MSX1 in relation to clefting, hypodontia and hydrocephaly in humans Marie-José van den Boogaard Promotor: Prof. dr. D.Lindhout Co-promotor: Dr. J.K. Ploos van Amstel Concept & Design by Sabel Design (Michel van den Boogaard), Bilthoven Lay out by Studio Voetnoot, Utrecht Printed and bounded by Drukwerkconsultancy, Utrecht ISBN 978-90-393-5903-7 Picture Cover: molar tooth bud mouse embryo (E12) – with thanks to D Sassoon and B Robert - Génétique Moléculaire de la Morphogenèse, Institut Pasteur, Paris, France. Foto: Vincent Boon – www.vincentboon.nl © 2012 M-J.H. van den Boogaard All rights are reserved. No parts of this publication may be reproduced, stored en a retrieval system of any nature, or transmitted in any form or by an y means, electronic, mechanical, photocopying, recording or otherwise, without prior permission of the publisher. 2 MSX1 in relation to clefting, hypodontia and hydrocephaly in humans MSX1 in relatie tot schisis, hypodontie en hydrocefalie bij de mens (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op dinsdag 29 januari 2013 des middags te 4.15 uur. door Marie-José Henriette van den Boogaard geboren op 2 augustus 1964 te Helmond 3 Promotor Prof. dr. D. Lindhout Co-promotor Dr. J.K. Ploos van Amstel Dit proefschrift werd mede mogelijk gemaakt met financiële steun van de Nederlandse Vereniging voor Gnathologie en Prothetische Tandheelkunde (NVGPT). 4 Voor Paul, Bram, Freek en Evy Manuscriptcommissie Prof.dr. R. Koole Prof.dr. M.S. Cune Prof.dr. R.C.M. Hennekam Prof.dr.ir. J.H.L.M. van Bokhoven Paranimfen M-L.E. van den Boogaard P.A.Terhal 6 Contents Contents Chapter 1 General introduction 11 Aims and Outline of the thesis Chapter 2 Orofacial Clefting and associated anomalies 39 A systematic review of associated structural and chromosomal defects in oral clefts J Med Genet. 2012; 49: 490-8 Chapter 3 MSX1 causes clefting in humans 75 MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans Nat Genet. 2000; 24: 342-3 Chapter 4 The role of Msx1 in development 83 MSX1 and partial anodontia and the Witkop syndrome Chapter 75: Inborn errors of development Inborn errors of development : the molecular basis of clinical disorders of morphogenesis / ed. by Charles J. Epstein, Robert P. Erickson, Anthony Wynshaw-Boris 2008 ISBN-13: 978-0-19-530691-0 Chapter 5 MSX1 and non-syndromic clefting 125 The MSX1 allele 4 homozygous child exposed to smoking at periconception is most sensitive in developing nonsyndromic orofacial clefts Hum Genet. 2008; 124: 525-34 7 Contents Chapter 6 WNT10A, rather than MSX1 is a major cause of 149 non-syndromic hypodontia Mutations in WNT10A are present in more than half of isolated hypodontia cases J Med Genet. 2012; 49: 327-331 Chapter 7 MSX1 and tooth dimensions 177 Three – dimensional analysis of tooth dimensions in the MSX1 – nonsense mutation Clin Oral Investig 2012 Aug 31. [Epub ahead of print] Chapter 8 MSX1 and hydrocephaly 199 Identification of a novel missense mutation in the MSX1 homeodomain, in a patient with hydrocephaly Submitted Eur J Hum Genetics Chapter 9 General Discussion and Summary 215 Future Prospects 225 Nederlandse Samenvatting (Summary in Dutch) 238 Curriculum Vitae 243 Dankwoord (Acknowledgements) 244 List of Publications 250 Addenda 254 8 1 Chapter 1 General introduction and aims and outline of the thesis 11 Chapter 1 1 General introduction A mother contacted our department because her son was born with an oro- facial cleft, just like her brother, uncle and cousin. Family history learned that the mother had an agenesis of more than 6 teeth. She remarked “ there is nothing unusual about this, because almost all of her family members misses a few or a larger number of teeth.” Orofacial cleft and hypodontia Orofacial clefting is a very common congenital abnormality. Clefts of the lip and palate are generally divided into two cagetories, cleft lip with or without cleft palate (CL±P) and isolated cleft palate (CP). 1 However, recent studies emphasized subdivision into three categories: cleft lip only (CL), cleft lip with cleft palate (CLP), and CP, because of differences concerning embryologic development, prevalence, risk factors, and associations with other congenital anomalies. 2-5 For most people an orofacial cleft (CL and CLP account for 66% of the cleft cases) 3, is an immediately recognizable birth defect. In the Netherlands approximately 300-350 children are born annually with a cleft lip and/ or palate 6. Often the newborn with cleft lip and/or palate is the first such a child in the family. However there is an increased risk for orofacial clefts to recur in families 7 , 8 The birth incidence of cleft lip with or without cleft palate (CL±P) and cleft palate (CP) show a striking variability that is dependent on geographic origins, ethnic groups but also on environmental exposures and socio-economic status. 