dental and craniofacial diagnostics / Inger Kjær. Description: Southern Gate, Chichester, West Sussex, UK ; Ames, Iowa : John Wiley & Sons Inc., 2017. | Includes bibliographical references and index. Identifiers: LCCN 2016018619| ISBN 9781118912126 (cloth) | ISBN 9781118912102 (ePub) | ISBN 9781118912119 (Adobe PDF) Subjects: | MESH: Tooth Abnormalities–diagnosis | Skull–embryology | Skull–growth & development Classification: LCC RK308 | NLM WU 101.5 | DDC 617.6/3075–dc23 LC record available at https://lccn.loc.gov/2016018619 A catalogue record for this book is available from the British Library. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Set in 9.5/12 pt MinionPro-Regular by Thomson Digital, Noida, India 1 2017

Contents Preface, ix Definition of developmental field, 37 Developmental fields in the cranium, 37 Introduction, xi Limited access to human material, xi The midaxial cranium, 37 Content and structure of the book, xi The paraaxial cranium, 37 Acknowledgments, xii Frontonasal field, 37 Maxillary field and palatine field, 38 1 Craniofacial development and the body axis: normal and Mandibular field, 40 pathological aspects from early prenatal to Theca field, 41 postnatal life, 1 Occipital field, 41 Body axis pre- and postnatally, 1 How can craniofacial fields be proven?, 42 Germ disk and notochord, 1 Frontonasal field, 42 Formation of the vertebral column, 1 Maxillary and palatine field, 42 Cervical spine pre- and postnatally, 1 Mandibular field, 43 The interrelationship between the body axis and the Theca field, 43 cranium, 2 Occipital field, 43 Craniofacial development pre- and postnatally, 4 Developmental fields in the alveolar process, 44 Cranial base (excluding the sella turcica), 4 The upper jaw and the dentition, 44 Sella turcica, 7 The lower jaw and the dentition, 44 Maxilla, 8 Highlights and clinical relevance, 45 Mandible, 12 Further reading, 45 Theca cranii, 15 Vomeral bone, 16 4 Tooth development and tooth maturation from early Nasal bones, 17 prenatal to postnatal life, 46 Temporal bone, 18 Histological evaluation of early tooth development, 46 Craniofacial morphology and growth, 19 Tissues involved in dental bud formation, 46 Highlights and clinical relevance, 19 Inner enamel epithelium and hard tissue Further reading, 19 formation, 46 Outer enamel epithelium and crown follicle, 46 2 Craniofacial development and the brain: normal and Root membrane and root development, 48 pathological aspects from early prenatal Sequences in prenatal tooth formation, 49 to postnatal life, 21 Radiographic evaluation of normal dental Central nervous system in relation to neurocranial maturation, 49 development pre- and postnatally, 21 Radiographic appearance of prenatal crowns Brain, 21 before GA 22 weeks, 50 Spinal cord, 24 Radiographic appearance of postnatal dental Trigeminal ganglia, 26 maturation, 50 Vomeronasal organs, 26 Clinical evaluation of dental maturity, 52 Pituitary gland and sella turcica, 28 Bilateral agreement in tooth maturation, 52 Peripheral nervous system pre- and Tooth formation from the initial stages to the eruption postnatally, 32 stages: relation to fields, gender, age, and skeletal Jaw innervation and bone formation, 32 maturity, 52 Highlights and clinical relevance, 34 Similarities and differences in primary and permanent Further reading, 35 dental development, 53 Highlights and clinical relevance, 53 3 Developmental fields in the cranium and Further reading, 55 alveolar process, 37 v

vi Contents 5 Periodontal membrane and peri-root sheet, 56 9 Deviations in tooth number: normal and pathological Periodontal membrane, 56 variations including syndromes, 111 Peri-root sheet, 56 Agenesis: possible etiologies, 111 Definition, 56 Agenesis of the primary and permanent dentition: Composition and function, 56 hypodontia, 111 The peri-root sheet in the primary and permanent Primary dentition agenesis, 111 dentition, 56 Permanent dentition agenesis, 112 Highlights and clinical relevance, 58 Syndromes, disruption, dysplasia, and Further reading, 60 hypodontia, 114 Supernumerary teeth: possible etiologies, 118 6 Normal tooth eruption and alveolar bone Supernumerary teeth in the primary and permanent formation, 61 dentition: hyperdontia, 118 Tooth eruption mechanism and alveolar bone formation, 61 Primary dentition supernumeraries, 118 Preemergence phase, 61 Permanent dentition supernumeraries, 118 Tooth eruption and jaw growth, 66 Syndromes, dysplasia, and supernumerary teeth, 120 Jaw size and space, 66 How to analyze the etiology behind deviation in tooth Eruption sequences in the primary and permanent number, 120 dentition, 68 Highlights and clinical relevance, 123 Bilaterality, 70 Further reading, 124 Early and late eruption, 70 Highlights and clinical relevance, 71 10 Tooth eruption and alveolar bone formation: abnormal Further reading, 72 patterns including syndromes, 125 Pathological eruption of primary teeth, 125 7 Etiology-based diagnostics: methods and classification of Abnormal times for eruption, 125 abnormal development, 73 Total failure to erupt, 125 Why use etiology-based diagnostics?, 73 Arrested eruption of single teeth, 125 Definitions of key words, 73 Pathological eruption of permanent teeth, 125 Etiology, 73 Abnormal times for eruption, 125 Other key words, 76 Ectopic eruption of maxillary canines, 126 Analyzing the dentition, oral cavity, and cranium: Ectopic eruption of mandibular canines, 127 practical guide, 77 Transposition, 129 Anamnestic record, 77 Ectopic eruption of molars, premolars, and other Diagrams for diagnostics, 80 teeth, 129 Highlights and clinical relevance, 80 Arrested eruption after trauma, 129 Further reading, 80 Arrested eruption due to lack of space, 131 Arrested eruption due to obstacles in the eruption 8 Deviation in tooth morphology and color: normal and pathway, 131 pathological variations including syndromes, 81 Primary retention of molars, premolars, and Primary dentition: crown, root, and pulp, 81 incisors, 132 Malformation of incisors, canines, and molars, 81 Secondary retention of molars, premolars, and Disruption in the primary dentition, 81 incisors, 134 Dysplasia in the primary dentition, 87 Primary failure of tooth eruption, 136 Permanent dentition: crown, root, and pulp, 88 Retention of teeth due to virus attack, 136 Malformation of incisors, canines, premolars, and Retention due to nonshedding of primary teeth, 137 molars, 88 Abnormal eruption in syndromes and dysplasia, 137 Disruption in the permanent dentition, 98 Amelogenesis imperfecta, 137 Dysplasia in the permanent dentition, 106 Ectodermal dysplasia, 139 Abnormal dental development: fields and Linear scleroderma en coup de sabre, 139 bilateralism, 107 Segmental odontomaxillary/mandibular dysplasia, 139 How to analyze the etiology behind deviation in tooth Eruption and heredity, 139 morphology: is it malformation, disruption or Eruption problems in both dentitions, 142 dysplasia?, 109 Localized abnormal alveolar bone formation, 143 Highlights and clinical relevance, 109 Juvenile periodontitis: theory and heredity, 143 Further reading, 110 Hypophosphatasia and Papillon–Lefèvre, 143

Contents vii Why analyze the etiology behind abnormal eruption?, 145 Dentitions with arrested eruption of primary molars, 174 Highlights and clinical relevance, 147 Dentitions suitable for tooth transplantation, 174 Further reading, 147 Dentitions with arrested eruption of permanent teeth, 174 11 Root and crown resorption: normal and abnormal pattern including syndromes, 149 Primary retention, 174 Tooth resorption theory, 149 Secondary retention, 175 Ectodermal tissue, 149 Primary failure of tooth eruption, 175 Mesodermal or ectomesenchymal tissue, 150 Dentitions with persistence of a primary molar in Neuroectodermal tissue, 150 adulthood, 176 Resorption in the primary dentition, 151 Dentitions with idiopathic collum resorption, 176 Pattern of resorption, 151 Highlights and clinical relevance, 176 Shedding times, 152 Further reading, 176 Resorption in the permanent dentition, 156 When does resorption occur in normally developed 13 Craniofacial syndromes and malformations: prenatal individuals?, 156 and postnatal observations, 177 Dentitions especially susceptible to root resorption, 156 Holoprosencephaly/solitary median maxillary central Root resorption and heredity: short roots or resorbed incisor (SMMCI) syndrome, 177 roots?, 158 Prenatal, 177 Root resorption in syndromes, dysplasia, and Postnatal, 177 disruptions, 160 Cerebellar hypoplasia/cri-du-chat syndrome, 180 Prevention of root resorption in the permanent Prenatal, 180 dentition, 160 Postnatal, 182 Other examples of resorption, 162 Myelomeningoceles/spina bifida and hydrocephalus, 185 Postemergence resorption, 162 Prenatal, 185 Collum resorption, 162 Postnatal, 185 Aggressive resorption, 162 Down’s syndrome (trisomy 21), 186 Preemergence resorption, 162 Prenatal, 186 Crown resorption before emergence, 162 Postnatal, 187 Conclusion, 163 Turner’s syndrome, 187 How to analyze the etiology behind abnormal root Prenatal, 187 resorption in the permanent dentition, 164 Postnatal, 187 Highlights and clinical relevance, 166 Fragile X syndrome, 187 Further reading, 166 Prenatal, 187 Postnatal, 188 12 Apparently normal nonsyndromic dentitions are Crouzon’s syndrome, 188 phenotypically different: the interrelationship between Prenatal, 188 deviations in the dentition and craniofacial profile, 168 Postnatal, 189 Introduction, 168 DiGeorge’s/velocardiofacial syndrome, 189 Heredity and the dentition, 168 Prenatal, 189 Agenesis and supernumerarity, 168 Postnatal, 189 Morphology, 168 Cleft lip and palate, 190 Eruption, 168 Cleft lip: pre- and postnatal findings, 190 Resorption, 168 Isolated cleft palate: pre- and postnatal findings, 190 Dentitions with agenesis of single teeth, 168 Combined cleft lip and palate: pre- and postnatal Dentitions with multiple tooth agenesis, 170 findings, 192 Dentitions with macrodontic maxillary central Cleft lip and palate etiologies, 193 incisors, 171 Comparison between pre- and postnatal findings: results Dentitions with supernumerary teeth, 171 and restrictions, 194 Dentitions with ectopic canines, 172 Results, 194 Buccal ectopia, 172 Restrictions, 194 Palatal ectopia, 172 Malformations: nonsyndromic examples, 194 Dentitions with transpositions, 173 Highlights and clinical relevance, 199 Further reading, 200

viii Contents 14 Craniofacial disruptions: prenatal and postnatal Perspectives for clinical and basic research, 219 observations, 202 The prenatal cranium as a predictor for postnatal Prenatal disruptions, 202 development, 219 Amniotic band: sequence, 202 The dentition as a diagnostic tool in medicine, 220 Virus infection and maternal alcohol intake, 202 Association between dental and craniofacial Postnatal disruptions, 202 development, 220 Premature birth, 202 Trauma, 202 Perspectives for anthropology, 221 Virus and bacterial attack, 202 Conclusion, 222 Brain tumors and radiation/chemotherapy, 203 Further reading, 223 Acromegaly, 203 Highlights and clinical relevance, 204 17 Clinical cases and unanswered questions, 224 Further reading, 206 Clinical cases, 224 Conditions in diagnostics, treatment planning, and 15 Craniofacial dysplasia: prenatal and postnatal outcome, 224 observations, 207 Optimal treatment situation, 224 Endochondral and intramembranous bone dysplasia in the Observation of the condition, 224 cranium, 207 Nonoptimal treatment situations, 224 Chondrodystrophy, 207 Examples of diagnostics and treatment of eruption Osteogenesis imperfecta, 207 problems, 225 Osteosclerosis, 207 Problems in permanent molar eruption: later diagnosed Hypophosphatemic rickets, 211 as primary retention, 225 Dysostosis cleidocranialis, 211 Problems in permanent molar eruption: later diagnosed Dysplasia in nonosseous tissue, 211 as secondary retention, 225 Ectodermal dysplasia, 211 Problems in permanent molar eruption: later diagnosed Localized scleroderma en coup de sabre, 211 as primary failure of eruption, 225 Amelogenesis imperfecta, 212 Problems in premolar eruption, 226 Dentinogenesis imperfecta and dentin dysplasia, 212 Eruption problems can be a sign of susceptibility to Suture dysplasia, 214 root resorption, 230 Highlights and clinical relevance, 214 Eruption problems caused by supernumerary teeth, 230 Further reading, 216 Unanswered questions, 230 “What is this?”, 230 16 Hard tissue as a diagnostic tool in medicine, 217 “Can medication influence tooth formation?”, 232 Introduction, 217 Further reading, 233 Perspectives for prenatal craniofacial pathology, 217 Perspectives for perinatal and pediatric Index, 235 pathology, 218

Preface What makes this book different from other textbooks on dental series of possibilities for predictions of development and treat­ and craniofacial diagnostics? ment during the entire life span. Normal and pathological fetal development should in all medical disciplines be the biological This book is meant for clinicians, for pre- and postgraduate basis for postnatal diagnostics. This way of thinking – from the students, and for researchers in different fields of dental and very beginning and forward – is not restricted to medicine and craniofacial diagnostics. Every deviation in dental and cranio­ odontology. facial disorders, as described in this book, is based on embryo­ logical insight. Thus embryology is not restricted to an isolated I would therefore like to end this foreword with a quote by chapter; insight from embryology and fetal pathology is applied Winston Churchill: throughout the entire book. “The further you can look back, the further you can look ahead.” Etiology implies the cause or origin of a disease or disorder. In this book, the embryological origin is the foundation for the Inger Kjær etiology-based postnatal diagnostics of disorders in the dentition and craniofacial region. Every congenital condition has a developmental path from conception to late adulthood. If the etiology is known, there is a ix



