Dento/Oro/Craniofacial Anomalies and Genetics Dento/Oro/Craniofacial Anomalies and Genetics Agnès Bloch-Zupan Professor, University of Strasbourg Reference Centre for Orodental Manifestations of Rare Diseases Hôpitaux Universitaires de Strasbourg, Strasbourg, France Heddie O. Sedano Emeritus Professor, University of Minnesota Lecturer, University of California, Los Angeles, USA Crispian Scully Emeritus Professor University College London University of Bristol, UK AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD PARIS • SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Elsevier 32 Jamestown Road, London NW1 7BY 225 Wyman Street, Waltham, MA 02451, USA First edition 2012 Copyright © 2012 Elsevier Inc. All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. 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Foreword Not many clinical geneticists will easily confess their knowledge about teeth is lim- ited to say the least. The opposite is probably also true: not many dentists will know much about genetics, or will recognize that the patient they treat with unusual den- tal findings also has unusual manifestations elsewhere. There are always exceptions to this rule, and probably the best known exception is late Professor Robert (‘Bob’) J. Gorlin. His knowledge both of dental and other intra-oral signs and symptoms, and the morphological characteristics of a huge number of syndromes elsewhere in the body is still unequalled. Bob went all the way to try to recognize entities. Once, when evaluating a patient with a cleft palate, he noticed unusual skin folds in the neck and subsequently he had no problem in checking the genital region for the pres- ence of skin folds as well. Even he had to acknowledge, however, that this was about as far as a dentist could go. Professor Gorlin worked mainly in a time of syndrome recognition based on the external phenotype and organ malformations. But progress in our understanding of the genetic background of syndromes and the function of the causative genes has been remarkable. Nowadays many syndromes are characterized not only by their phenotype but also by the gene(s) that cause it. This allows us to start to under- stand how the changes in genes cause particular signs and symptoms. And this also involves dental signs and symptoms. The present book by Professor Agnes Bloch-Zupan and her co-workers Crispian Scully and Heddie Sedano is based on this principle: the recognition of syndromes allows recognition of dental findings, and the recognition of genes causing syn- dromes allows recognition of genes causing specific dental manifestations. This offers us a tremendous insight in the genes involved in dental morphogenesis. The authors have done a splendid job: the book contains a wealth of details, it is up to date and it is very well illustrated. The book will serve clinical geneticists and den- tists alike, and patients of both groups of specialists will benefit by the information it provides. And Bob Gorlin? He would have loved this book! December 2011 Raoul C.M. Hennekam, MD, PhD Amsterdam Acknowledgments Dear Reader, Writing such a book was not an easy task as I was split between doubts, a busy schedule and life and continuously and fast evolving knowledge. I would like to take advantage of this tribune to thank warmly my co-authors who over the months and years remained patient and supportive. I would like also to pay a tribute to all my godmothers and fathers in paediatric dentistry, developmental biology and genetics: the late Pr Jeanne Sommermater, Pr Jean Victor Ruch, Pr Robert J Gorlin, Pr Robin Winter. I owe my inspiring colleagues, fruitful and stimulating discussions. Many of them gave me permission to publish their rare disease cases and I would like to acknowledge them for their trust (AC Acevedo, Y Alembick, I. Baileul-Forestier, N Chassaing, F Clauss, S Dewhurst, D Droz, M Fichbach, AL Garret, M Harrison, M Holder-Espinasse, M-C Maniere, GJ Roberts, A. Verloes, N Wolf, J Zschocke). Pr Raoul Hennekam has kindly accepted to write a foreword for this book. His generous advices, vision, enthusiasm, sharing and friendship are a continuous enlightenment. Heartfelt thanks to Dr. Ana Maria Johnson and Mr. Oliv Fluck for their invalu- able preparation of the illustrations and the meticulous revision of the original manu- script, as well as to Drs. Katrina Dipple, Yoshio Setoguchi, Henry Kawamoto and the rest of the Craniofacial Team at UCLA for helping one of us (HOS) to keep updated in the fast growing field of Craniofacial Dysmorphology. I am privileged to walk aside talented students. Dear G, H, B, M please accept my apologies for the stolen time. A special thanks to the patients and their families! Agnès Bloch-Zupan Heddie O. Sedano Crispian Scully Introduction Knowledge of aetiology of anatomical, cellular or metabolic disturbances may lead to the identification of developmental processes involved in normality. On the other hand, understanding of dental genetics and developmental biology will allow identi- fication of processes responsible for genesis of specific dental anomalies [1–3]. The objectives of this book are to present the background of dental and orofa- cial anomalies from their clinical and biological perspectives – discussing genes, their encoded proteins and the role of these proteins in developmental signalling pathways, sometimes via the analysis of genetically modified mice exhibiting such defects. The book attempts to clarify the bewildering array of factors involved in tooth development (odontogenesis). This insight into the pathology offers clinicians a modern biomedical view on human dental and orofacial defects found and proposes ways of understanding orofacial manifestations of these genetic diseases. The book will also present and illustrate the various dental and orofacial anoma- lies by type, signalling pathways and syndrome families. 1 Odontogenesis, Anomalies and Genetics 1.1 Odontogenesis 1.1.1 Tooth Development Tooth development is embedded within craniofacial development. It originates from pluripotential cephalic neural crest cells which subsequently migrate towards the first pharyngeal arch, there to trigger (in combination with mesodermal cells) the development of many elements of the craniofacial structures [4–6]. Mammalian embryonic tooth development (odontogenesis), especially the mouse dentition, is an interesting model. Odontogenesis leads to specific crown and root morphogenesis for each type of tooth (incisor, canine, premolar, molar), to enamel organ histomorphogenesis and to terminal cytodifferentiations of odontoblasts, ameloblasts and cementoblasts. Evolutionary study of mammals is often focused on detailed analyses of teeth shapes. Molecular patterning may influence dental evolution via differences in gene expressions correlated with morphological variations [7–9]. The continuous and progressive stages of odontogenesis have classically been divided into the dental lamina, bud, cap and bell stages, root formation and tooth eruption. Tooth development is a kinetic dependent process mediated via epithelio-mesenchymal inter- actions between ectomesenchymal cells originating from cephalic neural crest cells and the first pharyngeal arch ectoderm [10–14]. These cells contribute to the formation of the dental mesenchyme, the dental pulp, odontoblasts, dentine matrix, cement and peri- odontium [15,16]. Extracellular matrix (i.e. basement membrane, predentine, and den- tine) participates in odontogenesis