1, 5, 9 The highest rates of birth prevalences are reported in certain (Asian and Native American) population and are as high as 1:500. African derived populations show the lowest birth incidences of 1:2500. In the European population an intermediate birth incidence of 1:1000 is observed. 9 The prevalence of orofacial clefting in the Netherlands is 1:600 live births. 6 Cleft lip and/or palate are often associated with additional congenital anomalies. 5 An increasing number of studies demonstrate that in patients with CL±P or CP congenital tooth agenesis/hypodontia is significantly more frequent than in the general population. 10-19 The prevalence of hypodontia (excluding third molars or Wisdom teeth) in cases with orofacial clefting differs between populations and between types of clefts. The occurrence of hypodontia in cases with orofacial clefting ranges from approximately 5 % 10 to 77% 11 compared to 5,5 % in the general population. 20 Hypodontia can be attributed in part to the cleft itself or to the early surgical correction of the defects. However, hypodontia is also much more common outside the cleft region with reported frequencies 13 General introduction Aims and Outline of the thesis of approximately 30%. 12, 14, 17 A recent systematic review and meta-analyses showed a significant association between tooth agenesis and orofacial clefts. 21 The increased rates of hypodontia in orofacial clefting suggest a related etiology. This might be based on the close anatomic relation and developmental timing, shared morphological processes, such as outgrowth and differentiation, and underlying molecular mechanisms during the embryonic development of the face and teeth. Facial and tooth development: related processes During the development of the face, the morphogenesis of the primary palate (the upper lip and alveolar process) and the secondary palate (the hard and soft palates including the uvula), and the teeth entail a complex series of events. 8, 9, 22-37 The development of the face and the primary and secondary palates are the result of the narrowly coordinated formation, i.e. outgrowth, apoptosis and fusion of facial and palatal prominences/processes/shelves followed by their differentiation into musculature, bone and teeth (Figure 1.1 A/B and Figure 1.2). The fusion of the facial and palatal processes entails several steps. The facial and palatal processes consist of a mesenchymal core covered with ectoderm. Through outgrowth of the processes initial contact of the covering epithelial layers (ectoderm) of the opposite processes occur. After adhesion the intervening epithelium gradually disappear by the crucial process of apoptosis and epitheliomesenchymal transformation. 23, 28 First, the primary palate is formed bilaterally by outgrowth and fusion of the median nasal process with the maxillary and lateral nasal processes, respectively, during the 4th -7th week after conception. Then, the secondary palate starts to develop by outgrowth of the palatal shelves, emerging from the maxillary processes, at 7th weeks after conception. After elevation of the vertically oriented palatal shelves the fusion of the shelves takes place with the primary palate, with each other and the nasal septum. The formation of the secondary palate is completed at the 12th week after conception. 9, 23-29 (see Figure 1.1 B) 14 Chapter 1 1 Lateral nasal 1.1 A. Figure prominences Medial nasal prominences Maxillary prominencess Human embryo, approximate human age 6 weeks Lateral nasal prominences Medial nasal prominences Eye Maxillary prominences Nasolacrimal Mandibular prominences groove Philtrum Figure 1.1 A. Embryological lip development | by Drs. Kathleen K. Sulik and Peter R. Bream Jr. with the assistance of Mr. Tim Poe and Ms. Kiran Bindra. https://syllabus. med.unc.edu/courseware/embryo_images/unit-hednk/hednk_htms/hednk031.htm and https://syllabus.med.unc.edu/courseware/embryo_images/unit-hednk/hednk_htms/ hednk032.htm. Adapted with permission. 15 General introduction Aims and Outline of the thesis Figure 1.1 B. Figure 2. 1. 1. Maxilla with 4 incisor teeth 3. 2. Philtrum of lip 4. 3. Primary palate 4. Fused palatal plates Figure 1.1 B. Embryologic palatal development | by Drs. Kathleen K. Sulik and Peter R. Bream Jr. with the assistance of Mr. Tim Poe and Ms. Kiran Bindra. Human embryo : approximate human age 9 – 10 weeks | https://syllabus.med.unc.edu/courseware/embryo_images/ unit-hednk/hednk_htms/hednk039.htm and https://syllabus.med.unc.edu/courseware/ embryo_images/unit-hednk/hednk_htms/hednk040.htm - Adapted with permission. In the period the secondary palate develops, the fused medial nasal and maxillary processes of the primary palate form the presumptive upper lip, and alveolar process by their outgrowth in caudal direction, with the labial groove in between (see figure 1.1 A).