Dento/Oro/Craniofacial Anomalies and Genetics by Agnes Bloch-Zupan, Heddie Sedano, and Crispian Scully by Agnes Bloch-Zupan, Heddie Sedano, and Crispian Scully - Read Online

Book Preview

Dento/Oro/Craniofacial Anomalies and Genetics - Agnes Bloch-Zupan

You've reached the end of this preview. Sign up to read more!
Page 1 of 1

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. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangement with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library

Library of Congress Cataloguing-in-Publication Data

A catalogue record for this book is available from the Library of Congress

ISBN: 978-0-12-416038-5

For information on all Elsevier publications visit our website at elsevierdirect.com

This book has been manufactured using Print On Demand technology. Each copy is produced to order and is limited to black ink. The online version of this book will show color figures where appropriate.

Foreword

Not many clinical geneticists will easily confess their knowledge about teeth is limited 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 dental 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 presence 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 understand 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 syndromes 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 dentists 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 patients and supportive.

I would like also to pay a tribute to all my god mothers 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, A. Verloes, N Wolf, J Zschocke).

Pr Raoul Hennekam has kindly accepted to write a foreword for this book. His generous advises, vision, enthusiasm, sharing and friendship are a continuous enlighten.

Heartfelt thanks to Dr. Ana Maria Johnson and Mr. Oliv Fluck for their invaluable preparation of the illustrations and the meticulous revision of the original manuscript, 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 identification of processes responsible for genesis of specific dental anomalies [1–3].

The objectives of this book are to present the background of dental and orofacial 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 anomalies by type, signalling pathways and syndrome families.

Table of Contents

Cover Image

Title

Copyright

Foreword

Acknowledgments

Introduction

1. Odontogenesis, Anomalies and Genetics

1.1 Odontogenesis

1.2 Dental Anomalies

1.3 Syndromes and Dental Anomalies

2. Missing Teeth (Hypodontia and Oligodontia)

2.1 Transcription Factors

2.2 WNT Signalling Pathway

2.3 TNF/NF-Kappa B Signalling Pathway

2.4 TGFbeta Superfamily

2.5 SHH Signalling Pathway

2.6 Fibroblast Growth Factors (FGF) Pathway

2.7 Other Pathways

3. Supernumerary Teeth

3.1 Cleidocranial Dysplasia (CCD)

3.2 Familial Adenomatous Polyposis (FAP)

3.3 Nance-Horan Syndrome (NHS)

3.4 Tricho-Rhino-Phalangeal Syndromes

4. Abnormalities of Tooth Shape and Size

4.1 Rubinstein-Taybi Syndrome (RTS)

4.2 Otodental Syndrome

4.3 Oculo-Facio-Cardio-Dental Syndrome (OFCD)

4.4 KBG Syndrome (Herrmann-Pallister-Opitz Syndrome)

5. Anomalies in Structure of Teeth – Dentine

5.1 Dentinogenesis Imperfecta Type II and DGI-II or Hereditary Opalescent Dentine

5.2 Dentinogenesis Imperfecta Type III (DGI-III)

5.3 Dentine Dysplasia

5.4 Osteogenesis Imperfecta (OI)

6. Anomalies Structure of Teeth – Enamel

6.1 Amelogenesis Imperfecta

6.2 Syndrome with Enamel Defects

7. Anomalies of Teeth Eruption and/or Resorption

7.1 Sotos Syndrome (Cerebral Gigantism)

7.2 Hypophosphataemic Vitamin D-Resistant Rickets, Hypophosphataemia X-Linked

7.3 Osteopetrosis

7.4 Hypophosphatasia

7.5 Papillon–Lefèvre Syndrome (PLS)

7.6 Haim–Munk Syndrome (Cochin Jewish Disorder, Congenital Keratosis Palmoplantaris)

7.7 Familial Expansile Osteolysis Syndrome

8. Pathology and Dental Anomalies

8.1 Naevoid Basal Cell Carcinoma Syndrome (NBCCS; Gorlin syndrome)

8.2 Cherubism

Bibliography

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 interactions 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 periodontium [15,16]. Extracellular matrix (i.e. basement membrane, predentine, and dentine) participates in odontogenesis either as a substrate with temporospatial specificity in interaction with receptors of the plasma membrane or as a putative reservoir of endocrine, paracrine and autocrine factors such as peptide growth factors.

Tooth morphogenesis is under strict genetic control, as is general embryonic development, and the participating genes are being discovered at an increasing rate. By 2008, more than 300 of these genes had been listed in the database created by Pekka Nieminen from Helsinki University, Finland, gathering expression pattern at the various stages of odontogenesis obtained from the laboratories of experts worldwide (http://bite-it.helsinki.fi) [17].

