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romotie is er Jacobus Harmen Reitsma [email protected] Voor het Voor bijwonen van Craniofacial and Dental Aspects of Crouzon and Apert door Jacobus Harmen Reitsma Paranimfen: Z. Fourie Dr. 3015 CE, te Rotterdam. Na afloop van de p een receptie ter plaatse waarvoor u van harte bent uitgenodigd. de openbare verdediging van [email protected] Drs. A. Fongers [email protected] Op woensdag 19 maart om 15.30 in de Prof. Andries Queridozaal (Onderwijscentrum), Eg-370, ErasmusMC, Dr Molewaterplein 50, Syndrome het proefschrift romotie is er romotie is er romotie is er Jacobus Harmen Reitsma [email protected] Craniofacial Craniofacial and Dental Aspects of Crouzon and Apert door Jacobus Harmen Reitsma Paranimfen: Z. Fourie Dr. Voor het Voor bijwonen van een receptie ter plaatse waarvoor u van harte bent uitgenodigd. [email protected] Drs. A. Fongers [email protected] Op woensdag 19 maart om 15.30 in 3015 CE, te Rotterdam. Na afloop van de p de openbare verdediging van Syndrome de Prof. Andries Queridozaal (Onderwijscentrum), Eg-370, ErasmusMC, Dr Molewaterplein 50, het proefschrift Jacobus Harmen Reitsma [email protected] Craniofacial Craniofacial and Dental Aspects of Crouzon and Apert door Jacobus Harmen Reitsma Paranimfen: Z. Fourie Dr. 3015 CE, te Rotterdam. Na afloop van de p Voor het Voor bijwonen van een receptie ter plaatse waarvoor u van harte bent uitgenodigd. [email protected] Drs. A. Fongers [email protected] Op woensdag 19 maart om 15.30 in de Prof. Andries Queridozaal (Onderwijscentrum), Eg-370, ErasmusMC, Dr Molewaterplein 50, de openbare verdediging van Syndrome het proefschrift Jacobus Harmen Reitsma [email protected] Craniofacial Craniofacial and Dental Aspects of Crouzon and Apert door Jacobus Harmen Reitsma Paranimfen: Z. Fourie Dr. 3015 CE, te Rotterdam. Na afloop van de p Voor het Voor bijwonen van een receptie ter plaatse waarvoor u van harte bent uitgenodigd. [email protected] Drs. A. Fongers [email protected] Op woensdag 19 maart om 15.30 in de Prof. Andries Queridozaal (Onderwijscentrum), Eg-370, ErasmusMC, Dr Molewaterplein 50, de openbare verdediging van Syndrome het proefschrift

Jacobus Harmen Reitsma Jacobus Harmen Reitsma Jacobus Harmen Reitsma Jacobus Harmen Reitsma Jacobus Harmen Reitsma Jacobus Harmen Reitsma Jacobus Harmen Reitsma Craniofacial and Dental Aspects of Crouzon and Apert Syndrome

Jacobus Harmen Reitsma Publication of this thesis was supported by:

Stichting ter Bevordering van de Orthodontie Utrecht Dental ABN AMRO Ortho = Solutions 3M Unitek Nederland

ISBN: 978-94-6108-622-8 Cover: Beijlen Grafische Communicatie Layout and printed by Gildeprint - Enschede

© 2014 by JH Reitsma No parts of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without prior permission of the author, or, when appropriate, of the publishers of the publications. Craniofacial and Dental Aspects of Crouzon and Apert Syndrome

Craniofaciale en dentale aspecten van het syndroom van Crouzon en Apert

Proefschrift

ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus

Prof.dr. H.A.P. Pols

en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op

woensdag 19 maart 2014 om 15.30 uur

door

Jacobus Harmen Reitsma geboren te Dokkum Promotiecommissie:

Promotoren: Prof.dr. E.B. Wolvius Prof.dr. P.F. van der Stelt

Overige leden: Prof.dr. G.J. Kleinrensink Prof.dr. E.M.E.H. Lesaffre Prof.dr. I.M.J. Mathijssen

Copromotor: Dr. E.M. Ongkosuwito Table of Contents

Chapter 1. General Introduction 9

Chapter 2. Facial Growth in Patients With Apert and Crouzon Syndromes 31 Compared to Normal Children Cleft Palate Craniofacial Journal 2012; 49: 185-193.

Chapter 3. Mandibular Asymmetry in Patients With the Syndrome of Crouzon 53 and Apert Cleft Palate Craniofacial Journal (submitted).

Chapter 4. Dental Maturation in Children With the Syndrome of Crouzon and Apert 73 Cleft Palate Craniofacial Journal 2013; doi:10.1597/13-071.

Chapter 5. Patterns of Tooth Agenesis in Patients With the Syndrome of Crouzon 87 or Apert Cleft Palate Craniofacial Journal 2014; 51: 178-183.

Chapter 6. A Longitudinal Study of Dental Arch Morphology in Children With the 99 Syndrome of Crouzon or Apert European Journal of Oral Sciences 2013; 121: 319-327.

Chapter 7. Craniofacial Stability in Patients With Crouzon or Apert Syndrome After 119 Le Fort III Distraction Osteogenesis Cleft Palate Craniofacial Journal 2013; 50: 561-569.

Chapter 8. General Discussion 139

Chapter 9. Summary 155

Chapter 10. Samenvatting 161

Publications 169 Curriculum Vitae 171 PhD Portfolio 173 Acknowledgements 177

This thesis is dedicated to my teachers of life Ynskje Postma-Bijlsma Douwe Postma

Chapter 1

General Introduction R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

10 | Chapter 1 1.1 Introduction R1 1 R2 The cranium of an infant or young child consists of different bony plates intersected by sutures. A R3 R4 calvarial suture is a type of fibrous joint in the cranium. The growth of the cranium is effectuated R5 mainly in the sutures. Two important functions of the calvarial sutures are to secure flexibility R6 of the cranium during passage of a baby through the birth canal, and to facilitate growth and R7 separation of the calvarial bones during intrauterine and perinatal life (Posnick and Ruiz, 2000). It R8 is normal that the calvarial bones are separated by the sutures at the time of birth. Until the age R9 of six years the sutures allow bones of the skull to move. After the age of six years skull growth R10 mostly takes place by apposition of bone at the outer side of the skull and resorption of bone R11 tissue on the inner side of the skull (Herring, 2008). R12 Premature fusion of one or more sutures in the skull is defined as craniosynostosis (Virchow, R13 1851; Herring, 2008). The prevalence of craniosynostosis occurs one in 2,000 to 2,500 live R14 births (Cohen and MacLean, 2000). The prevalence of nonsyndromic craniosynostosis at birth is R15 estimated to be three to five per 10,000 births. The prevalence of syndromic synostosis at birth is R16 significantly lower, estimated in the range of 0.15 per 10,000 births (Cohen and MacLean, 2000). R17 When craniosynostosis is part of a syndrome, different syndromes with craniosynostosis R18 R19 show unique phenotypes, but share clinical features (Cohen, 1986; Gorlin et al., 2001). Initially R20 syndromes were classified on the basis of the clinical findings, but now most of the syndromes R21 are defined according to specific genetic mutations (Glass et al., 1994). Frequently children with R22 craniosynostosis have associated anomalies and conditions including adverse effects on sensory, R23 motoric, cardiovascular and respiratory functions (Cohen and Kreiborg, 1993; Turvey et al., 1996; R24 Anderson et al., 1997; Renier et al., 2000; Bhattacharjee et al., 2009). The Apert, Crouzon, R25 Saethre-Chotzen and Muenke syndromes represent the more commonly identified syndromes R26 with craniosynostosis. These familial craniosynostosis syndromes share many common features, R27 including midface hypoplasia, cranial base growth abnormalities, abnormal facies, and limb R28 abnormalities. A short overview is given of the common syndromes. R29 R30 R31 1.2 Common craniosynostosis syndromes R32 R33 R34 The pattern of inheritance in the Crouzon syndrome is autosomal dominant (mainly due to R35 mutations on the fibroblast growth factor receptor 2 (FGFR2), and rarely due to the FGFR1 R36 or FGFR3 gene). The specific gene mutation for the Crouzon syndrome is found in the third R37 extracellular immunoglobulin domain of FGFR2 (Reardon et al., 1994; Wilkie et al., 1995). A R38 R39