Introduction The scientific and clinical knowledge presented in this book is the roots of the primary teeth have not developed and the primarily based on personal research in normal and pathological periodontal tissue is therefore not available for histological prenatal cranial development combined with postnatal clinical research. The cranium, however, is nearly completely formed experience in pediatrics, orthodontics, and diagnostics of rare and can be studied radiographically, histologically, and anthro­ human developmental conditions. pologically. A main problem with prenatal tissue studies is that the tissue is often fragmented and it can be partially autolyzed. The purpose of this book is to focus on the etiology behind the clinical questions that are encountered in everyday practice, and Postnatal studies of the dentition are conducted clinically which make diagnostics and treatment difficult. These questions and are supplemented by radiological analysis, including three- include the following. dimensional (3D) analysis. These analyses concern tooth matu­ • What is the mechanism behind tooth eruption? Can we rity and morphology. Migration of teeth before eruption can also be studied. Histological studies of normal tooth develop­ explain this phenomenon? ment can be done on extracted teeth, but in these cases • How and when does the periodontal membrane develop? the periodontium is often lacerated and it can be difficult to • After a tooth has emerged, it continues to erupt. What happens describe the structure. The entire periodontium surrounding a tooth can only be studied in autopsy materials or by surgical in the periodontal membrane during this continued eruption? removal of a tooth and the surrounding tissue. Both cases • How is continued eruption associated with growth of the provide a cross-sectional insight into a periodontal membrane which can be normal but which is most likely not normal. In alveolar process? cases of pathological tooth development where the tooth is • Why do some areas in the jaws frequently contain abnormali­ removed, the specimens can provide information about the histomorphological diagnosis. Postnatally, the cranium ties while others do not? can be studied using anthropological, radiographical, and his­ • Can we explain correlations between findings in the maxilla topathological methods. and the mandible? The only studies that allow longitudinal observation are • Why is there such a great difference between primary and radiographical studies after birth. It is possible to conduct animal studies, but results from these studies cannot be trans­ permanent teeth regarding the occurrence of agenesis, resorp­ ferred uncritically to human conditions. tion, and eruption? • What protects a permanent tooth root from resorption? Content and structure of the book • Are there similarities between the periodontal membrane of a primary tooth and the periodontal membrane of a permanent A book like this has not been written before. It concerns normal tooth? hard tissue development in the cranium and the dentition and • Can signs in the primary dentition predict the later develop­ creates a foundation for clinical diagnostics and for the etiology ment of the permanent dentition? behind the diagnosis. Furthermore, this knowledge creates a • How do diseases and/or the intake of medicine influence basis for later genetic and molecular-biological research. dental and craniofacial development? All these central questions have had no clear answer until The book is structured into three main parts. now. The issue has been that traditional research in the cranio­ 1 The first part includes chapters which cover different aspects facial region has been restricted by ethical, technical, and biological limits. In this book, experience from prenatal research of normal dental and craniofacial development. The text is is introduced and it is demonstrated how several but not all of supplemented with fetal pathology cases. These chapters these questions can be answered. The results presented are cover the basic biological background for understanding primarily based on the author’s research referred to in the abnormal patient cases. Such cases are demonstrated. reference lists at the end of each chapter. 2 The second part (Chapter 7) demonstrates the obstacles faced in etiology-based diagnostics of the dentition and cranium. Limited access to human material This part also introduces the international classification of abnormal development used in the final part of the book. Prenatal human studies only allow studies on spontaneous or medically induced abortions by special indications and permis­ sions before gestational age (GA) 20 weeks. At this early stage, xi

xii Introduction 3 The third part covers abnormal development and focuses on tremendously to the concept of transferring the fields of the etiology behind everyday cases and unusual cases sporad­ embryology and fetal pathology to the clinic to allow ically observed in the clinic. The text is again highlighted with improved diagnostics and treatments. Without Birgit Fischer fetal pathology cases. The final chapter discuss questions on Hansen’s professional and encouraging support over many the treatment of severe cases as well as cases in which the years, this book could not have been written. etiologies are still unsolved. It is hoped that this text will lead Chief pathologist, Jean Keeling, MD, specialist in fetal pathol­ to thoughtful discussions and collaborations between profes­ ogy in the UK, has outstandingly supported the early research sionals in the clinic and the science laboratory. and promoted the international conceptualization of cranio­ In each chapter, the “why” questions will be the focus. This facial diagnostics. Several other pathologists specializing in fetal pathology are applies to both normal and pathological developmental pro­ acknowledged for their support of my studies. Among these is cesses. Some explanations of these “why” questions have been chief pathologist Ingermarie Reintoft MD who introduced me to documented. Others are still hypothetical and there are others unique cases of malformations for which I am very grateful. that have no clear answer. This book has been written to Professor in oral pathology, Jesper Reibel, DDS Dr Odont, is promote the improvement of dental and craniofacial diagnostics acknowledged for guidance in questions of oral pathology. and to provide ideas for future research. Anthropology. Colleagues at the medical museum, Medicinsk Museion, Copenhagen, have introduced me to the Saxthorp Acknowledgments collection for which I am very grateful. Special thanks to the director of the museum, Professor PhD Thomas Söderqvist. As a student of former Professor Arne Björk and as a colleague of Jan Jacobsen, DDS, and Pia Bennike, PhD and MSc, are both former Professor Beni Solow, I would like to acknowledge the former anthropologists at the university whom I would like to valuable and inspiring scientific environment that these distin­ acknowledge for supporting my studies in dental and crani­ guished teachers created in the orthodontic department in Copen­ ofacial anthropology. hagen for science, pioneer research and critical thinking during Hospital teams for rare developmental conditions. Kirsten the years 1951–2000. Professor Björk inspired me to attack Mølsted, DDS PhD, Head of the Cleft Lip and Palate Unit scientific problems nontraditionally and he gave me complete at Rigshospitalet, Copenhagen, is thanked for many fruitful freedom through five years to develop my own way of thinking. years of collaboration and for scientific inspiration. Kirsten Mølsted has been an excellent colleague. This book has become a reality due to collaboration between Bjørn Russel, DDS, former Head of the Dental Clinic at outstanding experts in widely varied subject fields: pedodontics, Vangedehuse Children’s Hospital for Severely Handicapped orthodontics, pediatrics, fetal pathology, anthropology, and Children, is thanked for collaboration. multidisciplinary hospital units for cleft lip and palate treatment Jette Daugaard-Jensen, DDS and MS, Head of the Center for and rare human developmental conditions. It is therefore both Rare Diseases at Rigshospitalet, Copenhagen, has through many an obligation and an honor for me to thank the following co­ years been a faithful and inspiring colleague whom I thank for workers for their constant support for my research which has scientific support. made this book possible. Hans Gjørup, DDS and PhD, Head of the Center for Rare Anatomy. Assoc. professor M. E. Matthiessen, DDS, MD is Diseases at Aarhus University Hospital, is thanked for being an excellent co-worker and colleague. acknowledged for permission to use the laboratory facilities The outstanding collaboration over many years with bio­ at the Department of Anatomy, University of Copenhagen, medical laboratory technologist Dorrit Nolting, BA, who has during a 5-years period, for fruitful collaboration and intro­ prepared all the histological images in the book, is highly duction to histochemistry. appreciated. Her skills, compassion, and dedication to tissue Pedodontics. A large network of dentists working in the Danish analysis have been essential for the results presented. healthcare systems for children and adults as well as dentists Linguistic support in several scientific papers forming the abroad have demonstrated cases for me and also inspired my base for this book has been provided during the years 2002–2012 studies by forwarding more than 2900 clinical inquiries. by Academic Secretary Maria Kvetny, MA. I am grateful for her Orthodontics. National and international specialists in ortho­ many professional contributions in this respect. dontics supported my studies by asking questions and by Ghita Lemminger, Secretary for Postgraduate Education, was demonstrating difficult cases regarding orthodontic diagnos­ an excellent colleague during my time as Director of the tics and unexplainable treatment outcomes. Postgraduate Program until 2014. Pediatrics. Medical doctors in pediatrics are thanked for their A special thank you to Sarah Liv Fischer Richmond, medical collaboration. These are especially doctors in the fields of student, for constant, professional, linguistic support and prep­ neuropediatrics and pediatric endocrinology. They appear as aration of the manuscript for this book. co-authors in the references of this book and have provided valuable input for craniofacial disorders. Inger Kjær Fetal pathology. Chief pathologist, Birgit Fischer Hansen, MD Dr Med, specialist in fetal pathology, has contributed

CHAPTER 1 Craniofacial development and the body axis: normal and pathological aspects from early prenatal to postnatal life Body axis pre- and postnatally vertebrae form around the notochord (Figure 1.5). Remnants of notochordal tissue remain in the intervertebral disks after Germ disk and notochord birth but not in the vertebrae. In the cranial portion of the If you ask a dentist or a medical professional “From where does body axis, the notochord ends in the region of the posterior the cranium develops in its initial phase?” they will probably not wall of the sella turcica (Figure 1.6). Thus the notochord also be able to answer you. Going back to basic embryology, recall organizes the main parts of the occipital bone and parts of the your memory of the germ disk. From this very early two-layered sphenoid bone corpus. disk, the whole body arises. Gradually the mesoderm forms the third layer in the body and the notochord develops. The noto­ The sequence in which the vertebral bodies ossify is always the chord is an axial row of cells of ectodermal origin which are same, starting with the lumbosacral region and gradually moving decisive for the closure of the neural tube, formation of the cranially. The arches in the vertebrae protecting the medulla central nervous system and visceral and skeletal development. spinalis develop in a sequence which is also constantly the same, The germ disk folds and begins to close centrally at approxi­ but the ossification of the arches starts cranially and moves mately day 18 of gestational age (GA) and openings in the cranial gradually caudally. The region in which the ossification of the and caudal ends arise (Figure 1.1). These openings are called vertebral bodies and vertebral arches meet each other is near to neuropores. the upper thoracic vertebra (Figure 1.7). In summary, the development of the head and brain is completely integrated Formation of the vertebral column with body axis development. The ridges (left and right) that surround the cranial neuropore are called the neural crest (Figure 1.2). The neural crest cells are Fetal pathology ectodermally derived and represent a “contact ridge” between the Malformations in the vertebral bodies occur in relation to the outer surface ectoderm and the inner neuroectoderm. The tissues notochord. These malformations could be twin bodies (com­ that are derived from the neural crest are called the ectomesen­ pletely separated body units) or partially cleft vertebral bodies. chyme – having ectodermal origin with the ability to differentiate Also fusion between bodies or the absence of a vertebral body into various cell types, including connective tissue (e.g. cartilage, may occur. Different types of abnormal vertebrae are demon­ bone). From different regions on the neural crest, different strated in Figure 1.8. ectomesenchymal cell groups migrate anteriorly through the fold between the neuroectoderm and the surface ectoderm, The mapping of the body axis in fetuses with different genetic bulging out and gradually forming the craniofacial skeleton. abnormalities demonstrates that abnormal development often occurs regionally in so-called developmental fields. Thus fetuses More posterior parts of the cranium arise from tissue located with trisomy 18 predominantly have abnormalities in the tho­ laterally to the notochord, called paranotochordal tissue. racic and lumbosacral vertebral fields and not in the cervical field. This is not the case in trisomy 21, trisomy 13 or triploidy. Gradually, the neuropores close and the germ disk forms the Mapping of the body axis shows that the different genotypes brainstem. From here the cerebral hemispheres develop from the affect the different fields in the vertebral column (Figure 1.9). foramen of Monro. Figure 1.3 depicts the craniofacial skeleton and the central nervous system. Cervical spine pre- and postnatally The bony bodies (corpora) of the cervical spine are formed by The notochord forms the body axis at a very early stage ossification of the cartilage encircling the early notochord. (Figure 1.4). The notochord is essential for the folding and Remnants of the notochord may persist in the nucleus pulposus closing of the germ disk and for formation of body structures in the intervertebral disks. The arches of the vertebrae encircle and the vertebral column. The bodies of the individual Etiology-Based Dental and Craniofacial Diagnostics, First Edition. Inger Kjær. © 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd. 1

2 Chapter 1 Figure 1.1 (Upper) Schematic drawing of the early human embryonic Figure 1.2 A schematic drawing of an embryo gestational age (GA) 4 formation of the germ disk (left), closure of the germ disk with a caudal weeks with an open cranial neuropore. Yellow contours mark the central neuropore, lower and upper cranial neuropores (center) and the neural nervous system and the colored dots mark the neural crest which borders tube (right). Yellow marks the central nervous system. The red line the inner neuroepithelium and the outer surface epithelium. Red dots indicates the notochord and the green dot the prechordal plate (region of mark the frontonasal region of the crest. Green dots mark the maxillary the later pituitary gland/sella turcica). The arrows mark directions of and palatine regions and blue dots mark the mandibular region of the molecular signals from the notochord. (Lower) Schematic illustration of crest. Source: Drews (1995) reproduced with permission of Thieme the location of the germ disk in the body, the neural tube and the contour Publishing Group. of the early body development in the frontal plane (left) and in the midaxial plane (right). cranium and face. Le Douarin found that the face and cranium had different regions with tissues that stem from different parts the spinal cord. The atlas, which is the upper vertebra of the of the neural crest. The original research involved radioimmune cervical spine, articulates with the occipital condyles on the marking which is a method not possible in human studies. external cranial base. Research on the early, embryological, facial development from the neural crest can therefore only be conducted on animals. Figure 1.10 demonstrates the normal cervical spine in a child. The cells from the neural crest are multipotent and can form Clinical relevance cartilage, bone, muscles, nerves, and vessels. In 1997, the knowl­ Prenatal defects are always present postnatally as well. Mapping edge gained by Le Douarin was applied to human cranial and of the malformations in the vertebral column is therefore essen­ facial development. Figure 1.3 is a schematic drawing of how the tial for clinical diagnostics of postnatal vertebral development. neural crest might influence the development of various parts of Figure 1.11 demonstrates examples of malformations of the the cranium and face. Immunohistochemical markings of the cervical column observed in children with known and unknown body axis in rat embryos have demonstrated how gene expres­ diagnoses. sion differs in the different fields of the body axis. For example, the Pax9 gene is expressed in the lumbosacral body axis and also The interrelationship between the body axis in the craniofacial region (see Chapter 13). and the cranium In 1974, Nicole Le Douarin published a study on cell migration in Clinical relevance animals from the front-most part of the neural crest field to the Occipitalization is a postnatal condition in which the upper vertebra (atlas) is fused to the occipital condyle (see Chapter 13). This is an abnormality observed postnatally which could be explained by a prenatal fusion or by nonseparation of the cartilage which forms both the atlas and the occipital bone.

Craniofacial development and the body axis 3 Figure 1.5 A midsagittal section of the developing vertebral column in a human embryo GA 7 weeks. The cartilaginous vertebral bodies are marked purple. The notochord is a lightly marked (nearly white) cell structure centrally and vertically located within the vertebral bodies. Figure 1.3 A schematic drawing of the skeleton of a human fetus about GA 17 weeks. The spinal cord and the brainstem (not the cerebellum) are marked dark yellow, and the hemispheres of the cerebrum and cerebellum are marked beige. Green arrows indicate paths of neural crest cell migration to the jaws forming the green jaws and facial bones. White indicates the theca bones and the vertebral column. Red lines mark structures with an ectodermal origin which includes the notochord within the vertebral bodies. Peripheral nerves to the jaws are marked in orange. Figure 1.4 Midsagittal section of a part of the body axis of a human Figure 1.6 Profile radiograph of a child. The red line indicates the former embryo GA 24 days demonstrating the early morphology of the location of the notochord from the vertebral bodies, through the basilar notochordal cells (red). part of the occipital bone to the rostral location in the posterior wall of the sella turcica.