1.1.2 Developing Through Epithelio-mesenchymal Interactions with Signalling Molecules and Transcription Factors

A similar language in cell communication, conserved during evolution, is used throughout embryonic and tooth development, respectively. Implicated signalling molecules and growth factors include transforming growth factor beta (Tgfβ) family with bone morphogenetic proteins (Bmps), activins and follistatin; fibroblast growth factors (FGFs); hedgehog (only sonic hedgehog, shh, plays a role during odontogenesis) and wingless-related MMTV integration site (Wnts) [18–23]. These molecules transmit their message via signalling pathways from the cell surface receptors towards the nucleus via effectors [24]. As a matter of writing convention used in this book, genes are in italics and proteins are non-italics; and human GENES and PROTEINS, capitalized; and mouse genes and proteins, non-capitalized. Protein is then not italicized, and the first letter is capitalized.

Transcription factors modulate the expression of target genes, thereby inducing a modification of response and cell behaviour. Most of the genes outlined in http://bite-it.helsinki.fi participate in this cell communication network, and mutations in some of these genes are responsible for dental and oro-facial anomalies [25] (Figure 1.1).

Figure 1.1 Signalling networks regulating tooth development. Genes displayed in green, if inactivated, are responsible for arrested tooth development.

Source: From Ref. [26].

Retinoids are also signalling molecules participating in dental and craniofacial development.

Other growth factors involved in odontogenesis include epidermal growth factor (EGF) family with EGF and transforming growth factor α (TGFα), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), Midkine and pleiotrophin, neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3) and neurotrophin 4/5 (NT4/5) [27–33].

Teeth, then, are indeed organs that develop as epithelial ectodermal appendages and whose development is mediated by epithelio-mesenchymal interactions [22].

1.1.3 Signalling Pathways

Following is a description of the involvement of signalling pathways at different key stages of tooth development.

Initiation Stage

The localization, identity, shape and size of the teeth are determined during early stages of tooth development [34]. Early signals like Bmp4 (incisor region) and FGF8 (molar region) from oral ectodermal cells elicit the odontogenic potentialities of the underlying mesenchyme [35,36]. Numerous transcription factors expressed in the mesenchyme are then activated [13,37], including genes coding for several homeobox divergent transcription factors (e.g. msx1 [muscle segment homeobox 1, alias hox-7], msx2, dlx1 [distal-less homeobox 1], dlx2, barx1 [BarH-like homeobox 1], lhx6 [LIM homeobox 6] and lhx7) and involved in patterning (Figure 1.2). Many of these transcription factors, even within the same family, are coexpressed and participate to functional redundancy, allowing rescue mechanism in case of dysfunctions. Activation of these genes is necessary for the continuation of tooth development, as shown by the phenotype of genetically modified mice carrying inactivation of these genes. Tooth development is arrested at the initiation stage when msx1 and msx2 or dlx1 and dlx2 are inactivated [38,39].

Figure 1.2 A divergent homeobox gene code within the maxilla and mandible.

Source: From Ref. [13] Reprinted by permission from Macmillan Publishers Ltd, copyright (2004).

Placode Formation

One of the key aspects of tooth development is the formation of ectodermal placodes, thickenings of the epithelium at the locations of each family of tooth. Similar placodes initiate the development of all organs developing as ectodermal appendages [22,40], such as the hair, nails, salivary, mammary and sebaceous glands.

Signalling molecules from the four well-known families previously listed (the Tgfβ, FGFs, hedgehog and Wnts families) participate in placode development. Fgfs and Wnts act as activators of placode formation in feather and hair follicle formation, and Bmps, as repressors [41,42], and this seems also to be the case during odontogenesis. Genes coding for molecules involved in placode formation participating in the TNF (tumour necrosis factor)/NF-kappaB signalling pathway, or the proto-oncogene p63, if mutated are responsible for ectodermal dysplasias, leading to diseases involving all these epithelial appendages and manifesting with hypodontia (less than six missing teeth), oligodontia (six or more missing teeth) and even anodontia (absence of all teeth) [43–46].

Bud-to-Cap Stage Transition

The underlying condensing mesenchyme controls the growth and folding of the epithelium. Mesenchymal signals induce, within the enamel organ, the formation of signalling centres called enamel knots – transitory structures which produce numerous signalling molecules at the cap stage [47]. The primary enamel knot is indispensable to crown development. These signals pass towards the mesenchyme, and within the epithelium regulate tooth shape. Shh is one signal essential for epithelial proliferation, but its direct action seems to target the mesenchyme, where it induces a feedback loop signal towards the epithelium [48]. Wnt and Bmp signalling regulate the formation of enamel knots.

Bmp4 induces the arrest of the cell cycle in enamel knot cells via the expression of a cyclin-dependent kinase inhibitor p21; Wnts are necessary for the expression of Fgf4 within the enamel knots [49–52].

Fgfs and their corresponding receptors are expressed both in epithelium and mesenchyme and reciprocally regulate proliferation in adjacent tissues [53,54]. Three transcription factors present at these stages in condensing mesenchyme are msx1, paired homeobox 9 (pax9) and runt-related homeobox 2 (runx2), whose expression is regulated by epithelial signals. Msx1 is induced by Bmp and Fgf; pax9 and runx2, by Fgf [55–58].