General Introduction | 11 R1 mutation of FGFR3 leads to a Crouzon syndrome with acanthosis nigricans, a skin disorder with R2 velvety hyperpigmentated skin. Even more severe manifestations can be seen, such as stenosis R3 of the choanae and malformation of the brain (Arnaud-López et al., 2007). The prevalence of R4 this manifestation is 1 in 25,000 live births (Reardon et al., 1994). The Crouzon syndrome is R5 characterized by premature fusion of calvarial sutures, midface hypoplasia, shallow orbits, and R6 ocular proptosis. The intelligence of patients with Crouzon syndrome is overall significantly better R7 than the intelligence of patients with Apert syndrome, with a mean IQ of 84 to 92 (Da Costa et R8 R9 al., 2006). The Pfeiffer syndrome is an autosomal dominant syndrome (mutations on the FGFR1 R10 or FGFR2 gene) (Muenke et al., 1994; Cornejo-Roldan et al., 1999). Genetically the Pfeiffer and R11 the Crouzon syndrome can often not be distinguished from each other (Rutland et al., 1995). R12 Both syndromes may belong to the same broad spectrum of the same disease (De Jong, 2012). R13 Mutations in FGFR1 usually give a less expressive phenotype than FGFR2 mutations in the Pfeiffer R14 patients. R15 The Apert syndrome is characterized by craniosynostosis, exorbitism, midface hypoplasia R16 and symmetric complex syndactyly of both hands and feet. The reported prevalence is one R17 in 60,000 live births (Cohen and Kreiborg, 1992). Most cases are sporadic, although several R18 cases with autosomal dominant transmission have been reported (mutations on the FGFR2 R19 gene). The specific gene mutations in Apert syndrome are found between the second and third R20 extracellular immunoglobulin domains of FGFR2 (Wilkie et al., 1995). 99% of sporadic cases of R21 Apert syndrome are caused by 1 or 2 common mutations in the FGFR2 gene, S252W or P253R R22 (Glacer et al., 2003). The heredity of Apert syndrome shows an autosomal dominance in most R23 R24 of the cases (Gorlin et al., 2001). The intelligence varies from near normal to mentally retarded R25 with a mean IQ of 62 to 74 (Da Costa et al., 2006). Apert is the most severe type of syndromic R26 craniosynostosis. R27 The Muenke syndrome is an autosomal dominant disorder (P250R mutation on the FGFR3 R28 gene) (Glass et al., 1994). It is one of the most commonly found mutations in the human genome, R29 but it does not always result in craniosynostosis (Gorlin et al., 2001). The phenotype of this R30 syndrome may incorporate macrocephaly, uni- or bilateral coronal synostosis, hearing loss and R31 developmental and language delay. The cognitive function seems to be normal with a mean IQ of R32 93 (Arnaud et al., 2002). The estimated birth prevalence is 1 per 30,000, but is probably higher R33 because not all cases come to medical attention (Carinci et al., 2005). R34 The Saethre-Chotzen syndrome is an autosomal dominant syndrome with a varying expression R35 (mutations or deletions in the TWIST gene) (Brueton et al., 1992; Gripp et al., 2000). In the R36 Saethre-Chotzen syndrome, the coronal sutures can be bilateral or unilateral affected. Other R37 features of this syndrome are upper eyelid ptosis, hypertelorism, strabismus, tear duct stenosis, R38 R39

12 | Chapter 1 brachydactyly, and cutaneous syndactyly of hand and feet. The estimated birth prevalence is R1 around 1 per 25,000 live births (Cohen, 1986; Carinci et al., 2005). 1 R2 Most syndromes with craniosynostosis show an autosomal dominant inheritance pattern. In R3 R4 these syndromes, often mutations in the gene encoding of the fibroblast growth factor receptor R5 (FGFR) or TWIST genes are found (Reardon et al., 1994; Wilkie et al., 1995; Meyers et al., 1995; R6 LaJeunie et al., 1999; Cohen and McLean, 2000). Not in all patients with a phenotypically R7 syndromic craniosynostosis can mutations be found. Fusion of two or more cranial sutures R8 without known FGFR or TWIST gene mutation have been described as complex craniosynostosis R9 (Bannink et al., 2010). R10 Besides the best known syndromes with craniosynostosis there are many less known syndromic R11 craniosynostosis with a sporadic prevalence, like: craniofrontonasal dysplasia (mutations on R12 EFNB1 gene), Antley-Bixler syndrome (mutations on POR gene), Carpenter syndrome (mutations R13 on RAB23 gene), Roberts syndrome (mutations on ESCO2), Greig syndrome (mutations on R14 GLI3 gene) or Alagille syndrome (mutations on JAG1 gene) (Gorlin et al., 2001). Progress has R15 been made in localizing specific genetic pathways related to the pathogenesis of syndromic R16 craniosynostosis in contrast to nonsyndromic craniosynostosis (Persing et al., 1989; Panchal and R17 Uttchin, 2003; Carinci et al., 2005; Sgouros, 2005). The cause of nonsyndromic craniosynostosis R18 R19 however, is still greatly unknown (Sgouros, 2005). Most likely biomechanical factors play a role, R20 as well as other environmental, hormonal and genetical factors leading to cell defects and early R21 suture fusion (Sgouros, 2005). R22 Although in the majority of cases with craniosynostosis a clinical diagnosis can be made, R23 some cases are not easily distinguished and classified (Cohen and McLean, 2000; Sgouros, 2005). R24 Geneticists, orthodontists, craniofacial surgeons, developmental biologists and pediatricians have R25 described the condition, craniosynostosis in different ways (Virchow, 1851; Bertelsen, 1958; R26 Tessier, 1971; Van der Meulen et al., 1983; Cohen, 1993; David et al., 2009). The contrast between R27 morphological and genetic descriptions may be explained when the pure genetic description of R28 the malformation can be given together with the phenotypic expression (Posnick, 2000). R29 R30 R31 1.3 Etiology of craniosynostosis R32 R33 R34 The etiology of craniosynostosis is mostly unknown although there are three main theories R35 (Vermeij-Keers et al., 1983). Craniosynostosis is probably a multifactorial congenital condition. R36 The first theory, “intrinsic bone malformation”, assumes that the origin of pathological R37 synostosis lies within disturbed bone formation early in the pregnancy. The cause can either be R38 genetic, metabolic, pharmaceutical or a mixture. R39