4 Chapter 1 Figure 1.7 (Left) A schematic drawing of the entire body ossification of a human fetus GA 12 weeks. Note that several bones including bones in the head have started ossification. (Right) A radiographic image of the thoracic and cervical parts of the vertebral column in a human fetus GA 12 weeks. Note that the bodies of the cervical vertebrae have not ossified at this early stage. Source: Kjær et al. (1999). Reproduced with permission of John Wiley & Sons. Figure 1.9 Schematic view of the body axis in a human fetus (left, lateral view; right, frontal view). The black contours marked from above: nasal bone, maxilla, sphenoid corpus, basilar occipital bone, corpora, arches of the vertebral column. (Right) Indication of malformed (red) and not malformed (green) areas in the body axis of a trisomy 18 fetus. Yellow indicates areas in which malformations sometimes occur. Source: Kjær et al. (1999). Reproduced with permission of John Wiley & Sons. Figure 1.8 Radiographic images of the vertebral bodies in a prenatal, bones in the cranial base, the maxilla, the mandible, the theca human body axis. (Left) Lateral view GA 16 weeks. The bodies are cranii, the vomeral bone, the nasal bone, and the temporal bone complete or partially cleft. (Right) Frontal view GA 20 weeks. The lower (Figure 1.13). These and other bones will be described in this bodies appear fused. section. It is characteristic for bone development that the indi­ vidual ossification sites always develop in a constant sequence at Craniofacial development pre- and the same locations and with the same morphology. The prenatal postnatally skeleton can therefore be used as a map to reveal where a malformation is located and when it arose. Bone tissue develops after the embryo has reached GA 7 weeks (Figure 1.12). The main components of the cranium are the Cranial base (excluding the sella turcica) We now focus on the horizontal plane and midaxial plane of the cranial base (Figure 1.14). The bones ossify midaxially in the following sequence: basilar part of the occipital bone, sphenoid

Craniofacial development and the body axis 5 Figure 1.12 A human fetus GA 8 weeks in a lateral and posterior view. The length of the body and head is 15 mm. Note that the head is very large compared to the length of the body. Eyelids have not formed and the ear openings (arrow) appear low-set. During downward and forward growth of the face, the interrelationship between the ears and the lower face will alter. Figure 1.10 Radiograph from a child demonstrating the normal structures All parts of the osseous cranial base has been formed from of the uppermost part of the body axis including the vertebral column, cartilage before birth. Between the bone components there are basilar occipital bone, and sella turcica. multiple cartilaginous synchondroses. In a five-month-old fetus, there are synchondroses between the sphenoidal bone and bone corpus, ethmoid bone, lower part of the frontal bone. The occipital bone (sphenooccipital synchondrosis) and three syn­ sequence is always the same. The morphology of the individual chondroses between the different sphenoidal components (pre­ bone components differs with age. The developmental outline of sphenoid, intersphenoid, and basisphenoid synchondrosis). the basilar part of the occipital bone at GA 20 weeks is seen in There are also two synchondroses between the occipital compo­ Figure 1.14. nents (anterior and posterior intraoccipital synchondroses). Synchondroses also exist between the occipital bone and tem­ poral bone (petrooccipital synchondrosis), and between the temporal bone and sphenoid bone (sphenopetrosal synchond­ rosis). These synchondroses allow growth of the cranial base in the sagittal and transversal planes. At birth, the synchondroses are significantly diminished. Only the sphenopetrosal and sphenooccipital synchondroses are maintained. Figure 1.11 Radiographic images from children with known and unknown diagnoses illustrating different malformations including fusion of vertebrae in the upper part of the body axis. (a) Patient with a mandibular overjet, etiology unknown. (b) Patient with Goldenhaar’s syndrome. (c) Patient with extreme maxillary overjet, etiology unknown. (d) No diagnosis. (e) Patient with skeletal deep bite and abnormal resorption of primary teeth, etiology unknown. Note the open sphenobasilar synchondrosis, (arrow) etiology also unknown.

6 Chapter 1 At puberty, there is only one active synchondrosis left – the sphenooccipital synchondrosis. This synchondrosis is a relatively common finding on a profile radiograph (Figure 1.15). It is difficult to analyze the amount of growth in this synchondrosis, which was studied in detail by Melsen in 1974. The growth of the cranial base has also been attempted in an anthropological analysis (Figure 1.16). This study shows that the central part of the cranial base that supports the brainstem only grows until approximately four or five years of age. This was determined by analyzing the distance between the stable innervation foramens in the cranial base (see Chapter 2). Figure 1.13 A profile radiograph of a cranium and cervical spine from a Fetal pathology human fetus, GA 20 weeks. The ossification of the vertebrae, cranial base, Different prenatal malformations can be traced in the basilar part jaw bones, and lower parts of theca cranii appears distinct, while the most of the occipital bone. As an example, different occipital bone cranial parts of the frontal and occipital bones and the parietal bone malformations related to specific diagnoses are shown in appear unossified radiographically. (Inset) A drawing of the most rostral Figure 1.17. There may also be signs of early fusion of bone part of the path of the notochord. From below, the notochord (red) crosses components in the cranial base (see Chapter 13). These early through the basilar part of the occipital bone and ends in the posterior malformations indicate early phenotypic characteristics for a sphenoid corpus. given disease. Clinical relevance If the cartilaginous tissue is abnormal, as seen in dwarfism (with short extremities), then the cranial base is also short. This results in a large, rounded, protruding frontal bone in order to provide enough space for proper brain development (Figure 1.18). Figure 1.14 Horizontal and midaxial views of a normal prenatal human cranial base. (Upper) The figure demonstrates the internal cranial fossae (left) seen from above (note the large sella turcica; arrow) and a horizontal histological section (right) of the caudal part of the cranial base, larynx, and mandible from a fetus GA 15 weeks. Note the cartilage surrounding the foramen magnum (star), the cartilage of the hyoid bone (black arrow), and the mental lower part of the mandible (red arrow). (Center) A radiograph of the cranial base from a fetus GA 20 weeks. (Inset)A deviscerated basilar part of an occipital bone from a fetus GA 20 weeks. (Lower) Midsagittal section (anterior direction to the left) of a human cranial base GA 15 weeks demonstrating ossification of the basilar part of the occipital bone and the morphology of the sella turcica formed in cartilage (purple, marked by arrow). The sella contains the pituitary gland marked dark blue for the adenopituitary gland (anteriorly) and light blue for the neuropituitary gland (posteriorly).

Craniofacial development and the body axis 7 Figure 1.15 A section of a profile radiograph from a child displaying normal sella turcica morphology. Behind the sella to the right is the sphenooccipital synchondrosis marked with an arrow. The morphology of the sella turcica formed in cartilage corresponds completely to the morphology of the sella later formed in bone. Figure 1.14 (Continued) Fetal pathology The mapping of the sella turcica in malformed fetuses with known and unknown genotypes has demonstrated that some conditions are associated with an abnormality in the anterior wall, some with abnormality in the posterior wall and some with an opening in the floor. Examples are given in Figure 1.21. Irregular cartilaginous walls have also been described. Clefting of the basilar part of the occipital bone can also arise Clinical relevance prenatally and persist through adulthood. This is observed in the When observing a profile radiograph, it is important to notice the anthropological case provided in Figure 1.19. posterior and anterior walls of the sella turcica. Absence or malformation of the posterior wall may be associated with Sella turcica abnormalities in the spine due to the notochordal relationship The sella turcica is formed by cartilage which gradually ossifies between the spine and the posterior wall of the sella (Figure 1.22). from the lower aspects and progresses cranially. The posterior Meanwhile, abnormalities in the anterior wall are often associ­ wall, the dorsum sellae, may retain remnants from the rostral end ated with malformations of the facial bones. In several skeletal of the notochord (see Figure 1.6). The sella turcica is the only part malocclusions, the sella often has an overlying bridge between of the medial cranial fossa which appears on a profile radiograph. the posterior and anterior walls (Figure 1.23). This is a sign which often appears early in postnatal life and indicates a malocclusion The sella turcica develops around the pituitary gland (hypoph­ with a grade of severity that cannot be corrected orthodontically ysis). The anterior part of the sella arises from the neural crest but which should rather be treated surgically. cells while the majority of the floor and the posterior wall arise from the notochordal mesoderm (Figure 1.20). The sella turcica appears as a border region in the cranial base between the anterior, neural crest-formed cranial base and the posterior, notochord-related cranial base (see Figure 1.20). This

8 Chapter 1 Figure 1.16 (Left) External human cranial bases from newborn to adult. The cranium from a newborn has persisting interoccipital synchondroses. (Right) Schematic drawing of an adult human cranial base. The striped part of the cranial base supports the brainstem and only grows until the age of four or five years. This was concluded by measuring the transverse distance between the nerve canal openings. The dotted area marks the area formed from neural crest cells. This area grows until after puberty. Source: Sejrsen et al. (1997). Reproduced with permission of Taylor & Francis Publishing Group. Figure 1.17 Deviant morphology of the pathological, prenatal, human, basilar occipital bone. The malformations illustrated are associated with deviations in signaling from the notochord. (Left) Deviscerated bone from a trisomy 18 fetus. (Center) Radiographic image from an anencephalic fetus. (Right) Radiographic image from a hydrocephalic fetus. of the occipital bone and/or in the vertebral bodies which are also formed around the notochord. Examples of sella turcica mal­ formations are demonstrated in Figure 1.23. Figure 1.18 An anthropological, human cranium demonstrating a Maxilla retrognathic maxillary complex which is supposed to be associated with an The maxilla is attached through the ethmoid bone and the abnormal development in the cartilaginous tissue in the short cranial base. vomeral bone to the cranial base. Ossification of the maxilla The maxillary incisors compensated for this skeletal deviation by appears in week 9 GA starting in the canine region. Again, there is increasing inclination. a completely reproducible sequence in the formation of the different bony elements. The orbital foramen is bound by is important to bear in mind in cases where deviations are bone tissue encircling the maxillary nerve. The infraorbital canal restricted to the anterior or posterior sella wall. As the cranial develops gradually as a result of external bone apposition. The end of the notochord ends in the posterior sella wall, it is palate is formed by vertically located, soft tissue palatal processes important in clinic to determine whether deviations in the on each side of the tongue (Figure 1.24). These processes shift posterior sella wall are related to deviations in the basilar part from a vertical to a horizontal position at the time when the tongue is lowered. This process is explained in further detail in the section on the mandible. The midpalatine suture arises gradually, as does the transverse palatine suture (see Figure 1.24). The transverse palatine suture is a layer of connec­ tive tissue between the slanted edges of the horizontal processes of both the palatal bones and the maxillary bones. This suture allows the maxilla to move downward and forward during growth. The palatal sutures are demonstrated in Figure 1.24. In the frontal region, the incisive fissure borders the posterior aspect of the incisors. This fissure is not a suture where growth occurs, nor is it a structure which borders the frontonasal region from the maxillary region (see Chapter 3). The fissure extends from the midpalatine suture to the region behind the canine and has a function during the enlargement of the incisive tooth buds

Craniofacial development and the body axis 9 Figure 1.19 External cranial base from an anthropological cranium with an occipital cleft. (Left) Overview. (Right) Magnification of the cleft (arrow). It is presumed that signaling from the notochord has not functioned in the cleft area. Figure 1.20 Profile radiograph from a child. The red and green markings nasal cavity and apposition on the palatine surface. All sutures represent the internal cranial base as it appears from a lateral view. Red that are responsible for growth in height have an orientation indicates the anterior cranial fossa, green indicates the posterior cranial which is mostly oblique and which ensures that the maxilla fossa. Note that the sella turcica, red anteriorly and green posteriorly, in moves downward and forward. Lastly, the growth of the maxilla fact belongs to the medial cranial fossa. The red area is formed by neural must also support the development of the alveolar process for crest cells. The green area is formed along the notochord by the paraxial erupting teeth. The growth in the transpalatine suture with an mesoderm. oblique orientation ensures that the maxilla during growth is transported forward and downward. During this sutural growth, and later during eruption of the incisors. After eruption has there is a gradual apposition of the maxillary tuber (Figure 1.25). occurred, the fissure has no known function. The palatine nerve is located in a groove in the horizontal part of the palatine bone. The palatine foramen is therefore located on The maxilla is composed of two, bilateral, osseous, hemi­ the opposite side of the first molar in early childhood, but due to maxillary components which meet the axial plane where they the gradual forward movement of the maxilla, as a result of form the midpalatine suture. This midpalatine suture is named growth in the transpalatine suture, it appears at the level of the differently in different regions: anteriorly –interincisal suture; second molar during puberty (see Figure 1.25). One can therefore centrally –intermaxillary suture; posteriorly –interpalatine appreciate that space for the third molar depends on the growth suture. The midpalatine suture forms the base for transverse in the transverse palatine suture and on bone apposition in the growth of the palate. tuber region. The height of the maxilla depends on the growth of the sutures The infraorbital canal arises gradually during the early growth between the maxilla and the neighboring bones (nasal bone, period by apposition at the anterior maxillary surface. The frontal bone, zygomatic bone, and palatine bone). In the palatine direction of the canal reflects the transverse and sagittal growth process of the maxilla, there is resorption of the surface facing the pattern in the maxilla. This direction also is supported by radiographic studies by Bjørk and by Solow of maxillary growth. Solow found that the midpalatine suture has a fan-shaped growth with more growth in the posterior than the anterior region. The incisive fissure is not a growth zone but a fissure which merely adapts to the gain in size of the incisors, and thus this fissure functions only until the permanent incisors have attained their full crown size (see Figure 1.25). Fetal pathology The most commonly observed malformations in the maxilla are clefts. Some of these are very severe and may extend all the way to the sella turcica region where the entire floor may be absent. Other midaxial malformations may involve a malformed palate, having a round shape as opposed to the normal horseshoe formation. This “round” palate is associated with abnormalities in the nasal cavity and the anterior cranial fossa and the absence of the anterior part of the midpalatine suture.

10 Chapter 1 Figure 1.22 Radiograph from a child referred for diagnostic clarification. Notice the malformed cervical vertebral column, malformed sella turcica, short cranial base, frontal bossing, thick occipital squama, maxillary retrognathia, and skeletal open bite. This child had several skeletal malformations, associated with malformation in the cervical vertebral column and cranial base. The etiology is unknown. Figure 1.21 Midaxial, histological sections of the pituitary gland/sella Figure 1.23 Sections of the sella turcica region on four profile radiographs turcica region from three human fetuses. All sellae are malformed. from four children with various diagnoses. (Upper left) Patient with Anterior points to the left. (Upper) From a hydrocephalic fetus with an maxillary hypoplasia. Notice the broad sphenooccipital synchondrosis absent anterior sella wall. (Center) From a trisomy 18 fetus with a deep (arrow). (Upper right) Patient with reverse overjet. Note a sella bridge on cleft (arrow) in the bottom of the sella turcica and a malformed posterior the radiograph “uniting” the anterior and posterior walls. (Lower left) sella wall. Ossification appears anteriorly to the cleft. Source: Kjær et al. Patient with ectopia of a maxillary canine on one side and transposition of (1999). Reproduced with permission of John Wiley & Sons. (Lower) From a canine and first premolar on the contralateral side. Note the abnormal a facially malformed fetus. The sella turcica appears without normal slant of the anterior wall. (Lower right) Radiograph from a deaf child contours – there is just a hole/canal in the region filled with adenopituitary demonstrating an abnormal posterior wall. gland tissue. A severely malformed trace of the notochord remains (arrow). Clinical relevance Fetal pathology is important not only for understanding of the depth and posterior extent of a cleft formation but also for understanding that the growth pattern of the two hemimaxillary

Craniofacial development and the body axis 11 Figure 1.24 Developmental aspects in the human maxilla. (Upper left) Figure 1.25 Different aspects of the human maxilla under Frontal section of a human fetal head demonstrating the two soft tissue development. (Upper) An anthropological maxilla in the occlusal view palatal shelves bordering the tongue. The palate has not yet formed. GA 11 from a child approximately five years of age. Note that the horizontal weeks. (Upper right) Frontal section of the nasal cavity after palate process of the palatine bone is absent on the left side. Also notice the formation. GA 15 weeks. (Lower) Radiographic appearance of the ossified incisive fissure and the vague marking of the borderline between the palate. GA 17 weeks. (Inset) A schematic drawing of the sutures in the frontonasal area and the maxillary area of the maxilla (arrows). palate and a sagittal cut (dotted line) demonstrating specifically the (Center) Schematic drawing of the sutures in the palate. A sagittal cut transverse palatine suture and the direction of growth in this suture (dotted line in Fig. 1.24) demonstrates the transverse palatine suture (arrow). Source: Kjær et al. (1999). Reproduced with permission of John which makes the direction of growth downward and forward possible. Wiley & Sons. The three figures are from three different ages (left, six years; middle, 14 years; right, 20 years). Red marks the horizontal processes of the components can be different. Such a difference in hemimaxillary palatine bone. Green marks the maxillary and palatine alveolar growth results in maxillary asymmetry which is demonstrated in processes including the tuber maxillae. White marks newly formed Figure 1.26. This figure displays how unilateral abnormal growth bone and the small circles within the red area (palatine bone) mark influences the shape of the palate and the nasal floor. the palatine foraminae. Note that the forward growth of the maxilla occurs predominantly at the maxillary edge of the transverse palatine What is a premaxilla? suture. The stable position of the red squares indicates why the The term premaxilla does not indicate an individual bone but is palatine foramen appears opposite to the first molar at six years, and used to describe the anterior maxillary region. This region is the later opposite the second or third molar. (Lower) A right hemimaxilla frontonasal area which is formed by the frontonasal neural crest from a child approximately three years of age (left) and a left cells. The border between the frontonasal area and the maxillary hemimaxilla from an adolescent (right) demonstrating the difference area cannot normally be observed on the bone. In anthropologi­ in bone size and bone apposition at the alveolar process and cal cases, a slight crease may appear, indicating the border resorption in the floor of the nasal cavity and of the orbital cavity. Source: Damgaard (2011). Reproduced with permission of Taylor & Francis Publishing Group.