Runx2-deficient mice show arrested tooth development at the bud stage [58,59].

Signalling molecules from the TNF (Eda/Edar) family may participate in cusp formation via the enamel knot [61,62].

The Wnt signalling pathway is involved in the tooth replacement cycle with the development of the primary and then permanent dentition [63–65]. This signalling pathway also leads to the formation of supernumerary teeth through the multiplication of signalling centres via budding from the dental epithelium. The subsequent molars formed have a simplified cusp pattern.

Bell Stage

Molar cusp development is initiated by secondary enamel knots appearing within the inner dental epithelium at the site of the tips of future tooth cusps. They express numerous signalling molecules, amongst them FGF4, and stimulate cusps growth. The lineage relationships between primary and secondary enamel knots are not completely unravelled [66].

Proliferation outside the enamel knots area and non-proliferation in the knots coordinate foldings of the inner dental epithelium around the condensing mesenchyme [67,68]. Marked apoptosis within the knots will induce the progressive disappearance and the end of the signalling activity of these structures at the end of the cap stage and in the early bell stage [11,69].

Cell Differentiations

Odontoblasts are specialized ciliated cells [70], differentiating following a defined temporospatial gradient from the cusp tip towards the cervical area of the tooth, and induction by the inner dental epithelial cells. Odontoblasts synthesize dentine matrix proteins [71]: collagens (I, type I trimer, III, V, VI) and non-collagen proteins like osteonectin and osteocalcin, and SIBLINGs (Small Integrin-Binding LIgand, N-linked Glycoproteins) family proteins like osteopontin, MEPE (an extracellular matrix phosphoprotein), bone sialoprotein (BSP), dentine matrix protein 1 (DMP1), dentine sialophosphosproteins (DSPP or DSP and DPP) [72,73]. Other molecules which contribute to dentine formation include the proteoglycans; serum proteins such as albumin; enamel proteins such as amelogenins; matrix metalloproteinases (MMPs); tissue inhibitors of metalloproteinases (TIMPs); cathepsin and phospholipids [74–77]. SIBLINGs can bind to MMPs [78].

Ameloblasts differentiate following the same temporospatial gradient but with a different time frame. Amelogenesis proceeds in the presence of predentine/dentine and after disappearance of the basement membrane, when odontoblasts are functional. Ameloblast synthesize, participate in mineralization and resorb the enamel matrix proteins during the maturation stage via the proteinases enamelysine (MMP20) and kallikrein 4 (KLK4) [79]) leading to enamel, the most densely mineralized tissue of the body (95% in weight).

Structural proteins present in enamel matrix include amelogenins, ameloblastin (sheathline or amelin), enamelin, tuftelin and amelotin [80,81]. Other proteins like sulphated glycoproteins, calcium-binding proteins, DPP (dentine phosphoprotein), lipids and phospholipids also participate in enamel formation [77], as do enzymes, metalloproteinases, serine proteases and phosphatases.

The terminal cytodifferentiation of odontoblasts [82,83] and ameloblasts, as well as synthesis of dentine and enamel matrices, are regulated by signalling molecules from the Tgfβ family – especially Bmps and Fgfs [18,83–85]. The four main families of signalling molecules are involved in these processes [87]. These signals participating in the epithelio-mesenchymal interactions are synthesized by pre-odontoblasts and pre-ameloblasts and are carried by the basement membrane and the predentine/dentine.

Inhibiting Bmp4 signals (signals sent by the mesenchyme and then by pre- and functional odontoblasts to the inner dental epithelium and then pre-ameloblasts) by follistatin impairs terminal differentiation of ameloblasts from the mouse labial epithelial loop, a normal process occurring in the mouse lingual epithelial loop devoid of any enamel [88].

Stratum intermedium cells whose development is relayed by msx2 would be involved in ameloblast differentiation via signalling through shh [89].

Odontoblasts and ameloblasts are vitamin D target cells [90].

Proteins synthesized by odontoblasts and ameloblasts could also play a signalling role, like DMP2 and amelogenin [87].

Dentine and enamel formation are interdependent. Odontoblasts secrete amelogenins [91], and ameloblasts transitory secrete DSP and DPP during enamel/dentine junction formation [92].

Eruption

As root and cement develop, eruption phenomena are regulated by tissue interactions mediated by various signals [93–96]. PtHrP (parathyroid hormone) seems to be involved in the regulation of surrounding bone resorption during tooth eruption [97,98]. Runx2 may participate in cementogenesis, formation of the periodontal ligament and in eruption per se [99].

1.2 Dental Anomalies

Developmental dental anomalies may exist in isolation or may be associated with extraoral clinical manifestations in syndromes: they can be of genetic origin or due to the action of teratogens [100–105].

Each dental anomaly can be classified into various categories, anomalies