General Introduction | 13 R1 The second theory, “fetal head constrain”, assumes that synostosis starts when the fetal head R2 gets compressed in the pelvic outlet during birth. R3 The third theory, “intrinsic brain malformation”, assumes that disturbed brain formation of R4 the two frontal lobes of the brain is the main issue behind the synostosis. Limited growth of the R5 frontal lobes leads to absence of stimuli for sutural growth, therefore causing premature fusion R6 of the metopic suture (Vermeij-Keers et al., 1983). Considering the literature the first theory is the R7 most probable explanation (Gorlin et al., 2001). R8 R9 R10 1.3.1 Normal craniofacial growth and development R11 In the past several theories have been presented and later dismissed with respect to the normal R12 growth of the cranium (Van der Klaauw, 1948 – 1952; Sarnat and Laskin, 1954; Brodie, 1955; R13 Weinmann and Sicher, 1955; Scott, 1959; Sarnat and Wexler, 1966). Later the functional matrix R14 concept influenced the theories of skull growth (Moss and Young, 1960; Moss, 1968; Moss, R15 1997). According to this concept the growth and development of the skull depend on influences R16 emanating from adjacent functional entities. The morphogenesis of the cranial cartilages and R17 bones is according to this theory controlled by the surrounding functional matrix of the skull. R18 Both the growth of the cranial cartilages and the growth of the sutures (Massler and Schour, R19 1951; Baer, 1954; Weinmann and Sicher, 1955) can partly be explained by the functional matrix R20 theory (Moss, 1997). The fundamental basis for this hypothesis is that bones do not grow but R21 are grown (Moss, 1997), thus stressing the morphogenetic primacy of function over form. This R22 is in contrast to the current conventional craniofacial growth theories that genetic, rather than R23 R24 epigenetic (non-genetic) factors control such growth. On the other hand, many authors reported R25 observations showing cranial cartilages to function as centers of growth (Sarnat and Laskin, R26 1954; Sarnat and Wexler, 1966). In contrast to the idea of Moss, it was shown that the sutural R27 area exhibits autonomy of growth and that the growth of the brain has only a limited influence R28 on the growth potential as such in the sutural area (Prahl, 1968; Herring, 2008). The correctness R29 of Moss’ theory has not been without doubt (Van Limborgh, 1970; Van Limborgh, 1972). R30 According to Van Limborgh, chondrocranial growth is mainly controlled by genetic factors, while R31 desmocranial growth is mainly controlled by local epigenetic and local environmental factors. R32 Epigenetic factors are determined genetically, but are effective outside the cells and tissues in R33 which they are produced. Local epigenetic factors have a direct effect on the structures (for R34 example, embryonic induction) and general epigenetic factors have an indirect distant influence R35 (for example, sex and growth hormones) (Herring, 2008). Research in animal models has led to R36 the idea that the dura mater plays an important role in determining closure or patency of the R37 suture (Opperman et al., 1994; Slater et al., 2008). Further it appears that the periosteum is not R38 R39 essential in causing closure or patency (Opperman et al., 1994; Slater et al., 2008).

14 | Chapter 1 In conclusion: there are many genetic and developmental factors that have contributed to the R1 concept of craniofacial growth and morphology. The major factors are probably the interaction of 1 R2 fusion timing of the various neurocranial and basicranial articulations and an increase in relative R3 R4 brain size. However, other factors such as facial size, facial orientation, and posture may also be R5 important to cranial morphology and variation (Mooney and Siegel, 2002). R6 R7 1.3.2 Craniofacial growth with premature closure of calvarial sutures R8 Craniosynostosis demonstrates the importance of sutural growth in skull and facial development R9 (Herring, 2008). Several studies have described skull and facial characteristics in children with R10 various forms of craniosynostosis using cephalometric measurements (Kreiborg et al., 1993; R11 Cohen and Kreiborg, 1994; Avantaggiato et al., 1996). While these measurements provide useful R12 information, it has been difficult to translate the measurements into a global understanding of R13 the growth of the head in patients with craniosynostosis. Knowledge of the craniofacial growth R14 pattern in patients with craniosynostosis may give a better understanding of normal sutural R15 growth and the impact on craniofacial development (Fig. 1.1) (Björk, 1955; Kreiborg and Björk, R16 1982; Prahl-Andersen, 2005). In syndromic craniosynostosis, multiple sutures in the skull fuse too R17 early and result in a variety of syndromes with affected growth of the head and face. R18 R19 Estimates of the frequencies of the different types of nonsyndromic synostoses vary. The R20 types, frequencies, and gender ratios of three large series of synostoses have been reviewed R21 by Cohen (Cohen and McLean, 2000). If one includes only the contributions from isolated R22 sagittal, coronal, metopic, and coronal synostoses, then sagittal synostosis occurs most often R23 of all cases, followed by coronal, metopic, and lambdoid synostosis. Due to craniosynostosis R24 normal skull growth is disturbed. In order to accommodate the growing brain, compensatory R25 skull growth results in different cranial deformations: scaphocephaly in case of involvement of R26 the sagittal suture, frontal plagiocephaly in case of one coronal suture, brachycephaly in case of R27 both coronal sutures, trigonocephaly in case of the metopic suture, and plagiocephaly in case R28 of synostosis of one lambdoid suture. Multiple synostoses of cranial sutures are described as R29 complex craniosynostosis. R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

General Introduction | 15 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 Figure 1.1 Sutures and fontanelles in the normal newborn skull. R20 R21 Craniosynostosis often results in increased intracranial pressure and compensatory intracranial R22 bone resorption and extracranial bone apposition. Inevitably, the restricted sutural growth leads R23 R24 to change in calvarial shape depending on which sutures are obliterated (Renier et al., 2000). R25 The Apert and Crouzon syndromes are the most common and best documented craniosynostosis R26 syndromes and therefore often subject of study (Cohen, 1986; Kreiborg and Cohen, 1998). Of R27 all syndromes with craniosynostosis the Crouzon and Apert syndromes show the most extreme R28 craniofacial malformations. At present, the Saetre-Chotzen, Carpenter and Muenke syndromes R29 are also found to be conditions with similar but far less severe craniofacial malformation (Cohen, R30 1986; Turvey et al., 1996). Craniofacial growth disturbances in children with Crouzon or Apert R31 syndrome have interested workers in various fields of medicine (Kreiborg and Aduss, 1986; R32 Marchac et al., 1999; Posnick and Ruiz, 2000; Sgouros, 2005; Reid, 2007; Vargervik et al., 2012). R33 The different genetic mutations seen in Crouzon or Apert syndromes express themselves in R34 craniofacial development and morphology. In general this may help to gain a better understanding R35 of clinical findings in craniofacial growth. R36 R37 R38 R39

16 | Chapter 1 Crouzon syndrome: craniofacial malformation R1 The craniofacial malformation in patients with Crouzon syndrome depends on the order and 1 R2 rate of progression of sutural synostosis. Craniosynostosis usually begins prenatally and is usually R3 R4 complete after two to three years. In some cases, craniosynostosis may be present at birth R5 (Kreiborg, 1981), but the phenotypic features of Crouzon syndrome may not be recognizable R6 at birth; they evolve gradually during the first few years of life (due to pansynostosis). Most R7 often brachycephaly is observed, but scaphocephaly, trigonocephaly or oxycephaly may also be R8 observed. In addition to synostosis in the cranial vault, knowledge about anterior cranial base and R9 facial sutures is scarce (Grayson et al., 1985; Kreiborg et al., 1993). Clinically the midface shows R10 a variable degree of hypoplasia that includes hypoplasia of the orbits, zygomas, and maxilla (Fig. R11 1.2) (Kreiborg, 1981; Kreiborg and Björk, 1982). Almost no maxillary sagittal growth in patients R12 with Crouzon syndrome can be expected, while some vertical maxillary growth may occur due R13 to the eruption of permanent teeth (Bachmayer et al., 1986; Kreiborg and Aduss, 1986). The R14 mandible has a normal growth rate but may become secondarily deformed due to abnormal R15 cranial base growth resulting in an obtuse gonial angle and relative prognatism (Bu et al., 1989). R16 R17