12 Chapter 1 Figure 1.26 An asymmetrical development of the maxilla from a child Figure 1.27 Histiological sections of different aspects in early mandibular nine years of age. (Upper) Occlusal view of a dental cast demonstrating a development. (Upper left) Newly formed bilateral Meckel’s cartilages (C) hypoplastic right hemimaxilla and a seemingly normal left hemimaxilla. GA 7 weeks. (Upper right) S-shaped Meckel’s (C) cartilage after Notice that the asymmetry starts behind the central incisor. (Lower) 3D ossification and cartilage breakdown has started, GA 13 weeks. The image demonstrating the asymmetry from a frontal view where the right symphysis menti is marked SM. (Lower) Mandibular and coronoid side appears raised compared to the left side. The case demonstrates processes of the mandible. The condyle to the right has a mushroom- normal development in the frontonasal area and abnormal development in shaped condylar cartilage (purple) and articular disks (arrow) appear the right maxillary-palatine area. between the lower and upper articular chambers. The temporal muscle (M) inserts on the coronoid process (left). GA 19 weeks. between the two areas (see Figure 1.25). In pathological cases, a From the canine region and anteriorly, bone is also developed cleft may appear at this borderline. lingually to Meckel’s cartilage. This is not the case posteriorly to the canine region. There is a muscle insertion in the inner aspects An infection in childhood manifested in a localized region of of the mandible of the geniohyoidei and genioglossi muscles. the mucosal palate can disturb the appositional growth in that Around GA 12 weeks, these muscles contract and draw the region. If the palatine bone apposition continues normally in the tongue downwards. It is this downward movement of the tongue region surrounding the infection site, a hole will gradually which gives the palatine shelf the possibility of moving to the develop at the initial infection starting point. This can occur horizontal position. When motion occurs, the cartilage bends to in the condition called segmental maxillary dysplasia described an S-shape and the mandible fans out transversely (Figures 1.14 in Chapter 10. and 1.27). After this movement, the cartilage stretches out and the mandible moves forward, resulting in a protrusion of the Mandible tongue between the lips, and later the mandible retracts to a The mandible is the first bone to ossify in the cranium at around position behind the lips. After these movements of the develop­ week 7 GA. Before the osseous mandible, there is a cartilaginous ing mandible, the mandibular condyle begins development from structure, Meckel’s cartilage, extending from the ear region to the early cartilaginous tissue which appears in the dorsal aspects of mental region. The bone is first laid down in the canine region the bony mandible at GA 15 weeks (see Figure 1.27). During from where bone formation stretches anteriorly and posteriorly.

Craniofacial development and the body axis 13 Figure 1.28 (Left) Histological section (toluidine blue staining) from a newborn illustrating the tissue layers covering the bony condylar tissue (dark blue, left). Over the bony tissue is a covering of a mature and a less mature cartilage layer. Above these layers is a germinative cell layer (light blue). Against the lower joint chamber is a fibrous tissue layer (lightly colored). The articular disk is seen in the upper right corner. (Inset) A rectangular region shown in a higher magnification and with a different staining technique in the image to the right. (Right) Region marked with black rectangle in left image. Histological section (Alcian green staining) from the same specimen demonstrated in left image. Green-blue marks cartilage (left, mature; right, immature). Above the cartilage layers is a light red germinative cell layer which produces and renews cells for both the cartilage layers and for the fibrous layer (red) above it. further development, the cartilage undergoes different changes, relatively flat bone compared to the postnatal mandible. It is resulting in the appearance at birth of a mushroom-shaped, backward tilted and without a fully developed ramus (see condylar cartilage covering the bony condyle (see Figure 1.27). Figure 1.29). After birth, the ramus develops gradually, possibly due to mastication. Cephalometric studies of postnatal mandib­ The condylar fossa and the condylar disk with the lower and ular growth have shown that there are vertical as well as sagittal upper joint chambers occur around GA 19 weeks. Special growth patterns, and that these growth patterns are related to attention should be given to the germinative cell layer located development of the occlusion. In the mandible, the mandibular between the cartilage and the perichondrial layer protecting the and mental canals indicate the directional growth of the mandi­ cartilage. This germinative layer produces prechondroblasts and ble (see Figure 1.29), just as the infraorbital canal indicates the fibroblasts in the inner layer of the perichondrium (Figure 1.28). maxillary directional growth. Also in the mandible, space should The vessels nourishing the cartilage appear in the germinative be gained in the alveolar process for the erupting teeth (see layer and in older fetuses also in the intracartilaginous canals. Figure 1.29). Gain in length of the alveolar process occurs by anterior resorption of the mandibular ramus and at the same The symphysis menti is the anterior midaxial joint structure time, a posterior apposition occurs on the posterior aspect of connecting the left and right mandibular formations. This the ramus. The bone apposition and resorption patterns in the symphysis in the early stages is bordered by Meckel’s cartilage, mandible are closely linked to the directional growth of later by Meckel’s cartilage covered on the labial surface by bone, the mandibular condyle. Space for the third molar depends on and thereafter by bone labially as well as lingually. In the mental the condylar growth pattern and the associated ramus resorption. region (chin region), the cartilaginous Meckel’s cartilage gradu­ ally disappears due to resorption. New cartilage formations Fetal pathology appear on the bone surfaces and the characteristic structure of The different parts of the mandible arise by cartilaginous ossifi­ the symphysis occurs. The symphysis menti is characterized by cation (anteriorly), by intermembranous ossification (medially), bilateral, endochondral, bony ends covering an interosseous and cartilaginous condylar growth (posteriorly). If one of these connective tissue layer. The symphysis menti is richly vascular­ ossification processes malfunctions then the result is visible on ized and is a site for prenatal, transverse, mandibular growth. prenatal radiographs (Figure 1.30). If the condylar cartilage does not develop then the mandible cannot gain in size. If this happens The bony components of the mandible with the main bilaterally, then agnathia (see Chapter 3) arises which is a lethal mandibular body and the three processes (condylar process, condition. coronoid process, and alveolar process) are also formed before birth (Figure 1.29). The mental foramen forms early by bone Clinical relevance tissue encircling the mental nerve. The mental canal arises Asymmetrical development of the mandible and condylar anky­ gradually by apposition at the mandibular surface. The man­ losis can be a congenital or acquired, unilateral, condylar, dibular foramen develops in the later part of prenatal life (see abnormal development. Asymmetrical development of the man­ Chapter 2). dible and condylar malformations are exemplified in the cases The growth center of the mandible is the germinative cell layer covering the condylar cartilage in both prenatal and postnatal life (see Figures 1.27 and 1.28). During prenatal life, the mandible is a

14 Chapter 1 Figure 1.29 An overview of the pre- and postnatal pattern in mandibular development. (Upper left) External view of the left hemimandible from a human fetus about GA 15 weeks. (Inset) An enlarged image of the developing mental foramen demonstrating that the bone around the future foramen has not yet been closed with bone tissue. The condyle has not developed. (Upper right) External view of left hemimandible from a human fetus GA 17 weeks. Note that the mental foramen has been formed (arrow) and the coronoid process is large but the contour of the condyle has not yet formed. (Center left) Left hemimandible from the same human fetus demonstrated in the upper right now viewed from above. A long fissure is present which later becomes the mandibular canal. The floor in this fissure is the lowest part of the later mandibular canal. (Center right) Left hemimandible seen from behind. This is the same specimen as the upper right and center left. Note that the mandibular condyle has not formed. A hole is present in the condylar region (arrow). The hole contained the deviscerated, cone-shaped cartilage which later forms the condylar cartilage. Right of the hole is a groove which later becomes the mandibular canal entrance for the inferior alveolar nerves. The mandibular foramen develops later in the prenatal period. (Lower left) Two schematic drawings from Björk’s studies on profile radiographs of two different individuals demonstrating different mandibular morphology and different growth patterns. The growth patterns are illustrated by arrows in the mandibular condyle (left, vertical growth pattern; right, sagittal growth pattern). For each specimen, two markings are provided for two different ages (dotted = younger period). Inserted in these two mandibles are the size and morphology of the prenatal human mandible (black). The red line indicates the contour of the mandibular canal. Note that the prenatal fissure containing the inferior alveolar nerves has a straight course while the bent contour of the canal appears later in postnatal life. The course of the bend differs according to growth pattern. The arrows in the developing tooth buds are from Björk’s study on eruption direction. Source: Björk (1955). (Lower right) A human mandible in the late prenatal period. Note the alveolus for the teeth and the midaxial symphysis menti (arrow). Space for the developing first molar is created by resorption of the anterior border of the mandibular ramus. demonstrated in Figure 1.31. Unilateral condylar hypoplasia and growth, then the canal direction will be different from the other unilateral condylar ankylosis result in mandibular asymmetry side. If this occurs later in life, the asymmetry is less and the during postnatal life. An anthropological analysis of the direction direction of the two canals more symmetrical. Figure 1.31 shows of the mental canal can indicate when the defect in the condylar a cranium in which an early condylar growth arrest contributes region arose. If the affected side of the mandible has arrested to severe asymmetry.

Craniofacial development and the body axis 15 Figure 1.30 Radiographs (occlusal views) from two human fetuses with severe mandibular malformations. White indicates bone tissue. The figures demonstrate how fetal pathology can explain mandibular development. (Left) The contour of the mandible appears in the figure with the tongue located centrally. The symphysis menti appears lowest in the image as a gap between two bony components. Noteworthy is that the bony components anteriorly and posteriorly in the mandible are not continuous. The lateral gaps are unossified remnants from the anterior Meckel’s cartilage. The bones between these gaps are seemingly formed by apposition. The posterior part of the mandible and the mandibular condyles have formed. (Right) Contour of the mandible from an agnathic fetus where the symphysis menti is present in the lower part of the image but the mandibular bone has not been fully formed. Source: Kjær et al. (1999). Reproduced with permission of John Wiley & Sons. Figure 1.31 An anthropological, human cranium and two human mandibles demonstrating severe malformations in the mandible. (Left) The mandible is asymmetrical with an underdeveloped left side. In the underdeveloped side, the mental foramen appears clearly from the frontal view and the mental canal appears to run in the posterior- anterior direction. This indicates an early arrest in condylar growth. On the right side, the canal cannot be seen from the frontal view and metal markers have indicated that the directions of the mental canals are different in the two sides. (Inset) A photograph of a cranium with a mandibular ankylosis in the left side. In ankylosis, fusion occurs between the mandibular condyle and the fossa articularis. If this happens during a growth period, noticeable asymmetry results and jaw function is affected. (Right) Two mandibles displaying unilateral (upper) and bilateral (lower) condylar malformations. The etiology is not known. The uppermost part of Meckel’s cartilage produces the malleus Congenital absence of mandibular incisors appears in Ellis– and incus of the inner ear. It is logical to associate deviations in van Creveld syndrome which involves malformation of cartilag­ these small bones with deviations of the mandible which is also inous tissue (Figure 1.33). This might indicate the influence of the dependent on Meckel’s cartilage. surrounding endochondral tissue (ectomesenchyme) anteriorly in the mandible on tooth formation in this region. A median cleft in the mandible and/or nonclosure of the symphysis menti are very rare findings shown in Figure 1.32. If Theca cranii the bilateral hemimandibles do not fuse correctly in the midaxial The theca cranii protecting the brain ossifies first in the most plane, a midline mandibular cleft can occur (see Figure 1.32). anterior and lower part of the frontal bone and in the posterior This abnormality and the persistence of the symphysis menti are part by the occipital squama. Later, thin, porous bone mem­ rarely observed. branes appear in the protuberantia frontalis and protuberantia parietalis. The intramembranously formed bone structure radi­ Diseases such as juvenile arthritis result in complete or partial ates out from these protuberantiae (Figure 1.34). The theca arrest of mandibular growth which leads to asymmetry or sutures do not develop until after GA 22 weeks. Between the retrognathia. Other forms of congenital or acquired conditions can also result in deviant mandibular growth.

16 Chapter 1 Figure 1.32 Sections from two orthopantomograms depicting midline malformations in the mandible. (Left) A partial mandibular midline cleft or a condition resembling this condition observed in a young child. The radiograph is not optimal due to movement of the head during exposure. (Right) A shadow (arrow) suggesting nonclosure of the symphysis menti. The patient is a child with an ear defect and severe mandibular retrognathia. Figure 1.33 A section from an orthopantomogram illustrating an Ellis– Clinical relevance van Creveld-like condition in a child with an altered cartilage metabolism Different craniofacial malformations are interrelated with vari­ (short body height). The anterior mandibular incisors in the symphysis ous malformations in the theca cranii (Figure 1.35). It has been menti region have never developed. This is a prenatal change in tissue debated whether the theca cranii has a neural crest origin or development which indicates that the ectomesenchymal tissues (cartilage paranotochordal origin or a mixture of the two (the last being the and bone) are also important for tooth development. more probable theory). The different theca malformations observed in different craniofacial malformations cannot clearly squamous bones (frontal squama, parietal sqama, sphenoidal identify the relationship between the malformations of the theca squama and occipital squama), there are large sheets of connec­ and malformations in other regions of the cranium. tive tissue called fontanelles, which allow cerebral growth. At birth, these fontanelles (especially the frontal fontanelle) are still Synostoses are suture closures. They are observed in different very large. The pattern of sutures and fontanelles differs in syndromes as well as in cases without a syndromic diagnosis different craniofacial malformations. The postnatal thickness (Figure 1.36). The bone thickness of the theca seems to be and size of the theca cranii increase gradually and can be interrelated with various skeletal malocclusions. One example measured by cephalometry. The thickness varies under normal is observed in skeletal deep bite where the theca is statistically conditions and normal malocclusions. The lower part of the thicker than average. Pathological thickness of the theca appears occipital squama has a cartilaginous origin. in skeletal disorders mentioned in Chapter 15. Vomeral bone The vomeral bone is made up of two bilateral ossifications on each side of the nasal septum around 13 weeks GA. The two bilateral bone units fuse caudally and develop a broad base which lies above the midpalatine suture (Figure 1.37). The suture Figure 1.34 Theca cranii development. (Left) Radiograph of the theca from a fetus. The anterior direction points upwards. The white cross represents the theca sutures (above and midaxially, the interfrontal suture; below and midaxially, the interparietal suture; transversely, the coronal suture). The meeting area indicates the anterior fontanelle. From the protuberantia frontalis and the left protuberantia parietalis, bony trabeculae radiate towards the sutures. (Right) Sagittal cut of a human cranium from a newborn demonstrating the large neurocranium, the cranial base and the less developed upper facial cranium. Note the thinness of the theca bone. Note also the appearance of the partly calcified falx cerebri posteriorly (arrow).