Apert syndrome: craniofacial malformation R18 R19 The craniofacial skeletal abnormalities in the Apert syndrome are present at birth and often show R20 fusion of the coronal sutures bilaterally, and abnormal formation or fusion of the synchondroses R21 in the anterior cranial base and the midfacial sutures (Kreiborg et al., 1993). Extra compensatory R22 growth of the skull is facilitated by the enlarged anterior fontanel that stays open for a relatively R23 long period, compensating for the development of increased intracranial pressure (De Jong et R24 al., 2012a). Fusion of sagittal and lambdoidal sutures may follow after birth. The typical facial R25 appearance is a flat, elongated forehead with bitemporal widening and ocular hypertelorism R26 with proptosis (Fig. 1.3) (Kreiborg and Cohen, 1992). In Apert syndrome earlier closure of R27 sutures, fontanelles and synchondroses is observed than in Crouzon syndrome (Kreiborg, 1993). R28 Moreover, in Apert syndrome the cranial vault takes an turricephalic (tower-like) shape, which R29 is not encountered in Crouzon syndrome (Cohen and Kreiborg, 1996). The synchondroses in R30 the cranial base and the sutures of the upper face are to a variable degree involved, resulting in R31 sagittal midface deficiency (Kreiborg et al., 1993). Furthermore, asymmetric cranial base and an R32 excessively obtuse cranial base angle are more common in Apert than in Crouzon syndrome (Figs. R33 R34 1.2 and 1.3) (Kreiborg et al., 1993). Facial asymmetry is frequent in both syndromes (Cohen and R35 Kreiborg, 1996). Sagittal maxillary growth may not be expected, while vertical growth occurs R36 with the eruption of teeth (Meazzini et al., 2005). Mandibular growth seems close to normal, R37 although longitudinal data are lacking (Costaras-Volarich and Pruzansky, 1984; Kreiborg and R38 Cohen, 1992). R39

General Introduction | 17 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 Figure 1.2 Clinical and radiologic representation of Crouzon syndrome. R38 R39

18 | Chapter 1 R1 1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 Figure 1.3 Clinical and radiographic representation of Apert syndrome. R38 R39

General Introduction | 19 R1 Oral and dental manifestations in Crouzon or Apert syndrome R2 The described maxillary hypoplasia results in a shortened anteroposterior and transversal dental R3 arch. An anterior open bite, crowding of mandibular anterior teeth and in a few cases cleft palate R4 is observed. Severe crowding of maxillary teeth and ectopic eruption are the result of lack of R5 growth in the posterior part of the maxilla (Aduss, 1981; Bachmayer et al., 1986; Kreiborg and R6 Aduss, 1986). In patients with Crouzon syndrome there is variation from very mild to very severe R7 oral malformations, while oral characteristics in patients with Apert syndrome are very severe and R8 R9 show less variation. R10 Specific intraoral characteristics associated with Apert syndrome include a soft palate that is R11 thicker and a hard palate that is shorter than in healthy children (Peterson and Pruzansky, 1974; R12 Marsh et al., 1991). The reported prevalence of cleft palate in Apert syndrome varies from 4% R13 (Letra et al., 2007) to 11% (Peterson and Pruzansky, 1974), and up to as high as 41% (Kreiborg R14 and Cohen, 1992). Maxillary hypoplasia results in irregular positioning and severe crowding of R15 teeth. In Apert syndrome the combination of maxillary hypoplasia and excessive palatal soft tissue R16 decreases pharyngeal space, and the probably normal growing tongue produces an open mouth R17 posture with a protrusive tongue and open bite (Marsh et al., 1991). R18 Children with Crouzon or Apert syndromes are more likely to have dental anomalies R19 compared to normal children (Cohen, 1986). These dental anomalies can occur with regard R20 to number, shape, size and structure of teeth, timing of development, eruption of teeth and R21 dental occlusion (Cohen and Kreiborg, 1996; Kaloust et al., 1997; Krarup et al., 2005). Dental R22 anomalies tend to be more frequent in Apert syndrome and may reflect the greater complexity R23 R24 of the total clinical manifestation compared to Crouzon syndrome (Cohen and Kreiborg, 1996; R25 Kreiborg and Cohen, 1998). Both syndromes always show severe arch length deficiency with lack R26 of space for the accommodation of the permanent erupting teeth in the upper jaw (Fig. 1.4). R27 However, information about the prevalence of dental agenesis, dental maturation and dental R28 arch development in children with Crouzon or Apert syndromes is scarce. R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

20 | Chapter 1 R1 1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 Figure 1.4 Orthopantomogram of a Crouzon patient with severe space deficiency of maxillary permanent R15 teeth. R16 R17 1.4 Functional impairment of patients with Crouzon or Apert syndromes R18 R19 R20 The Crouzon and Apert syndromes are often severe and functional impairing anomalies. R21 Depending on the number and location of prematurely fused sutures expansion of the cranium R22 is restricted to a varying degree (Reardon et al., 1994; Cohen and MacLean, 2000). A mismatch R23 between intracranial volume versus brain and ventricle volume is thought to be one of the R24 causes of brain abnormalities and elevated intra cranial pressure. However, a raised intracranial R25 pressure is more likely to result from raised cerebrospinal fluid pressure than from a mismatch R26 between intracranial and brain volume, because the majority of patients with craniosynostosis R27 showed a normal or even enlarged intracranial volume (De Jong et al., 2012a). If the increased R28 intracranial pressure is left untreated, brain abnormalities, papilloedema and optic nerve atrophy R29 may develop eventually resulting in possible partial or complete blindness (Reid, 2007). Structural R30 brain lesions may lead to loss of complex cognitive functions, including reduction in mental R31 speed, concentration and overall cognitive efficiency and have influence on behavior (De Jong et R32 al., 2012a; Florisson et al., 2011). The long-term intelligence is within the normal limits in most R33 R34 patients with Crouzon and in some patients with Apert syndrome. In the normal population, R35 2.3% of the patients have an IQ of ≤ -2 standard deviations. Patients with Crouzon syndrome R36 showed ≤ - 2 sd in 16% and patients with Apert syndrome showed ≤ - 2 sd in 46% of the cases R37 (De Jong, 2012). Recently it was suggested that the combination of the expanding brain and R38 R39

General Introduction | 21 R1 excess of cerebrospinal fluid might be the driving forces behind compensatory growth of the R2 skull in patients with craniosynostosis (De Jong et al., 2012a). If the increased intracranial pressure R3 is left untreated, brain lesions, papilloedema and optic nerve atrophy may develop eventually R4 resulting in possible partial or complete blindness (Reid, 2007). R5 Another functional problem lies in the severe hypoplasia of the midface causing exorbitism, R6 lagophthalmos, severe malocclusion, poor esthetics and diminished nasal and nasopharyngeal R7 airway space possibly leading to obstructive sleep apnea (OSA) (Posnick and Ruiz, 2000). This R8 R9 means that patients with Crouzon or Apert syndrome can have partial or complete upper airway R10 obstruction, characterized by snoring, apneas during sleep and difficulty in breathing (Bannink R11 et al., 2010). It is highly unlikely that if severe obstructive sleep apnea syndrome (OSAS) is not R12 present early in life it will develop during childhood (Driessen et al., 2013). Besides obstructive R13 components, patients with craniosynostosis can also have a central sleep apnea caused by a R14 temporary absence of a signal from the brain’s respiratory center. Without this signal, there is no R15 effort to breath (Cohen, 1986). The newborns with limited nasal airflow may experience difficulty R16 with oral feeding, while breathing through the mouth and eating at the same time (Bhattacharjee R17 et al., 2009). R18 As children with craniosynostosis get older, the discrepancy between the two jaws becomes R19 accentuated. The skeletal discrepancy between the maxilla and mandible gives functional R20 problems (e.g. feeding, breathing, speaking). Also Crouzon and Apert patients will often require R21 oral surgery. For example, the development and eruption of teeth must be carefully monitored R22 because of the high prevalence of maxillary hypoplasia. Dental crowding is exacerbated as the R23 R24 permanent teeth erupt, often leading to displacement or even impaction of the teeth. Extractions R25 of some deciduous and selected permanent teeth are often needed. R26 Characteristic malformations and health related problems in Crouzon and Apert syndromes R27 may cause psychological problems that can influence the quality of life of patients with Crouzon R28 and Apert syndromes. Known psychological problems in patients with congenital disfigurements R29 are low satisfaction with appearance, fear of negative appearance evaluation and low self-esteem R30 (Van den Elzen et al., 2012; Versnel et al., 2012). Psychological stress occurs in the period around R31 craniofacial surgery related to: the change in facial appearance; feeding difficulties and removal of R32 external distractor (Bredero-Boelhouwer et al., 2013). Parents can experience stress because they R33 have to make a decision for their child regarding surgical intervention and consequent changing R34 in appearance and feeding problems during treatment (Bredero-Boelhouwer et al., 2013). R35 R36 R37 R38 R39

22 | Chapter 1 1.5 Treatment of midfacial deficiency R1 1 R2 Regarding pressing surgical midfacial advancement, timing and type of operations for the R3 R4 correction of the retruded midface show a wide variety (Posnick and Ruiz, 2000; Renier et R5 al., 2000; Panchal and Uttchin, 2003; Prahl-Andersen, 2005; Reid, 2007). Surgical midfacial R6 advancement is pressing at an early age when midface hypoplasia is the main cause of OSA and R7 exorbitism threatening the eyesight (Nout et al., 2008). At this stage (Class III) malocclusion is a R8 relatively minor issue and dealt with later. In the absence of increased intracranial pressure or need R9 to urgently protect the eyes or the airway, the optimal timing of surgery can be a problem. Over R10 time, different surgical reconstructive methods have been developed for the retruded midface R11 (Gillies and Harrison, 1950; Hanson et al., 1977; Tessier; 1971, 1982; Hoffman and Mohr, 1976; R12 Marchac and Renier, 1979. Gillies and Harrison reported the first high midface osteotomy in an R13 attempt to correct morphologic craniofacial deformity (Gillies and Harrison, 1950). The Le Fort III R14 introduced by Tessier demonstrated the feasibility and safety of massive block mobilization of the R15 midfacial segment of the craniofacial skeleton (Tessier, 1971). After this surgical milestone, many R16 surgeons around the world practiced and modified these techniques. Before the introduction of R17 DO, the necessary horizontal advancement of the midface during surgery could not be achieved R18 R19 in one procedure in order to produce satisfactory or acceptable treatment results in the long R20 run. The midfacial soft tissue envelope hindered an unlimited advancement. Unstable treatment R21 results after surgery (sometimes due to continuing mandibular growth) were frequently observed R22 when using these techniques (Marchac and Renier, 1987; Marchac and Arnaud, 1999). R23 With the introduction of DO as a surgical technique to lengthen the mandible in the early R24 nineties of the last century (McCarty et al., 1992), later advancements with DO became also R25 possible for the retruded midface with less need for second operations (Chin and Toth, 1996; R26 Chin and Toth, 1997; Cohen et al., 1997; Polley and Figueroa, 1997). The distraction device R27 is applied after successful completion of an osteotomy (Polley and Figueroa, 1997), such as R28 Le Fort III osteotomy, monobloc or facial bipartition procedure. Treatment results showed that R29 the often large sagittal movement of the retruded midface seemed to be stable (Iannetti et R30 al., 2006; Hopper et al., 2010; Shetye et al., 2010). Different opinions about post-surgical R31 growth of the maxilla-mandibular complex after midfacial advancement in patients have been R32 published (Pruzansky, 1982; Bachmayer et al., 1986; Kreiborg and Aduss, 1986; Ianetti et al., R33 R34 2006). Current opinions expect no postsurgical maxillary growth while vertical lengthening of the R35 maxilla may occur with the continued eruption of permanent teeth. Conclusions about possible R36 midfacial post-surgical growth should be made with caution because most studies are based R37 on small numbers of patients and have a short follow-up. Due to the variation in craniofacial R38 R39

General Introduction | 23 R1 morphology and related functional or psychosocial problems in patients with Crouzon or Apert R2 syndrome, adjustment of treatment protocols for the individual patient is necessary but difficult. R3 Many current treatment protocols recommend to start advancement of the midface in childhood R4 (Adolphs et al., 2012; Medra et al., 2012), but scientific evidence is lacking for beneficial results R5 in the long term. Midfacial advancement in patients treated in childhood needs an overcorrection R6 because the mandible is still growing (Shetye et al., 2010). Predicting the correct amount of R7 overcorrection is difficult, because precise reference data for amount and direction of mandibular R8 R9 growth are lacking for these syndromic patients. In case of distraction at an early age (before R10 skeletal maturity), the advancement is stopped at the point where the OSA is corrected and R11 sufficient peri-orbital projection is accomplished. Ideally, the patients do not need a second major R12 surgical procedure like a monobloc or Le Fort III operation. However, additionally Le Fort I and R13 mandibular osteotomies are usually necessary to correct a malocclusion preferably when facial R14 growth has ceased (Renier et al., 2000). There are functional and psychosocial circumstances in R15 which the choice of surgery in the immature skeleton outweighs the risks of waiting (Sarwer et R16 al., 1999; Reid, 2007; NVCP, 2010). To date, little knowledge exists regarding the craniofacial R17 growth and development in these patients. But the midfacial growth of children with Crouzon R18 or Apert syndrome is always restrained compared to normal development. Therefore surgical R19 intervention may be necessary at one time or another. R20 Knowledge of timing, amount and variation of facial growth and development in patients R21 with Crouzon or Apert syndrome is fundamental for the timing of any kind of intervention in R22 these patients (Aduss, 1981; Kolar et al., 1988; Panchal and Uttchin, 2003; Sgouros, 2005). R23 R24 Even though efforts have been made, most craniofacial longitudinal growth studies have to deal R25 with a limited number of patients and an insufficient amount of data, due to the rarity of both R26 syndromes (Cohen, 1986). The goal of developmental studies of rare syndromes is to be able R27 to construct an effective multidisciplinary treatment plan. The lack of consensus and evidence R28 based treatment methods regarding the timing and technique used for midfacial reconstruction R29 reflects lack of knowledge of craniofacial morphology and growth and development in syndromic R30 craniosynostosis. Consequently this may imply inconsistencies of the result achieved with any R31 approach to treatment. Therefore growth of developing facial structures should be evaluated R32 in order to favorably alter the trajectory of the abnormal facial growth and development (Prahl- R33 Andersen, 2005). R34 R35 R36 R37 R38 R39