Craniofacial development and the body axis 17 Figure 1.35 The theca field in cranial development. Anterior direction points upwards. (Right) Schematic drawing of the sutures and fontanelles in a cranium without malformations. (Left) (Figures with blue background). Five different malformed crania from the perinatal period seen from above. The crania are from newborns with various severe facial malformations (see Chapter 3). Note the different morphologies of the anterior fontanelle. These crania demonstrate how abnormalities in the neural crest field development are associated with abnormal development of the theca cranii. Whether the thecal malformation is a trait which is part of the neural crest abnormality pattern or whether it is secondary to a brain malformation is not known. It is still debated whether the theca cranii develops from neural crest cell migration or whether it has a paranotochordal origin. It is also possible that the theca development is dependent of both developmental processes. Source: T. Söderqvist, Medicinsk Museion, Copenhagen, Denmark. Reproduced with permission of T. Söderqvist. between the vomeral bone and the maxilla allows the maxilla to move forward during growth. Clinical relevance Be aware of the nasal septum when analyzing an orthopantomo­ gram. Malformations often appear here in relation to facial and dental malformations. When the vomeral bone appears abnor­ mal in morphology, it is often associated with a malformation in the maxillary insicive region. This could be in cases with super­ numerary incisors or malformed incisors. Figure 1.36 Two crania with different synostoses. (Left) Radiograph of a Nasal bones cranium from a young adult demonstrating a short theca cranii These are formed as bilateral membranous bones supported (oxycephaly-like) and presumably a synostosis or retarded growth in the during ossification by cartilage. A sagittal view of the prenatal, coronal suture. (Right) A human cranium with a scaphocephalic shape. bilateral nasal bones appears in Figure 1.38. A range of normal (Inset) A view of the same cranium from above where the long and narrow nasal bone morphologies as they appear on profile radiographs is shape can be seen. The etiology behind this shape is early closure of the demonstrated in Figure 1.39. sagittal suture. Figure 1.37 Formation of the vomeral bone. (Left) The black vomeral bone in the center of the figure is shaped like a tuning fork with a broad base which rests on the intermaxillary suture. The cleft of the fork contains the cartilaginous septum from the ethmoid bone (small circles). The shape of the fork allows maxillary growth as well as growth of the nasal bones. (Center) Radiograph of a frontal section of a human fetus GA 15 weeks. Note the fork axially in the nasal cavity. The symphysis menti appears clearly in the lower part of the radiograph. (Right) Histological frontal section of a human fetus GA 17 weeks with a green-blue, axial nasal cartilage supported by the fork of the vomeral bone which again has a broad base resting on the maxillary suture. Lateral aspects indicate the early nasal conchae development.

18 Chapter 1 Figure 1.38 Development of the nasal bones. (Left) Prenatal development of the nasal bone (arrow). During development, the bony components rest on the cartilage of the nasal septum. Note the initial calcification of the incisors in the bottom left corner (two white dots). (Right) Normal appearance of a human nasal bone from a child 14 years of age, lateral view. The nose is externally supported by a small rod to secure the correct position in the cephalostat. The nasal bone appears with a broad base and is pointed anteriorly (left side). The shadow of the entire bone is apparent and the suture bordering the maxillary bone is also visible. (Inset) An axial radiograph of the anterior part of the maxilla and nasal bones from a human fetus GA 21 weeks marking the broad and rounded shape of the nasal bones. It is important to remember that the nasal bone is wide and is a bilateral structure. Figure 1.39 Sections from profile radiographs of three different individuals between 12 and 14 years of age displaying varying nasal bone lengths. The etiology behind these nasal bone lengths is not understood. In all three cases, other associated deviations occur and are described below. (Left) The patient has a severely asymmetrical nasal cavity and agenesis of the maxillary lateral incisors. The nasal bone is short. (Center left) The patient is cross- eyed and has an abnormal sella turcica with a broad bridge from the anterior to the posterior wall. The nasal bone is short. (Center right) The patient has a short, maxillary base and an ectopic maxillary canine. The nasal bone is abnormally long. Fetal pathology Temporal bone In some malformations, the nasal bone is phenotypically char­ The mastoid part of the temporal bone surrounding the inner ear acteristic for the condition. A short nasal bone may be seen is formed bilaterally in the cranial base from GA 10 weeks. The prenatally in trisomy 21 and 18 as well as in fragile X syndrome tympanic membrane is composed of invaginated epithelium on and cleft lip cases. A short nasal bone is not observed in complete its outer surface. The tympanic ring is seen prenatally as a cleft lip and palate or triploidy syndromes. In interuterine relatively large, ossified, half moon-shaped ring before the screening, the nasal bone is a key structure for analysis and mastoid process ossifies. assessment of syndromes such as Down’s syndrome but it can also be a symptom of other inherited conditions. Fetal pathology In rare cases, absence of the tympanic ring can occur. Clinical relevance Be aware of the nasal bone when analyzing profile radiographs. Clinical relevance Figure 1.39 demonstrates different lengths and morphologies of Children with reduced hearing may, among other symptoms, abnormal nasal bones. A short nasal bone may be seen in have a cranial base malformation associated with malformation association with deviations in the dentition and/or the anterior of the inner ear. Also, an ectodermal deviation which involves wall of the sella turcica. the tympanic membrane (ear drum) could cause a hearing deficit. In clinic, it is important to observe whether the patient In hypophosphatemic rickets, the nasal bone often has a has a hearing aid. An example of a patient with an ectodermal specific morphology (see Chapter 14). disease involving the ear drum, the skin, and the dentition is shown in Chapter 10. As the nasal bone occurs bilaterally, the observation of two nasal bone contours on a profile radiograph may indicate facial asymmetry see (Figure 1.39).

Craniofacial development and the body axis 19 Craniofacial morphology and growth Further reading Insight into craniofacial growth has expanded within the last 60 Bach-Petersen S, Kjær I. Ossification of lateral components in the human years. Craniofacial morphology has been intensively studied prenatal cranial base. J Craniofac Genet Dev Biol 1993;13:76–82. through postnatal, longitudinal, and radiographic studies using cephalometric methods, including three-dimensional (3D) anal­ Bach-Petersen S, Kjær I, Hansen BF. Prenatal development of the human ysis. These studies have documented that tooth position and osseous temporomandibular region. J Craniofac Genet Dev Biol occlusion are dependent on craniofacial growth. Cephalometric 1994;14:135–143. studies are also conducted on prenatal autopsy material. Such studies are cross-sectional and they clearly demonstrate in Bach-Petersen S, Solow B, Hansen BF, Kjær I. Growth in the lateral part seemingly normal material how the cranial base angle is very of the human skull during the second trimester. J Craniofac Genet Dev large prenatally and gradually decreases during early childhood Biol 1995;15:205–211. development until it stabilizes. Björk A. Facial growth in man, studied with the aid of metallic implants. Highlights and clinical relevance Acta Odont Scand 1955;13:7–34. • There is a constant sequence in bone development of the Björk A. Prediction of mandibular growth rotation. Am J Orthod cranium. 1969;55:585–599. • There is coordination between the maxillary and mandibular Björk A, Skieller V. Growth of the maxilla in three dimensions as development controlled by the tongue muscles. revealed radiographically by the implant method. Br J Orthod 1977;4:53–64. • The mandible fans out transversely before formation of the mandibular condyle. The sella turcica region divides the Björk A, Skieller V. Normal and abnormal growth of the mandible. A cranial base in two parts with different origins. synthesis of longitudinal cephalometric implant studies over a period of 25 years. Eur J Orthod 1983;5:1–46. • The etiology of the cranial base behind the sella turcica (posterior cranial fossa) correlates with the notochord while Caspersen LM, Christensen IJ, Kjær I. Inclination of the infraorbital the frontal cranial base anterior to the sella turcica (anterior canal studied on dry skulls expresses the maxillary growth pattern: a cranial fossa) develops from the neural crest cells. new contribution to the understanding of change in inclination of ectopic canines during puberty. Acta Odontol Scand 2009;67: • The head is completely integrated with the body axis 341–345. development. Christensen LR, Kjær I, Græm N. Comparison of human dental and • The bones in the body axis and the bones in the cranium craniofacial maturation on prenatal profile radiographs. Eur J Orthod develop in an interdependent, constant sequence. 1993;15:149–154. • The maxilla and the mandible both start ossification in the Damgaard C, Caspersen LM, Kjær I. Maxillary sagittal growth evaluated canine region. on dry skulls from children and adolescents. Acta Odontol Scand 2011;5:274–278. • The skeleton can be used as a map to reveal where the initial malformation is located and when it arose. Drews U. Color atlas of embryology. Thieme New York 1995. Goto S, Uhthoff HK. Notochord action on spiral development. Acta • The palate formation depends on the activity of the tongue muscles. Odontol Scand 1985;57:85–90. Jacobsen PE, Kjær I, Sonnesen L. Skull thickness in patients with skeletal • The mental canal and the infraorbital canal have a direction which is associated with the direction of mandibular and deep bite. Orthod Craniofac Res 2008;11:119–123. maxillary growth. Kjær I. Histochemical investigations on the symphysis menti in the • If the condylar cartilaginous tissue does not appear posteriorly human fetus related to fetal skeletal maturation in the hand and foot. to the bony mandible at about 15 weeks GA, then the condyle Acta Anat (Basel) 197593:606–633. will never develop. How and why this cartilage appears is not Kjær I. Histochemical and radiologic studies of the human fetal man­ known but it is essential for postnatal condylar growth. dibular condyle. Scand J Dent Res 1978;86:279–299. Kjær I. Prenatal skeletal maturation of the human maxilla. J Craniofac • The anterior mandibular region is endochondrally formed. Genet Dev Biol 1989;9:257–264. Absence of teeth in this region may indicate the importance of Kjær I. Formation and early prenatal location of the human mental the ectomesenchyme for tooth development. foramen. Scand J Dent Res 1989;97:1–7. Kjær I. Human prenatal palatal closure related to skeletal maturity of the • The anterior and posterior walls in the sella turcica have jaws. J Craniofac Genet Dev Biol 1989;9:265–270. different origins. The sella morphology must therefore be Kjær I. Radiographic determination of prenatal basicranial ossification. analyzed on profile radiographs. Deviations in the posterior J Craniofac Genet Dev Biol 1990;10:113–123. wall where the rostral end of the notochord appears are related Kjær I. Ossification of the human fetal basicranium. J Craniofac Genet to deviations in the bodies of the cervical column. Dev Biol 1990;10:29–38. Kjær I. Human prenatal palatal shelf elevation related to craniofacial • The pattern of sutures and fontanelles differs in different skeletal maturation. Eur J Orthod 1992;14:26–30. craniofacial malformations. Kjær I. Mandibular movements during elevation and fusion of palatal shelves evaluated from the course of Meckel’s cartilage. J Craniofac Genet Dev Biol 1997;17:80–85. Kjær I. Neuro-osteology: developmental interrelationships between nerve tissue and hard tissue in the human body axis. Based on review article in Crit Rev Oral Biol Med 1998;92224–244.

20 Chapter 1 Kjær I, Keeling JW, Hansen BF. The prenatal human cranium, normal Schoenwolf GC, Bleyl SB, Brauer PR, Francis-West PH. Larsen’s human and pathologic development. Munksgaard Copenhagen 1999. embryology, 4th edn. Churchill Livingstone Philadelphia 2009. Kjær I, Kjær TW, Græm N. Ossification sequence of occipital bone and Sejrsen B, Jakobsen J, Skovgaard LT, Kjær I. Growth in the external vertebrae in human fetuses. J Craniofac Genet Dev Biol 1993;13:83–88. cranial base evaluated on human dry skulls, using nerve canal openings as references. Acta Odontol Scand 1997;55:356–364. Kyrkanides S, Kjær I, Hansen BF. Development of the basilar part of the occipital bone in normal human fetuses. J Craniofac Genet Dev Biol Sejrsen B, Kjær I, Jakobsen J. Human palatal growth evaluated on 1993;13:184–192. medieval crania using nerve canal openings as references. Am J Phys Anthropol 1996;99:603–611. Le Douarin NM. The neural crest in the neck and other parts of the body. Birth Defects 1975;11:19–50. Silau AM, Hansen BF, Kjær I. Normal prenatal development of the human parietal bone and interparietal suture. J Craniofac Genet Dev Le Douarin NM, Ziller C, Couly GF. Patterning of neural crest deriv­ Biol 1995;15:81–86. atives in the avian embryo: in vivo and in vitro studies. Dev Biol 1993;159:24–49. Silau AM, Njio B, Solow B, Kjær I. Prenatal sagittal growth of the osseous components of the human palate. J Craniofac Genet Dev Biol Melsen B. The cranial base. Acta Odontol Scand 1974;32(suppl 1):72–85. 1994;14:252–256. Mentz RG, Engel U, Kjær I. Nasal bone length trimosy 18, triploidy and Solow B, Iseri H. Maxillary growth revisited: an update based on recent Turner syndrome analyzed on postmortem radiographs. Ultrasound implant studies. In: Davidovitch Z, Norton LA, (eds) Biological Obstes Gynecol 2009;34:607–608. mechanisms of tooth movement and craniofacial adaptation. Harvard Moore KL. The developing human. Clinically oriented embryology, 4th Society for Advancement of Orthodontics, Boston 1996. edn. WB Saunders Philadelphia 1988. Pálsson SR, Kjær I. Morphology of the mandibular canal and the Takashi O, Hansen BF, Nolting D, Kjær I. Nerve growth factor receptor angulation between the mandibular and mental canals in dry skulls. immunolocalization during human palate and tongue development. Eur J Orthod 2008;31:59–63. Cleft Palate-Craniofacial J 2003;40:116–125. Sandikcioglu M, Mølsted K, Kjær I. The prenatal development of the human nasal and vomeral bones. J Craniofac Genet Dev Biol van den Eynde B, Kjær I, Solow B, Græm N, Kjær T, Mathiesen M. 1994;14:124–134. Cranial base angulation and prognathism related to cranial and general skeletal maturation in human fetuses. J Craniofac Genet Dev Biol 1992;12:22–32.