24 | Chapter 1 1.6 General aim R1 1 R2 The syndromes of Crouzon and Apert are very similar in their craniofacial manifestations. Patients R3 R4 with these syndromes often reveal severe growth disturbances of nearly all craniofacial regions. R5 The craniofacial morphology in Crouzon and Apert syndromes is somewhat similar, including R6 calvarial deformities, exophthalmos, hypertelorism, and maxillary hypoplasia. In addition, patients R7 with Apert syndrome have syndactyly of hands and feet. Due to the very little craniofacial growth R8 data for both syndromes it has been argued whether craniofacial development in these two R9 conditions is the same or different. In the literature data analysis of both syndromes have often R10 been pooled (Tessier, 1971; Ousterhout et al., 1985). However, Crouzon and Apert syndromes R11 are different disorders and it is reasonably to expect different craniofacial and dental growth R12 and development. The aim of the present study is to gain a better understanding of craniofacial R13 growth and development in patients with Crouzon or Apert syndrome. R14 Aims: R15 • To describe and examine vertical and sagittal maxillary facial growth and development R16 of children with Crouzon or Apert syndrome compared with healthy children. R17 R18 • To describe and examine mandibular asymmetry in children with Crouzon or Apert R19 syndrome compared with healthy children. R20 • To describe and compare dental age of children with Crouzon or Apert syndrome with R21 healthy children. R22 To describe and compare patterns of tooth agenesis in children with Crouzon or Apert • R23 syndrome with healthy children. R24 • To describe and compare dental arch dimensions of children with Crouzon or Apert R25 syndrome with healthy children. R26 • To evaluate and compare the results of Le Fort III distraction osteogenesis in children R27 with Crouzon or Apert syndrome with age-matched healthy children. R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

General Introduction | 25 R1 1.7 References R2 R3 Adolphs N, Klein M, Haberl EJ, Menneking H, Hoffmeister B. frontofacial advancement by internal distraction R4 devices. A technical modification for the management of craniofacial dysostosis in early childhood. Int J Oral Maxillofac Surg. 2012;41:777-82. R5 Aduss H. Form, function, growth, and craniofacial surgery. Otolanryngol Clin North Am. 1981;14:783-825. R6 Anderson PJ, Hall CM, Evans RD Jones BM, Hayward RD. Hand anomalies in Crouzon syndrome. Skeletal R7 Radiol. 1997;26:113-115. R8 Arnaud E, Meneses P, Lajeunie E, Thorne JA, Marchac D, Renier D. Postoperative mental and morphological outcome for nonsyndromic brachycephaly. Plast reconstr surg. 2002;110:6-12; discussion 13. R9 Arnaud-López L, Fragoso R, Mantilla-Capacho J, Barros-Núñez P. Crouzon with acanthosis nigricans. Further R10 delineation of the syndrome. Clin Genet. 2007;72:405-410. R11 Avantaggiato A, Carini F, Curioni C. Apert’s syndrome: cephalometric evaluation and considerations on R12 pathogenesis. J Craniofac Surg. 1996;7:23–31. R13 Bachmayer DI, Ross RB, Munro IR. Maxillary growth following LeFort III advancement surgery in Crouzon, Apert, and Pfeiffer syndromes. Am J Orthod Dentofacial Orthop. 1986;90:420-430. R14 Baer MJ. Patterns of growth of the skull as revealed by vital staining. Human Biol. 1954;26:80-126. R15 Bannink N, Mathijssen IMJ, Joosten KF. Can parents predict obstructive sleep apnea in children with syndromic R16 or complex craniosynostosis? Int J Oral Maxillofac Surg. 2010;39:421-423. R17 Bannink N. Obstructive sleep apnea in children with syndromic craniosynostosis. Rotterdam: Erasmus R18 University; 2010. Dissertation. Bertelsen TI. The premature synostosis of the cranial sutures. Acta Opthalmol 1958;36(suppl 51):1-176. R19 Bhattacharjee R, Kheirandish-Gozal L, Pillar G, Gozal D. Cardiovascular complications of obstructive sleep R20 apnea syndrome: evidence from children. Prog Cardiovasc Dis. 2009;51:416-433. R21 Björk A. Facial growth in man, studied with the aid of metallic implants. Acta Odontol Scand. 1955;13:9-34. R22 Bredero-Boelhouwer H, Joosten KF, Van Veen-Van der Hoek M, Mathijssen IM. Family-centred care during R23 midface advancement with a rigid external device: what do families need? J Plast Reconstr Aesthet Surg. 2013;66:1103-8. R24 Brueton LA, van Herwerden L, Chotai KA, Winter RM. The mapping of a gene for craniosynostosis: evidence R25 for linkage of the Saethre-Chotzen syndrome to distal chromosome 7p. J Med Genet. 1992;29:681- R26 685. R27 Bu BH, Kaban LB, Vargervik K. Effect of Le Fort III osteotomy on mandibular growth in patients with Crouzon and Apert syndromes. J Oral Maxillofac Surg. 1989;47:666-671. R28 Carinci F, Pezzetti F, Locci P, Becchetti E, Carls F, Avantaggiato A, Becchetti A, Carinci P, Baroni T, Bodo R29 M. Apert and Crouzon syndromes: clinical findings, genes and extracellular matrix. J Craniofac Surg. R30 2005;16:361-368. R31 Chin M, Toth BA. Distraction osteogenesis in maxillofacial surgery using internal devices: review of five cases. J Oral Maxillofac Surg. 1996:54:45-53; discussion 54. R32 Chin M, Toth BA. Le Fort III advancement with gradual distraction using internal devices. Plast Reconstr Surg. R33 1997:100:819-830; discussion 831-812. R34 Cohen SR, Burstein FD, Stewart MB, Rathburn MA. Maxillary-midface distraction in children with cleft lip and R35 palate: a preliminary report. Plast Reconstr Surg. 1997:99:1421-1428. Cohen MM Jr. An etiologic and nosologic overview of craniosynostosis syndromes. Birth Defects Orig Artic R36 Ser. 1975;11:137-189. R37 Cohen MM Jr. Craniosynostosis: Diagnosis, evaluation, and management. New York: Raven Press; 1986. R38 R39

26 | Chapter 1 Cohen MM Jr, Kreiborg S. New indirect method for estimating the birth prevalence of the Apert syndrome. Int J Oral Maxillofac Surg. 1992;21:107-109. R1 Cohen MM Jr. Sutural biology and the correlates of craniosynostosis. Am J Med Genet. 1993;47:581-616. 1 R2 Cohen MM Jr, Kreiborg S. An updated pediatric perspective on the Apert syndrome. Am J Dis Child. R3 1993;147:989-993. R4 Cohen MM Jr, Kreiborg S. Cranial size and configuration in the Apert syndrome. J Craniofac Genet Dev Biol. R5 1994;14:153–162. R6 Cohen MM Jr, Kreiborg S. A clinical study of the craniofacial features in Apert syndrome. Int J Oral Maxillofac Surg. 1996;25:45-53. R7 Cohen MM Jr, MacLean RE. Craniosynostosis: diagnosis, evaluation and management. 2nd ed. New York; R8 Oxford University Press: 2000. R9 Cornejo-Roldan LR, Roessler E, Muenke M. Analysis of the mutational spectrum of the FGFR2 gene in Pfeiff R10 er syndrome. Human genetics 1999;104:425-431. Costaras-Volarich M, Pruzansky S. Is the mandible intrinsically different in Apert and Crouzon syndromes? Am R11 J Orthod. 1984;85:475-487. R12 Da Costa AC, Walters I, Savarirayan R, Anderson VA, Wrennal JA, Meara JG. Intellectual outcomes in R13 children and adolescents with syndromic and nonsyndromic craniosynostosis. Plast Reconstr Surg. 2006;118:175-181; discussion 182-183. R14 David L, Glazier S, Pyle J, Thompson J, Argenta L. Classification system for sagittal craniosynostosis. J Craniofac R15 Surg. 2009;20:279-282. R16 De Jong T. Long-term results in syndromic craniosynostosis. Rotterdam: Erasmus University; 2012. Dissertation. R17 De Jong T, Rijken BF, Lequin MH, van Veelen ML, Mathijssen IM. Brain and ventricular volume in patients with R18 syndromic and complex craniosynostosis. Childs Nerv Syst. 2012a;28:137-140. R19 Driessen C, Joosten KF, Bannink N, Bredero-Boelhouwer HH, Hoeve HL, Wolvius EB, Rizopoulos D, Mathijssen IM. How does obstructive sleep apnoea evolve in syndromic craniosynostosis? A prospective cohort R20 study. Arch Dis Child. 2013;98:538-543. R21 Figueroa AA, Polley JW. Management of the severe cleft and syndromic midface hypoplasia. Orthod Craniofac R22 Res. 2007;10:167-179. R23 Florisson JM, Dudink J, Koning IV, Hop WC, Van Veelen ML, Mathijssen IM, Lequin MH. Assessment of white matter microstructural integrity in children with syndromic craniosynostosis: a diffusion-tensor imaging R24 study. Radiology. 2011;261:534-541. R25 Gillies H, Harrison SH. Operative correction by osteotomy of recessed malar maxillary compound in a case of R26 oxycephaly. Br J Plast Surg. 1950;3:123-127. R27 Glaser RL, Broman, KW Schulman RL, Eskenazi B, Wyrobek AJ, Jabs EW. The paternal-age effect in Apert syndrome is due, in part, to the increased frequency of mutations in sperm. Am J Hum Genet. R28 2003;73:939-947. R29 Glass IA, Chapman S Hockley AD. A distinct autosomal dominant craniosynostosis-brachydactyly syndrome. R30 Clin Dysmorphol. 1994;3:215-223. R31 Gorlin RJ, Cohen MM Jr, Hennekam CM. Syndromes of the head and neck. New York: Oxford University Press, 2001. R32 Grayson, BH, Wintraub, N, Brookstein, FL, and Mc-Carthy, JG. A comparative cephalometric study of the R33 cranial base in craniofacial anomalies: Part I: Tensor analysis. Cleft Palate J. 1985;22:75-87. R34 Gripp KW, Zackai EH, Stolle CA. Mutations in the human TWIST gene. Hum Matat. 2000;15:150-155. R35 Herring SW. Mechanical influences on suture development and patency. Front Oral Biol. 2008;12:41-56. R36 Hoffman HJ, Mohr G. Lateral canthal advancement of the supraorbital margin. A new corrective technique in the treatment of coronal synostosis. J Neurosurg. 1976;45:376-381. R37 R38 R39

General Introduction | 27 Hopper RA, Sandercoe G, Woo A, Watts R, Kelley P, Ettinger RE, Saltzman B. Computed tomographic analysis R1 of temporal maxillary stability and pterygomaxillary generate formation following pediatric Le Fort III R2 distraction advancement. Plast Reconstr Surg. 2010;126:1665-1674. R3 Iannetti G, Fadda T, Agrillo A, Poladas G, Iannetti G, Filiaci F. LeFort III advancement with and without osteogenesis distraction. J Craniofac Surg. 2006;17:536-543. R4 Kaloust S, Ishii K, Vargervik K. Dental development in Apert syndrome. Cleft Palate Craniofac J. 1997;34:117- R5 121. R6 Kolar JC, Munro IR, Farkas LG. Patterns of dysmorphology in Crouzon syndrome: an anthropometric study. R7 Cleft Palate J. 1988;25:235-244. R8 Krarup S, Darvann TA, Larsen P, Marsh JL, Kreiborg S. Three-dimensional analysis of mandibular growth and tooth eruption. J Anat. 2005;207:669-682. R9 Kreiborg S. Craniofacial growth in plagiocephaly and Crouzon syndrome. Scand J Plast Reconstr Surg. R10 1981;15:187-197. R11 Kreiborg S, Aduss H. Pre- and postsurgical facial growth in patients with Crouzon’s and Apert’s syndromes. R12 Cleft Palate J. 1986;23(suppl):78-90. R13 Kreiborg S, Aduss H, Cohen MM Jr. Cephalometric study of the Apert syndrome in adolescence and adulthood. J Craniofac Genet Dev Biol. 1999;19:1-11. R14 Kreiborg S, Björk A. Description of a dry skull in Crouzon syndrome. Scand J Plast Reconstr Surg. 1982;16:245- R15 253. R16 Kreiborg S, Cohen MM Jr. Is craniofacial morphology in Apert and Crouzon syndromes the same? Acta R17 Odontol Scand. 1998;56:339-341. Kreiborg S, Marsh JL, Cohen MM Jr, Liversage M, Pedersen H, Skovby F, Borgesen SE, Vannier MW. R18 Comparative three-dimensional analysis of CT-scans of the calvaria and cranial base in Apert and R19 Crouzon syndromes. J Craniomaxillofac Surg. 1993;21:181-188. R20 Lajeunie E, Cameron R, El Ghouzzi V, de Parseval N, Journeau P, Gonzales M, Delezoide AL, Bonaventure J, Le R21 Merrer M, Renier D. Clinical variability in patients with Apert’s syndrome. J Neurosurg. 1999;90:443- 447. R22 Letra A, de Almeida AL, Kaizer R, Esper LA, Sgarbosa S, Granjeiro JM. Intraoral features of Apert’s syndrome. R23 Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:e38-e41. R24 Marchac D, Renier D. The “floating forehead”. Early treatment of craniofacial stenosis. Ann Chir Plast. 1979;24:121-126. R25 Marchac D, Renier D. Early monobloc frontofacial advancement. In: Marchac D (ed) Craniofacial surgery: R26 Proceedings of the First International Congress of Cranio-maxillo-facial Surgery. Springer, Berlin R27 Heidelberg New York, pp 130-136. R28 Marchac D, Arnaud E. Midface surgery from Tessier to distraction. Childs Nerv Syst. 1999;15:681-694. R29 Marsh JL, Galic M, Vannier MW. The craniofacial anatomy of Apert syndrome. Clin Plast Surg. 1991;18:237- 249. R30 Massler M, Schour I. The growth pattern of the cranial vault in the albino rat as measured by vital staining R31 with alizarin red “S”. Anat Rec. 1951;110:83-101. R32 McCarty JG, Schreiber J, Karp N et al.,. Lengthening the human mandible by gradual distraction. Plast R33 Reconstr Surg. 1992;89:1-8. R34 Meazzini MC, Mazzoleni F, Caronni E, Bozetti A. Le Fort III advancement osteotomy in the growing child affected by Crouzon’s and Apert’s syndromes: presurgical and postsurgical growth. J Craniofac Surg. R35 2005;16:369-377. R36 Medra AM, Marei AG, Shehata EA, McGurk M, Habib A. simultaneous and differential fronto-orbital and R37 midface distraction osteogenesis for syndromic craniosynostosis using rigid external distractor II. J Craniofac Surg. 2012:23:1306-13. R38 R39