CHAPTER 2 Craniofacial development and the brain: normal and pathological aspects from early prenatal to postnatal life In this chapter, the focus is on the relationship between the development, and the falx cerebri, the membrane separating central nervous system (CNS), the neurocranium, and the the bilateral hemispheres, is formed. Falx cerebri is attached to cervical spine. Attention is also given to the peripheral nervous the crista galli axially on the ethmoid bone (Figure 2.3). The system (PNS) and jaw development. This discipline describing cerebrum is covered by the bones in the theca cranii on its outer the interrelationship between development of nerve and bone surface, separated by sutures and fontanelles (see Chapter 1). The tissues is called neuroosteology. tentorium cerebelli is a membrane separating the cerebrum from the cerebellum. It is attached anteriorly to the posterior cleinoid Central nervous system in relation to processes of the dorsal sella wall and posteriorly to the occipital neurocranial development pre- and squama schematically marked in Figure 2.2. postnatally The sequence in which the cranial bones ossify is described in The CNS is composed of the brain and the spinal cord. Chapter 1. Here we explain how the development of the brain is coordinated with the development of the cranium. As a general Brain rule, theca ossification protecting the lower part of the hemi­ The brain develops from the inner neuroectodermal layer of the spheres anteriorly and the cerebellum posteriorly commences germ disk in specific regions – the prosencephalon, the mes­ before the ossification of the cranial base. Shortly after, ossifica­ encephalon, and the rhombencephalon. Each of these regions tion starts in the tuber regions which become lateral supports for develops further into specific brain regions located in the neuro­ the growing hemispheres. The inferior aspect of the brain is cranium. The prosencephalon thus develops into the tel­ protected by a bowl of cartilage, the cranial base, on which there is encephalon (the cerebral hemispheres) and the diencephalon an exact impression of the inferior surface of the brain. After (Figure 2.1). The diencephalon is situated centally in the cranial ossification of the squama of the occipital bone protecting the base with an extension (infundibulum cerebri) in the axial plane cerebellum, the first part of the cranial base to ossify is the basilar to the sella turcica forming the neuropituitary gland. part of the occipital bone supporting the pons. The ossification also takes place laterally to support the temporal lobes of the The rhombencephalon forms the part of the brain which is hemispheres. Gradually bone appears below the pituitary gland located in the posterior cranial fossa (Figure 2.2). Anteriorly, this located in the posterior part of the sphenoid bone corpus. part of the brain includes the pons, which is bordered and Thereafter, ossification occurs in the anterior cranial fossa below supported by the corpus of the occipital bone. The cerebellum the bilateral olfactory bulbs and in the orbital squama of the develops from the posterior aspect of the rhombencephalon frontal bone which separates the ocular cavity from the hemi­ covered posteriorly by the lower part of the occipital squama. spheres (Figure 2.4). At a late stage in the course of development, This part of the squama has a cartilaginous origin. the mastoid, which is a part of the temporal bone enclosing the inner and middle ear, is ossified. The ossification pattern dem­ Brainstem onstrates how ossification encircles the regions of the sensory The brainstem is a collective term for the diencephalon, the organs: the eyes, the inner ear, and the nasal cavity. It is obvious mesencephalon, and the rhombencephalon (see Figure 2.1). The that the sella turcica is relatively large at this early stage of structure does not always include the cerebellum. development compared to the length and width of the cranial base. Therefore, considerable differentiation and growth take The hemispheres forming the cerebrum bulge out from the place not only in the cranial base but also in the brain. prosencephalon anteriorly through the foramen of Monro. The hemispheres enlarge and move gradually posteriorly during The growth in the inferior aspects of the brain is difficult to ascertain, but it seems clear that the pituitary gland in the sella Etiology-Based Dental and Craniofacial Diagnostics, First Edition. Inger Kjær. © 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd. 21

22 Chapter 2 Figure 2.1 Schematic drawing of the main components of the brain Figure 2.3 Horizontal histological section through the crista galli (G) and observed midaxially. Dark yellow indicates the diencephalon, light yellow the posterior wall of sella turcica (S) from a human fetus GA 15 weeks. the hemispheres. The red region is the metencephalon. The upper part of The anterior direction points upwards. The falx cerebri separating the the green region composing the pons and the medulla oblongata is the bilateral hemispheres (H) is attached to the crista galli. brainstem. The cerebellum belongs from a developmental point of view to this region. The lower part of the green region is the cervical spinal cord. The cartilaginously derived cranial base and the lower cartilaginously derived part of the occipital squama and vertebrae are colored purple. The theca bones, nasal bone, maxilla, and part of the mandible are intramembraneously derived (light red) while the anterior part of the mandible has an endocartilaginous origin (purple). Figure 2.4 Radiograph of a midsagittal section of a human fetus GA 19 weeks. In the cranial base, the basilar part of the occipital bone (O) has ossified. The corpus of the sphenoid bone (S) has also formed, enclosing the pituitary gland. The frontal bone is marked by “F,” the nasal bone by “N,” and the maxilla by “M.” The symphysis menti region of the mandible appears in the lower part of the section (SM). This figure demonstrates how the posterior part of the cranial base supporting the brainstem ossifies before the anterior part. Figure 2.2 A schematic drawing of the cranium and brain components in turcica is stable in its location. At the border region between the the midaxial plane. The dark red area illustrates the location of the brain and the spine, ossification gradually forms the bony cerebellum, the lower part of the brainstem, and the cervical spinal cord. foramen magnum. Ossification occurs first at the posterior The uppermost contour of the red area indicates the tentorium cerebelli. edge of the foramen, then laterally, and finally at the front. Synchondroses are formed between the bony elements, enabling the foramen magnum and the spine to increase in diameter prenatally. The synchondroses close after birth.

Craniofacial development and the brain 23 As a final remark, it is characteristic that the differential ossification patterns in the cranium reflect the growth patterns of the CNS. As long as a cranial region is composed of cartilage, more expansive growth can occur. Fetal pathology The interrelationship between the CNS development and surrounding bone development has been observed in several cases of fetal pathology. Most intensive studies have been conducted on the pituitary gland in different sella turcica malformations. Hemispheres Figure 2.5 The brain and cranium in anencephaly. (Upper left) A schematic There are severe hemisphere malformations which affect the drawing of the outer appearance of an anencephalic fetus. Note the absence development of the neurocranium. The first involves the non- of the theca cranii. (Upper right) A human anencephalic fetus on which a formation of the hemispheres – known as anencephaly. This brain has been drawn. The green portion indicates the part of the brain that condition involves the absence of the theca cranii and neuro­ is present, while the yellow part, representing the hemispheres, does not pituitary gland due to the nonexistence of the cerebral infundib­ develop. (Lower) A sagittal, histological section of the upper cranium from a ulum (Figures 2.5 and 2.6). There is no posterior wall in the sella human, anencephalic fetus indicating the presence of (with slight turcica and there are large deviations in the rostral end of the misplacement) the jaw bone and the cranial base bone/cartilage. The lower notochord. Another severe malformation involves fused or non- part of the frontal bone (arrow) is tilted backward. The pituitary gland (P) separated hemispheres (Figure 2.7) which occurs in holopro­ is also malpositioned (see Figure 2.6 for more information). Also the sencephaly in association with a diminutive and malformed/ maxillary central incisor (I) is present. This figure demonstrates that the displaced adenopituitary gland. In this chapter, only anenceph­ cranium (except the theca cranii) and the dentition can develop aly will be discussed (see Chapter 13 for information on independently of the hemispheres. Source: Kjær (2010). holoprosencephaly). malformations of the basilar part of the occipital bone and the Characteristic for anecephalic fetuses is a normal facial con­ cervical spine (Figure 2.8). tour, but as the cerebrum has not developed, parts of the forehead and the theca cranii are not present. The condition is lethal and Encephaloceles the cause is not known. Seemingly, the signals in the most rostral Midaxial encephaloceles/myelomeningoceles are malformations part of the notochord have failed or malfunctioned. This is in different parts of the lumbar, thoracic, cervical, and occipital suggested because the basilar part of the occipital bone, the sella regions. They have been analyzed and associated with an abnor­ turcica, and the pituitary gland are malformed. In the pituitary mal anterior wall of the sella and changes in the facial profile. An gland, the neuropituitary gland is absent and the sella turcica has example of a lumbar myelomeningocele appears in Figure 2.9. a highly deviated shape. The infundibulum cerebri appears to be Bilateral encephaloceles of the parietal and frontal regions of the missing or to be dysfunctional. The cerebrum is absent but bilateral hemispheres are also associated with abnormalities in remnants of the cerebellum exist. the cranium and sella turcica (Figure 2.10). Furthermore, ence­ phaloceles can occur in the ethmoid bone and axially in the body The external appearance of an anencephalic fetus contains a of the sphenoid bone. sharp, nearly linear border between the theca cranii and the rest of the cranium. The analysis of an anencephalic fetus thus indicates that the existence of the theca field in the cranium depends on the existence of the cerebrum. The relationship between the notochord and the development of the pituitary gland can be understood from an anencephalic analysis which reveals that the rostral part of the notochord and the dorsum sellae are malformed. Interestingly, the facial structures such as the nose, the maxilla, and the mandible are developed and are seemingly not affected by the absence of cerebrum. The lower part of the frontal bone is formed and is backward tilted (see Figure 2.5). Cerebellum Clinical relevance Agenesis of the cerebellum, a diminutive cerebellum or a mal­ If the posterior wall of the sella turcica is malformed, then it can formation of the pons often occurs in association with be presumed that the rostral part of the notochord has been

24 Chapter 2 Figure 2.6 The sella turcica and pituitary gland in normal development and in anencephaly. (Upper left) A frontal, histological section of the pituitary gland from a normal fetus GA 10 weeks demonstrating how the neuropituitary gland (N) appears like a process shooting out from the diencephalon (D) of the brain. The offshoot is called the infundibulum cerebri. The bilateral, circular structures are from the bean-shaped adenopituitary gland (A). (Upper right) A sagittal, histological section of the cranium and brain from a normal fetus GA 10 weeks demonstrating the interrelationship between the notochord (NO), the posterior cranial base, and the upper cervical vertebrae. The rostral extension of the notochord is the sella turcica region (S). The tongue is marked T and the palate has not yet formed. (Lower left) A sagittal, histological section of the sella turcica/pituitary gland region from a human anencephalic fetus GA 19 weeks. Note the absence of the neuropituitary gland but the presence of the adenopituitary gland (A) which appears to be lying over the underdeveloped dorsum sella. Remnants of the notochord (NO) appear disorganized and malformed in the cartilage. (Lower right) A schematic drawing of the sagittal view of the sella turcica region from a human anencephalic fetus. Blue indicates cartilage, white is ossification, and red denotes adenopituitary gland tissue. The appearance differs from the lower left image. However, neither image contains neuropituitary gland tissue. The image also demonstrates the subpharyngeal location of the adenopituitary gland tissue which arises from the pharyngeal mucosa. There is a canal in the bottom of the sella turcica which can be seen in approximately 50% of anencephalic fetuses. dysfunctional. This also indicates that the cerebellum might be abnormal. This is demonstrated in Figure 2.11. Absence of the posterior wall of the sella turcica has been seen in relation to diseases and malformations of the inner ear resulting in a hearing deficit (Figure 2.12). When the contour of the sella turcica is unrecognizable, it is important to be aware of a possible tumor. Figure 2.13 illustrates a profile radiograph with such unrecognizable contours where the orthodontist has referred the patient to a neurologist. The final diagnosis was hydrocephalus and a large tumor in the thamalus region. In Figure 2.14, other sella malformations are demon­ strated in patients with hydrocephalus (with shunt) and in patients with other types of brain operation. Figure 2.7 The hemispheres in holoprosencephaly. This is a photo from Spinal cord behind demonstrating the cerebellum (B) and the diencephalon (D) which As the formation of the vertebral bodies is closely related to the is usually covered in the posterior view by the cerebral hemispheres (H). In notochord, the morphology of the bodies depends on the normal holoprosencephaly, the hemispheres appear underdeveloped and are fused development of the notochord and seemingly also on the spinal (arrow) in the midsagittal plane. This is a midline defect involving the cord. At the time of closure of the neural tube, the neuro­ upper face and the hemispheres. It also involved the midaxially located epithelium gradually forms. The spinal cord is closely associated maxillary incisors (see Chapter 13 for more information). Source: Keeling with the spinal ganglia and the arrangement of the dermatomes. (1995). Reproduced with permission of Elsevier. The interrelationship between the development of the vertebrae and the spinal cord is not described here.

Craniofacial development and the brain 25 Figure 2.8 These figures illustrate the interrelationship between malformations in the cerebellum and in the basilar part of the occipital bone. (Left) A profile radiograph of the midsagittal segment of a head from a spontaneously aborted fetus GA 21 weeks seemingly without malformations. Notice, however, a groove in the basilar part of the occipital bone (arrow) which led to a special neurohistological analysis of the cerebellum. The conclusion was that the cerebellum was also malformed. The cranial base angle appears smaller than normal. (Center) A profile radiograph of the upper part of the cranium from an anencephalic fetus (mandible not included). This anencephalic fetus GA 20 weeks has a malformed cerebellum and a split basilar part of the occipital bone (split into upper and lower part) indicated by an arrow. The cranial base angle is extremely small (almost 90°). (Right) A profile radiograph of the midsagittal segment of a head from a trisomy 18 fetus GA 18 weeks. A characteristic finding in trisomy 18 is a notch in the basilar part of the occipital bone. This is marked in the figure with an arrow. Figure 2.9 Photograph taken from behind of a spontaneously aborted Figure 2.10 Photograph of the frontolateral view (left) and lateral view human fetus GA 20 weeks demonstrating a lumbar myelomeningocele. (right) of a spontaneously aborted human fetus approximately GA 14 This CNS malformation is associated with malformations in the vertebral weeks. Note the bilateral protrusions (encephaloceles) from the anterior column and in the anterior wall of the sella turcica. Source: Keeling (1995). part of the frontal lobes of the hemispheres. This malformation is Reproduced with permission of Elsevier. associated with abnormalities in the local cranial area and with malformations of the anterior sella turcica. Source: Kjær et al. (1996). Being the uppermost part of the axial skeleton, the cranium is a Reproduced with permission of Taylor & Francis. part of the body axis that must be considered in connection with the entire body axis. As mentioned in Chapter 1, the notochord is A change in the cranial base angulation occurs in these cases. the early embryonal connecting link between the vertebral bodies Severe cranial and body axis malformation is also seen in the rare and the cranial base posterior to the sella turcica. condition called iniencephaly which is a neural tube defect involving severe spinal malformations. In the Arnold–Chiari Fetal pathology condition, in which caudal displacement of the cerebellum In prenatal occipital encephalocele, which is a severe CNS malformation, the cervical spine also contains abnormalities.

26 Chapter 2 Figure 2.11 The interrelationship between the cerebellum and the basilar part of the occipital bone demonstrated in a section of a profile radiograph from an adult human with cri-du-chat syndrome (for more information, see chapter 13). Notice the malformed posterior wall of the sella (arrow). This figure demonstrates that the cri-du-chat condition with a malformed or severely reduced cerebellum also affects the dorsal sella wall. Source: Kjær and Niebuhr (1999). Reproduced with permission of John Wiley & Sons. Figure 2.12 These figures all demonstrate the interrelationship between malformation in the inner ear and posterior wall of the sella turcica. The mastoid part of the temporal bone which contains the inner ear has a developmental association with the notochord which in its rostral part extends into the posterior wall of the sella turcica. (Left) Profile radiograph of a child approximately 14 years old with hearing loss. Notice the absence of the sella turcica (arrow). The exact severity of the hearing deficit is unknown. (Center) A profile radiograph of a child approximately 14 years old with a cochlear implant (white square). Notice the absence of the posterior wall of the sella turcica (arrow). (Right) A young adult approximately 18 years old with cochlear implant (star). Notice the diminutive sella turcica with an abnormal dorsum sellae contour (arrow). Source: Neel De Vos Riis, School of Dentistry, Aarhus University, Aarhus, Denmark. Reproduced with permission of Marie Cornelis. occurs through the foramen magnum, a large foramen magnum Trigeminal ganglia is observed. The spinal nerves appear at the end of the fourth week of gestation. They arise from the basal plates of the developing Clinical relevance spinal cord and the nerves are covered by myelin sheaths which It is important to be aware of the relationship between deviations form from the Schwann cells. The neural crest cells migrate to the in the cervical spine, the cranial base, and the sella turcica spinal cord where they form the spinal ganglia. In the cranial (associated by the notochord). area, they form the trigeminal ganglia. Figure 2.15 shows a case with a malformed sella, open sphe­ Vomeronasal organs nooccipital synchondrosis, and cervical spine malformation The vomeronasal organs develop in the nasal septum as two observed in the clinic. bilateral organs arising from the invagination of the surface mucosa (Figure 2.17). These glands persist from GA 8 weeks For the clinician who diagnoses bone tissue, there are only a to GA 15 weeks whereafter they disappear but may also be few opportunities for viewing brain scans. One case where both preserved as remnants. These glands produce lutenizing hor­ the radiographic brain analysis and the bone analysis were mone releasing hormone (LHRH) (Figure 2.18) which through conducted is demonstrated in Figure 2.16. In this case, absence neuronal migration along the terminal nerves approaches the of the posterior wall of the sella turcica was observed on a profile olfactorial process and arrives at the hypothalamus where LHRH radiograph. This finding led to a brain scan which revealed is stored (Figure 2.19). LHRH is especially functional during displacement of the cerebellum into the cervical spinal cord. This puberty. is a mild form of the Arnold–Chiari type I condition. If the vomeronasal organs, which are endocrine glands, are not Absence of the posterior wall of the sella turcica can indicate formed or do not function properly, the absence of LHRH will not only cerebellum and foramen magnum abnormalities but influence growth during puberty. This condition is called also malformations in the inner ear, as demonstrated in Figure 2.11.

Craniofacial development and the brain 27 Figure 2.13 Profile radiograph of a 12-year-old child with an Figure 2.15 Profile radiograph of a child 11 years of age with an abnormal unrecognizable sella turcica and with impressiones digitatae in the sella turcica and a broad sphenobasilar synchondrosis. (Inset) A cranium. Because of these deviations, the child was referred to a magnification of the upper cervical vertebrae in the radiograph. Note the neurologist who diagnosed hydrocephalus as well as a tumor in the abnormal corpora and the likelihood of occipitalization (fusion of the atlas hypothalamus region. and the external cranial base). There are several axial malformations in this child indicating the need for a scanning. Notice also the dark, sinus- like formations in the lower frontal bone (possibly encephaloceles). Kallmann’s syndrome. The olfactorial epithelium, which is Clinical relevance located cranially in the roof of the nasal cavity, in the early Be aware of patients with a lack of smell. They might also have stages develops closely to the mucosa, forming the vomeronasal endocrine, glandular disturbances due to abnormal or mal­ organs. Patients with Kallmann’s syndrome therefore lack LHRH formed vomeronasal organs. The mucosa forming the vomer­ and often also their sense of smell, a condition called anosmia onasal organs and the mucosa forming the olfactorial epithelium (Figure 2.20). A cleft lip and palate condition is seen in some are closely related in the embryonic period. Even if these two Kallmann patients. tissue types have different functions (vomeronasal origin: endo­ crine; olfactorial epithelium: smell), patients with dysfunction in Fetal pathology the glands often have problems with their sense of smell. The In cases with specific ectodermal deviations affecting the oral vomeronasal glands secrete LHRH which is important for mucosa, absence of the nasal septum and the presence of oral growth during puberty. Patients with Kallmann’s syndrome clefts mean that the vomeronasal organs may be missing. Figure 2.14 Examples of sella turcica malformations in congenital brain malformations. (Left) Profile radiograph of a child approximately five years old. Note the steep and narrow sella turcica, the broad dorsum sellae (arrow), and the operation staples in the theca cranii. (Right) Profile radiograph of a child 14 years old. Note the malformed sella turcica and the slim, irregular dorsum sellae. There is an operative opening in the theca cranii (right arrow) and a ventricular shunt (left arrow).

28 Chapter 2 Figure 2.16 These figures demonstrate the interrelationship between deviations in the cerebellum diagnosed as Arnold–Chiari type 1 condition and malformations in the sella turcica and the foramen magnum. (Left) Radiograph of a child five years of age with an inserted magnification of the sella turcica region illustrating the absence of the posterior sella wall. This discovery led to a consultation with a neurologist who diagnosed Arnold–Chiari syndrome on the brain scan seen to the right. (Right) The red arrow on the brain scan marks how the lower cerebellum appears to have been squeezed through the foramen magnum. Source: Kjær (2015). Figure 2.17 The early development of the human vomeronasal organs. (Left) A frontal, histological section of the nasal septum from a human fetus GA 7 weeks demonstrating a broad nasal septum at the time when the nasal cartilage (arrow) has just begun development. The large, bilateral nerve pathways illustrate the terminal nerve endings (N). The lower part of the frontal hemispheres (H) appears in the uppermost part of the section. Bone tissue has not yet formed. (Center) A horizontal histological section (the upward direction is anterior) of the nasal cavity in a human fetus GA 12 weeks. The cartilaginous nasal septum is marked by an arrow. The bilateral vomeronasal organs (V) have developed from an invagination of the surface mucosa. Nares are marked by stars. (Right) A frontal, histological section of the nasal cavity from a human fetus GA 13 weeks. An arrow indicates the cartilaginous nasal septum. The bilateral vomeronasal organs are marked by V. The palate has developed from the two bilateral maxillary shelves (M) which have fused in the midline to form the palate but the palate has not yet ossified. Source: Kjær et al. (1996). Reproduced with permission of John Wiley & Sons. lack LHRH and often have anosmia (lack of smell). A profile and the surrounding sella turcica is a good example of a radiograph of a patient with Kallmann’s syndrome displays a neuroosteological process. long and retrognathic face (see Figure 2.20). In the initial stage of pituitary gland formation, there is an Pituitary gland and sella turcica adhesion between the infundibulum cerebri and the pharyngeal The pituitary gland and the sella turcica will receive special focus ectoderm. This adhesion persists and is illustrated by a neuronal in this book. This central endocrine gland has been investigated marker in the intermedial part, the pars intermedium, of the fully and described in several syndromes and malformations. developed pituitary gland (Figure 2.21). Due to invasion of the neural crest cells, this early adhesion region is drawn cranially so The sella turcica provides a central reference point in that a pocket appears. This cranial “pull-up” of pharyngeal cephalometric analysis of the cranium. The sella turcica devel- mucosa creates a pocket called “Rathke’s pouch.” The pituitary ops when the pituitary gland has been formed. The discipline gland gradually develops a bean-shaped anterior acinar lobe with which describes the relationship between nerve tissue and secretory functions and a circular, posterior neuropituitary lobe bone tissue development is called neuroosteology and the (Figures 2.21, 2.22, and 2.23). Between these two lobes, the development of the pituitary gland (neuropituitary gland) intermedial lobe persists (see Figures 2.21 and 2.23).

Craniofacial development and the brain 29 Figure 2.18 This figure illustrates the function of the vomeronasal organs in humans. (Left) A magnified histological section of the vomeronasal organ of a human fetus GA 14 weeks illustrated by immunohistochemical staining for the presence of LHRH which appears red/ brown (visible above the organ). (Right) A frontal, histological section from a human fetus with immunohistochemical staining. The brown color indicates the terminal nerves innervating the vomeronasal organs. The rhinoolfactorial epithelium located in the upper part of the nasal cavity and the nerve paths from this epithelium to the olfactorial bulb are also marked brownish. Source: Kjær et al. (1996). Reproduced with permission of John Wiley & Sons. This means that the shape of the sella turcica depends com­ pletely on the formation of the pituitary gland. If the upward drawing of the initially fused tissue parts of the pituitary gland does not function well, the result can be a malformation in the anterior wall and/or a defect in the floor of the sella. If the notochordal induction in its cranial aspect does not function well, then the posterior wall and/or the posterior part of the floor are malformed. Fetal pathology The endocrine pituitary gland can be totally displaced and located subpharyngeally. In this case, a severely malformed sella turcica occurs without a floor normally supporting the gland. Several types of displacement of the adenopituitary gland tissue are associated with sella turcica malformations. Examples are provided in Figures 2.24 and 2.25. In cases with absence of the neuropituitary gland, such as in anencephaly, the sella appears flat without anterior or posterior walls. Malformations in the pituitary gland include absence of the neuropituitary gland, reduction or displacement of the adeno­ pituitary tissue or absence of the sella turcica with displacement of the gland tissue. The displacement of the adenopituitary tissue is localized to the submucosa of the pharyngeal epithelium from which it arises. It appears as though the adenopituitary tissue has not followed the upward movement of the gland from the extra- to the intracranial position. Figure 2.19 Schematic drawing demonstrating how the LHRH, by Clinical relevance neuronal migration along the terminal nerves and olfactory bulbs, reaches A small sella turcica is not necessarily the cause of a small the hypothalamus for storage. Source: Kjær and Niebuhr (1999). pituitary gland or reduced hormonal secretion. However, it Reproduced with permission of John Wiley & Sons. might indicate reduced growth hormone production. This is illustrated in Chapter 13 in the section on single median maxil­ lary central incisor (SMMCI). A very rare condition called single

30 Chapter 2 Figure 2.20 Two profile radiographs of patients in whom the vomeronasal organs have not developed (Kallmann’s syndrome). The patients cannot produce LHRH and often lack a sense of smell (anosmia). The patient to the left is a male 16 years of age with a long, retrognathic face. The patient to the right is a male 14 years of age and has this syndrome as well as a cleft lip and palate condition. Both receive endocrinological treatment. Figure 2.21 Overview of the three segments of the pituitary gland with different origins and functions – the adenopituitary, the neuropituitary, and the pars intermedium. (Left) Overview of immunohistochemical staining (p75NGFR) for demonstration of adhesion between the adenopituitary and neuropituitary gland at GA 16 weeks. See magnification to the right. (Right) Magnification of pars intermedium seen to the left showing a positive reaction (red-brown) of p75NGFR in the cell layer bordering tissue with ectodermal, mucosal origin and tissue with neuro-ectodermal origin. Source: Kjær et al. (2004). Reproduced with permission of Elsevier. Figure 2.23 Immunohistochemical staining of the human pituitary gland at GA 16 weeks with the anterior aspect pointing to the left. The cells colored blue are the adenopituitary cells and the light red cells make up the neuropituitary gland. Figure 2.22 A horizontal, histological section of the human pituitary gland median maxillary lateral incisor (SMMLI) involves the absence of at GA 16 weeks with the anterior aspect pointing to the left. The anterior a broad, cranial, midaxial tissue segment which stretches from part of the gland (A), the hormone-secreting adenopituitary gland, is bean- the lateral teeth to the pituitary gland. Both SMMCI and SMMLI shaped while the posterior pituitary gland (P) is pea-shaped. Between the can be combined with abnormal pituitary gland function. If a two parts of the gland is the pars intermedium (M), appearing without a young patient is shorter than normal, has a deviation in the lumen midaxially. incremental growth curve, has advanced osseous maturity in relation to body height or a deviation in the sella turcica, it is recommended to refer the patient to an endocrinologist.

Craniofacial development and the brain 31 Figure 2.24 Histological sections demonstrating severe prenatal malformations in the sella turcica/pituitary gland region. (Upper left) A sagittal, histological section of the sella turcica and pituitary gland from a human fetus with trisomy 18, GA 16 weeks. Notice that there is no floor in the sella and that the dorsum sellae has an abnormal notch posteriorly (arrow). The notochordal remnant (N) is malformed. Adenopituitary gland tissue is observed subpharyngeally and in the sella. The neuropituitary gland has been removed during the neurological autopsy procedure. (Upper right) A sagittal, histological section in a spontaneously aborted human fetus approximately GA 18 weeks without known diagnosis. However, a large amount of adenopituitary gland tissue (A) was found subpharyngeally. (Lower left) A sagittal, histological section of the sella turcica/pituitary gland region in a human fetus with triploidy GA 16 weeks. Two separate units of adenopituitary gland tissue (A) were observed respectively above and below the pituitary diaphragm. (Lower right) A sagittal, histological section of a severely facially malformed fetus approximately GA 18 weeks demonstrating a complete absence of the sella turcica as well as a malplacement of the pituitary gland (adenopituitary gland tissue) in the pharynx (arrow). The cartilage appears green (stained with Alcian green). Figure 2.25 Overview of various malformations in the pituitary gland/sella turcica region (anterior points to the left). (Left) A sagittal, histological section of the pituitary gland region demonstrating a severe invagination defect (arrow) in the anterior wall of a human fetus GA 17 weeks with myelomeningocele. (Center) A sagittal, histological section of the pituitary gland region demonstrating a deep and narrow groove in the floor of the sella as well as subpharyngeal adenopituitary tissue (A) from a human fetus GA 15 weeks with combined cleft lip and palate condition. (Right) A sagittal, histological section of the pituitary gland region from a human fetus GA 18 weeks with facial malformation demonstrating a severe malformation in the sella. The pituitary gland appears as an oblong structure of adenopituitary gland tissue stretching from the subpharyngeal area throughout the cranial base. Figure 2.26 demonstrates the contour of the sella turcica in Figure 2.26 Examples of various sella turcica contours drawn from profile children with spina bifida/encephalocele. The drawing shows radiographs of children with myelomeningoceles and spina bifida. The that this condition involves a flattened, deviated anterior sella anterior face points to the left. It appears that all of these sellae have an wall which in some cases is completely absent. abnormal, oblique anterior wall. Source: Kjær (1998). Acromegaly is a condition with a benign tumor (adenoma) in the pituitary gland. The condition results in hormonal activity after arrested growth which leads to changes in bite (open bite) due to extraordinary growth in the mandibular condyle (Figure 2.27). In these cases, the sella turcica appears enlarged, especially in late diagnosed cases.

32 Chapter 2 Figure 2.27 Two profile radiographs from patients with acromegaly. (Left) The acromegaly condition was diagnosed due to abnormal occlusion of the teeth. Gradually, a lateral open bite and a reverse overjet arose which was the reason for an endocrine analysis of the patient which demonstrated a hormonal defect (which was treated). Protrusion of the lower part of the frontal bone is apparent as well as an enlarged sella turcica. (Right) Radiograph of an elderly patient taken before treatment of acromegaly was possible. Notice the very large sella turcica and the significantly protruding mandible. The patient wears full dentures. Figure 2.28 Fetal, anthropological mandibles demonstrating the different innervation paths to different groups of teeth at approximately GA 30 weeks. (Left) On a left hemimandible, guttapercha points demonstrate how different nerves follow different paths. (Right) Guttapercha points demonstrate that different holes on the oral surface of the mandibular ramus serve as entrances for different nerves to different teeth. Source: Chavéz- Lomeli et al. (1996). Reproduced with permission of Sage Publications. Peripheral nervous system pre- and with different time intervals. The inferior alveolar nerve is a postnatally bundle of nerves in which the lowermost nerve endings are the first to sprout out from the CNS and extend to the incisors Each spinal nerve innervates a specific region of the body (Figure 2.28). The uppermost nerve endings in the bundle are the (dermatome). The trigeminal nerve, for example, supplies inner­ last to sprout out and these extend to the molars. The mandibular vation to the jaws. A dermatome site in the jaw could be the canal develops around the individual nerves which gradually thickened mucosa from which the tooth bud arises. The derma­ form the inferior alveolar nerve bundle. The understanding of the tomes are not precisely separated and this means that overlap in innervation in the mandible can be supported by the oral the innervation may occur. foraminae observed prenatally on the labial side of the ramus (see Figure 2.28). These holes cannot be seen clearly at birth due Jaw innervation and bone formation to jaw growth by apposition which gradually covers the holes and The peripheral nervous system (PNS) develops very early and because the area at birth is covered by the lingula mandibula. The before ossification of the jaws occurs. Thus, the bony holes first hole observed in the ramus is the hole for the nerves to the (foraminae) in the cranial base and in the jaws occur secondarily. incisors, the second is the hole for the mental nerve bundles It is the bone tissue that surrounds the peripheral nerves already innervating the canines and premolars, and thereafter, several present which creates the foraminae. As an example, the first holes develop around nerves for the molar roots. The mandibular bone tissue to appear in the maxilla and mandible, in the formerly canal is still only an open groove (or fissure) at GA 30 weeks (see named canine region, appears around the infraorbital nerve and Figure 2.28). Near the end of the fetal period the groove closes the mental nerve. and the mandibular canal arises. The canal-enclosed nerves are separated by delicate osseous layers which reveal different origins The mandible for these nerves as well as different times for enclosure. A The inferior alveolar nerve bundle forms gradually. The different schematic overview of the innervation of the mandible is seen peripheral nerves in the jaws extend to different tooth groups in Figure 2.29.

Craniofacial development and the brain 33 Bone growth and innervation The interrelationship between human bone growth and inner­ vation has immunohistochemically demonstrated that osteo­ blasts are nerve growth factor receptor (NGFR) positive. This indicates that growing human bone tissue is dependent on innervation (Figure 2.30). As a result, a hypothesis has been proposed that compensatory and dysplastic jaw growth, described by Björk, is regulated by the peripheral nervous system via the trigeminal ganglion. This aspect concerning innervation and bone growth has also been demonstrated in the laboratory by experimental research where neuroreceptors have been identi­ fied on the bone cells. Figure 2.29 A schematic drawing of the jaws separated in the midaxial Clinical relevance plane for illustration. Both in the maxilla (above) and in the mandible The nerve paths in the jaws occur in bony canals which are stable there are separate innervations to the different tooth groups; red for structures during development. Also the anterior wall of the sella incisors (I), green for canines/premolars (C/P), and blue for molars (M). turcica and the pterygopalatine fossa encircling the pituitary Note that the innervation paths for the incisors differ in the jaws. In the gland and the pterygopalatine ganglia are stable structures. These mandible, innervation reaches the lateral incisor before the central incisor stable structures encircling the CNS and PNS are important for while the opposite pattern occurs in the maxilla. Also note that the understanding differential growth patterns in the cranium. innervation paths are united posteriorly in the mandible and that the innervation to the incisors is located deepest in the mandibular canal When superimposing profile radiographs for analysis of jaw followed by the innervation to the canines/premolars and uppermost by growth, it is recommended to use stable structures such as the the innervation to the molars which develop latest. Source: Kjær (1998). anterior wall of the sella turcica, the pterygopalatine fossa, and the mandibular channel as reference points (Figure 2.31). These The maxilla are all structures that encircle innervation pathways. In anthro­ The innervation to the maxilla is anteriorly called the nasopa­ pology, the direction of a nerve canal, for example the infraorbital latine nerve, medially the maxillary nerve, and posteriorly the canal, the mental canal and the mandibular canal, can be an palatine nerve. The development of these nerve branches to expression of growth pattern (see Figure 2.31). Of these canals, different tooth groups occurs at different times, starting from the only the mandibular channel can be seen by radiography. The anterior aspect. A schematic drawing of the jaw innervation can curvature of the canal follows the morphology of the mandible be seen in Figure 2.29. and expresses the growth direction after birth. Perinatally, this canal has a straight course (Figures 1.29 and 2.32). Figure 2.30 A schematic drawing of the trigeminal ganglion and nerve paths to the jaws. The nerve paths to the different tooth groups are colored differently. The yellow arrow points to a histological section from the jaw which is immunohistochemically stained with NGFR. The brown color indicates osteoblast activity. The figure demonstrates the influence of the peripheral nerves on bone formation. It is hypothesized that the trigeminal ganglion plays a role in compensatory and dysplastic growth of the jaws. Source: Kjær and Nolting (2008). Reproduced with permission of John Wiley & Sons.

34 Chapter 2 Figure 2.31 (Left) A profile radiograph of the cranium indicating the bone structures (yellow markings) which Bjørk found to be stable (not moving) during growth after superimposing several profile radiographs of the same child taken at different ages. The bony structures are the anterior wall of the sella turcica, the pterygopalatine fossa, and the mandibular canal which are all structures encircling the peripheral/central nervous system. (Right) Schematic drawing of the central and peripheral nervous system inserted on a profile radiograph. Note the three main nerve branches to each jaw. Figure 2.32 A schematic drawing of the human mandible demonstrating nontraditional sites. In these sites teeth may occur (Figures 2.33 the relationship between the outer mandibular morphology and the and 2.34). Such cases demonstrate the importance of the inner­ mandibular canal morphology. (Left) The outer angle of the mandible (the vation for tooth formation. Furthermore, the opening of the angle between the posterior ramus and the mandibular base) is small. The mental foraminae and the direction of the mandibular canals can angulation of the mandibular canal (red) is small and the angle of the be analyzed in asymmetrical anthropological crania. Such an mental canal (yellow) from the contour of the lower mandibular canal to analysis can supplement insight into the etiology behind the the mental foramen is large. (Right) The outer angle of the mandible (the malformation. The degree of asymmetry and the direction of angle between the posterior ramus and the mandibular base) is large. The the deviant canal can indicate the length of the period in which angulation of the mandibular canal (red) is large and the angle of the the asymmetrical growth occurred. mental canal (yellow) from the contour of the lower mandibular channel to the mental foramen is small. Source: Pálsson and Kjær (2008). Highlights and clinical relevance Reproduced with permission of John Wiley & Sons. • The different parts of the brain are developmentally linked and In anthropological cases, unilateral absence of the mandibular located to different parts of the cranium. canal has been observed. In such mandibles, the bone morphol­ ogy differs bilaterally. Tooth agenesis also occurs in the affected • The discipline describing the interrelationship between side. In such cases, bone canal entrances may be observed in nerve (e.g. CNS) and bone tissue (e.g. cranium) is called neuroosteology. • In the jaw region, the peripheral nerves are present before bone formation and the peripheral nerves are decisive for bone formation. • The vomeronasal organs are endocrine glands which develop from the nasal mucosa. A defect in the gland development during early prenatal life leads to Kallmann’s syndrome, often Figure 2.33 Anthropological human mandible missing several teeth in the right side. (Left) Frontal view. (Center) Ramus and corpus mandibulae seen from the inside. Notice a low-lying molar and the absence of the mandibular foramen. A furrow from the ramus runs towards the molar. (Right) Radiograph taken of the mandible from the same perspective as in the center photograph. Notice the arrested molar and the absence of the mandibular canal. The question is “why is the canal not there and why is there an absence of teeth in this region except for one molar, which is arrested in eruption?” (see Figure 2.34). Source: Jakobsen et al. (1991). Reproduced with permission of John Wiley & Sons.

Craniofacial development and the brain 35 Figure 2.34 Same mandible as seen in Figure 2.33. (Left) A hole in the inner aspect of the mental region of the mandible. (Center) A radiograph of the mental region of the mandible with a metal ligature inserted into the hole. The radiograph shows that the hole is the entrance to a canal in which a nerve may have passed on its way to the incisors. (Right) A schematic drawing of the innervation of the mandible. To the right, the innervation has an abnormal pattern due to the lack of the mandibular canal in which the nerve tends to run. The nerve lies on the inside surface of the mandible instead and first penetrates the bone anteriorly through the hole shown in the left and center photographs. This is a mandibular deviation with embryonic origin. It could be suggested that the innervation to the retained molar previously ran in the furrow shown in the center photograph. Source: Jakobsen et al. (1991). Reproduced with permission of John Wiley & Sons. combined with anosmia (lack of smell sense). This means that regard to their origin from the ectoderm of nasal cavity presumptive the etiology behind Kallmann’s syndrome is a malfunction of territory. Neuroendocrinology 1993;57:991–1002. the nasal epithelium at GA 8–9 weeks. Jakobsen J, Jørgensen JB, Kjær I. Tooth and bone development in a • The adenopituitary gland arises from the pharyngeal epithe­ Danish medieval mandible with unilateral absence of the mandibular lium. Deviations in the adenopituitary gland can therefore canal. Am J Phys Anthropol 1991;85:15–23. occur in ectodermal dysplasia or in other ectodermal diseases. Keeling JW, Fetal pathology. Churchill Livingstone, New York, 1995. • Tooth development is dependent on innervation. Deviations in Kjær I. Correlated appearance of ossification and nerve tissue in human the innervation of jaws can therefore result in agenesis, which is fetal jaws. J Craniofac Genet Dev Biol 1990;10:329–336. discussed in Chapter 8. The innervation of the jaws provides a Kjær I. Human prenatal craniofacial development related to brain method for etiology-based diagnostics of the changes seen in development under normal and pathologic conditions. Acta Odontol the dentition. Remember the innervation diagram. Scand 1990;53:135–143. • Anthropologically, the absence of nerve foraminae can supply Kjær I. Neuro-osteology. Crit Rev Oral Biol Med 1998;9:224–244. the explanation for abnormal jaw and tooth development Kjær I. Prenatal traces of aberrant neurofacial growth. Acta Odontol which are both dependent on innervation. Scand 1998;56:326–330. • Craniofacial cephalometric growth analysis is based on super­ Kjær I. Orthodontics and foetal pathology: a personal view of cranio­ imposed profile radiographs. It has earlier been demonstrated facial patterning. Eur J Orthod 2010;32:140–147. that the anterior wall of the sella turcica and the pterygopa­ Kjær I. Sella turcica morphology and the pituitary gland – a new latine fossa can be applied as fixed-point bone structures. This contribution to craniofacial diagnostics based on histology and chapter illustrates that these structures which protect the neuroradiology. Eur J Orthod 2015;37:28–36. pituitary gland and the pterygopalatine ganglion are “non­ Kjær I, Hansen BF. Postmortem axial skeletal radiography can reveal moving,” brain-protecting structures. fetal CNS malformations. APMIS 1995;103:574–581. Kjær I, Hansen BF. The adenohypophysis and the cranial base in early Further reading human development. J Craniofac Genet Dev Biol 1995;15:157–161. Kjær I, Hansen BF. Luteinizing hormone-releasing hormone and inner­ Chavéz-Lomelí ME, Mansilla Lory J, Pompa JA, Kjær I. The human vation pathways in human prenatal nasal submucosa: factors of mandibular canal arises from three separate canals innervating dif­ importance in evaluating Kallmann’s syndrome. APMIS ferent tooth groups. J Dent Res 1996;75:1540–1544. 1996;104:680–688. Kjær I, Hansen BF. The human vomeronasal organ: prenatal develop­ Drews U. Color atlas of embryology. Thieme, New York, 1995. mental stages and distribution of luteinizing hormone-releasing Dudek RW., High-yield embryology, 2nd edn. Lippincott Williams & hormone. Eur J Oral Sci 1996;104:34–40. Kjær I, Niebuhr E. Studies of the cranial base in 23 patients with Cri-du- Wilkins, Philadelphia, 2001. Chat syndrome suggest a developmental field involved in the condi­ El Amraoui A, Dubois PM. Experimental evidence for an early com­ tion. Am J Med Genet 1999;82:6–14. Kjær I, Nolting D. Immunohistochemical PGP 9.5 positivity in human mitment of gonadotropin-releasing hormone neurons with special osteoblasts may indicate that compensatory and dysplastic

36 Chapter 2 craniofacial growth are under control by peripheral nerves. Orthod Lerner UH. Neuropeptidergic regulation of bone resorption and bone Craniofac Res 2008;11:196–200. formation. J Musculoskelet Neuronal Interact 2002;2 (5):440–447. Kjær I, Hansen BF, Keeling JW. Axial skeleton and pituitary gland in human fetuses with spina bifida and cranial encephalocele. Pediatr Mølsted K, Kjær I, Giwercman A, Vesterhauge S, Skakkebæk NE. Pathol 1996;16:909–926. Craniofacial morphology in patients with Kallmann’s syndrome Kjær I, Nolting D, Hansen BF. p75-NGFR expression in the human with and without cleft lip and palate. Cleft Palate Craniofac J prenatal pituitary gland. Pediatr Neurol 2004;5:345–348. 1997;34:417–424. Kjær I, Reintoft I, Poulsen H, et al. A new craniofacial disorder involving hyperterolism and malformations of external nose, palate and pitui­ Müller F, O’Rahilly R. The human chondrocranium at the end of the tary gland. J Cranifac Genet Dev Biol 1997;17:23–34. embryonic period, proper, with particular reference to the nervous Kjær I, Wagner A, Madsen P, Blichfeldt S, Rasmussen K, Russell B. The system. Am J Anat 1980;159:53–58. sella turcica in children with lumbosacral myelomeningocele. Eur J Orthod 1998;20:443–448. Noback CR, Demarest RJ. The human nervous system. Basic principles of neurobiology, 3rd edn. McGraw Hill, Singapore, 1984. Schoenwolf GC, Bleyl SB, Brauer PR, Francis-West PH. Larsen’s human embryology, 4th edn. Churchill Livingstone, Philadelphia, 2009.

CHAPTER 3 Developmental fields in the cranium and alveolar process Definition of developmental field the maxillary fields innervated by the maxillary nerves, and the palatine fields innervated by the nasopalatine nerves. Also the A developmental field is a region or a part of an embryo which bilateral mandibular fields innervated by branches of the man­ responds as a coordinated unit to embryonic interaction. In other dibular bundle are paraaxial fields. The innervation paths in the words, a developmental field contains structures that respond to jaws are also demonstrated schematically in Figure 3.3. It is the same nerve supply. characteristic that the craniofacial fields spread like water from a fountain from the sella turcica region which contains the rostral The pattern of dermatome innervation has been recognized end of the notochord. The sella turcica may therefore contain for a long time in the skin, including the head and face. However, malformations which are related to specific craniofacial fields. the craniofacial fields which express the depth and composition These interrelationships can be explained through fetal pathol­ of tissues belonging to the specific developmental segments in the ogy cases demonstrated in Chapters 1 and 2. cranium have only recently been described. The borderlines between these fields have also recently been mapped in the The craniofacial fields are illustrated in Figure 3.1 and face and cranium (Figure 3.1). described below. Developmental fields in the cranium Frontonasal field The frontonasal field stretches out from the pituitary gland to the The midaxial cranium facial surface. It is important to be aware that there are two, The bony structures located midaxially in the cranium are the bilateral frontonasal fields – one from the left side of the neural following (in the posteroanterior direction): occipital squama, crest and one from the right side of the neural crest. Together, this basilar part of the occipital bone, body of the sphenoid bone, creates a common field on the facial surface which covers the area ethmoid bone, and nasal septum. between the eyes, the external nose, and the philtrum. Intraorally, the field contains the superior labial frenulum, the incisive The paraaxial cranium papilla, and the incisors (Figure 3.4). The nerve branches from the trigeminal ganglia are important for understanding the paraaxial craniofacial fields. These branches Enclosed in this field are the following osseous structures: the are the ophthalmic branches, the maxillary branches, and the anterior sella wall, the crista galli on the ethmoid bone, the nasal mandibular branches. These peripheral nerves develop from the bone, the nasal septum, and the anterior part of the maxilla, neural crest cells. formerly called the premaxilla. The interorbital region and the lowermost part of the frontal bone also belong to this field. The The ophthalmic branches and the nasopalatine nerve arise central and the lateral incisors are the teeth marking the field (see from a bilateral neural crest area situated anteriorly on the neural Figure 3.4). The occlusal view of the palate and the maxillary tube. These nerves innervate the tissues between the medial alveolar process is illustrated in Figure 3.5. From this figure, it can aspects of the eyes and the intermaxillary region. From this be seen that the yellow, anterior part belongs to the frontonasal neural crest area, the ectomesenchymal tissue arises, stretching field. from the pituitary gland region to the area between the eyes. Similarly, the peripheral nerves that develop from regions more Fetal pathology caudally on the neural tube represent other tissue segments in the In fetal pathology, malformations within the frontonasal field jaws. The segments, also called fields, in the jaw arise from and on the borders of the frontonasal and maxillary fields can be different neural crest regions (see Figure 3.1). distinguished. In Figure 3.6, two cases are demonstrated with malformations within the frontonasal field. The first case (left) is Accordingly, the paraaxial craniofacial fields are the fronto­ an oroocular defect combined with the absence of the frontonasal nasal fields innervated by the nasopalatine nerves (Figure 3.2), structures. The second case is a fetus with cyclopia in which the Etiology-Based Dental and Craniofacial Diagnostics, First Edition. Inger Kjær. © 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd. 37