28 | Chapter 1 Meyers GA, Orlow SJ, Munro IR, Przylepa KA, Jabs EW. Fibroblast growth factor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet. 1995;11:462-464. R1 Mooney MP, Siegel MI. Understanding craniofacial anomalies. New York; Wiley-Liss, Inc., 2002. 1 R2 Moss ML, Young RW. A functional approach to craniology. Am J Phys Anthropol. 1960;18:281-292. R3 Moss ML. A theoretical analysis of the functional matrix. Acta Biotheor. 1968;18:195-202. R4 Moss ML. The functional matrix hypothesis revisited. 1. The role of mechanotransduction. Am J Orthod R5 Dentofacial Orthop. 1997;112:8-11. R6 Muenke M, Schell U, Hehr A, et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat Genet. 1994;8:269-274. R7 Nederlandse Vereniging voor Plastische Chirurgie. Richtlijn behandeling en zorg voor craniosynostose. 2010. R8 Nout E, Cesteleyn LL, van der Wal KG, van Adrichem LN, Mathijssen IM, Wolvius EB. Advancement of the R9 midface, from conventional Le Fort III osteotomy to Le Fort III distraction: review of the literature. Int J R10 Oral Maxillofac Surg. 2008;37:781-789. R11 Opperman LA, Persing JA, Sheen R, Ogle RC. In the absence of periosteum, transplanted fetal and neonatal rat coronal sutures resist osseous obliteration. J Craniofac Surg. 1994;5:327-332. R12 Ousterhout DK, Vargervik K, Clark S. Stability of the maxilla after Le Fort III Advancement in Craniosynostosis R13 Syndromes. Cleft Palate J. 1986;23Suppl 1:91-101. R14 Panchal J, Uttchin V. Management of craniosynostosis. Plast Reconstr Surg. 2003;111:2032-2048. R15 Persing J, Jane J, Shaffrey M. Virchow and the pathogenesis of craniosynostosis: a translation of his original R16 work. Plast Reconstr Surg. 1989;83:738–742. Peterson SJ, Pruzansy S. Palatal anomalies in the syndrome of Apert and Crouzon. Cleft Palate J. 1974;11:394- R17 403. R18 Polley JW, Figueroa AA. Management of severe maxillary deficiency in childhood and adolescence through R19 distraction osteogenesis with an esternal, adjustable, rigid distraction device. J Craniofac Surg. 1997;8:181-185. R20 Posnick JC, Ruiz RL. The craniofacial dysostosis syndromes: current surgical thinking and future directions. R21 Cleft Palate Craniofac J. 2000;37:433-1-24. R22 Prahl-Andersen B. Controversies in the management of craniofacial malformations. Semin Orthod. R23 2005;11:67-75. R24 Reardon, W, Winter RM, Rutland P, Pulleyn LJ, Jones BM Malcolm S. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet. 1994;8:98-103. R25 Reid RR. Facial skeletal growth and timing of surgical intervention. Clin Plast Surg. 2007;34:357-367. R26 Renier D, Lajeunie E, Arnaud E, Marchac D. Management of craniosynostoses. Childs Nerv Syst. 2000;16:645- R27 658. R28 Rutland P, Pulleyn LJ, Reardon W, et al. Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon R29 syndrome phenotypes. Nat Genet. 1995;9:173-176. Sarnat BG, Laskin DM. Cartilage and cartilage implants. Int Abstr Surg. 1954;99:521-541. R30 Sarnat BG, Wexler MR. Growth of the face and jaws after resection of the septal cartilage in the rabbit. Am R31 J Anat. 1966;118:755-767. R32 Sarwer DB, Bartlett SP, Whitaker LA, Paige KT Pertschuk MJ Wadden TA. Adult psychological functioning of R33 individuals born with craniofacial anomalies. Plast Reconstr Surg. 1999;103:412-418. R34 Scott JH. Further studies on the growth of the human face. Proc R Soc Med. 1959;52:263-268. R35 Sgouros S. Skull vault growth in craniosynostosis. Childs nerv syst. 2005;21:861-870. Shetye PR, Davidson EH, Sorkin M, Grayson BH, McCarthy JG. Evaluation of three surgical techniques for R36 advancement of the midface in growing children with syndromic craniosynostosis. Plast Reconstr Surg. R37 2010;126:982-994. R38 R39

General Introduction | 29 Slater BJ, Lenton KA, Kwan MD, Gupta DM, Wan DC, Longaker MT. Cranial sutures: a brief review. Plast R1 Reconstr Surg. 2008;121:170e-8e. R2 Tessier P. Treatment of facial dysmorphisms in craniofacial dysostosis (DCF). Crouzon and Apert diseases. Total R3 osteotomy of the facial massif. Sagittal displacement of the facial massif. Neurochirurgie. 1971;17:295- 322. R4 Tessier P. Autogenous bone grafts taken from the calvarium for facial and cranial applications. Clin Plast Surg. R5 1982;9:531-538. R6 Turvey TA, Vig KWL, Fonseca RJ. Facial Clefts and Craniosynostosis Principles and Management. Philadelphia: R7 WB Saunders; 1996. R8 Van den Elzen ME, Versnel SL, Hovius SE, Passchier J, Duivenvoorden HJ, Mathijssen IM. Adults with congenital or acquired facial disfigurement: Impact of appearance on social functioning. J Craniomaxillofac Surg. R9 2012;40:777-82 . R10 Van der Meulen JC, Mazzola R, Vermey-Keers C, Stricker M, Raphael B. A morphogenetic classification of R11 craniofacial malformations. Plast Reconstr Surg. 1983;71:560-572. R12 Van der Klaauw C. Size and position of the functional components of the skull. Arch Neerl Zool. 1948- 1952;9:1-559. R13 Van Limborgh J. A new view of the control of the morphogenesis of the skull. Acta Morphol Neerl Scand. R14 1970;8:143-160. R15 Van Limborgh J. The role of genetic and local environmental factors in the control of postnatal craniofacial R16 morphogenesis. Acta Morphol Neerl Scand. 1972;10:37-47. R17 Vermeij-Keers C, Mazzola RF, Van der Meulen JC, Strickler M. Cerebro-craniofacial and craniofacial malformations: an embryological analysis. Cleft Palate J. 1983;20:128-145. R18 Versnel SL, Plomp RG, Passchier J, Duivenvoorden HJ, Mathijssen IM. Long-term psychological functioning of R19 adults with severe congenital facial disfigurement. Plast Reconstr Surg. 2012;129:110-7. R20 Virchow R. Uber den Crestinismus, namentlich in Franken, und uber pathologische Schadelformen. Verh Phys R21 Med Ges Wurzbg. 1851;2:230-271. Warschausky S, Kay JB, Buchman S, Halberg A, Berger M. Health-related quality of life in children with R22 craniofacial anomalies. Plast Reconstr Surg. 2002;110:409-414. R23 Weinmann JP, Sicher H. Bone and bones. Fundamentals of bone biology. St Louis; Mosby: 1955. R24 Wilkie AO, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, Hayward RD, David DJ, Pulleyn LJ, R25 Rutland P et al., Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995;9:165-172. R26 Santiago PE, Grayson BH, Degen M, Brecht LE, Singh GD, McCarthy JG. The effect of an early Le Fort III R27 surgery on permanent molar eruption. Plast Reconstr Surg. 2005;115:423-427. R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

30 | Chapter 1 Chapter 2

Facial Growth in Patients With Apert and Crouzon

Syndromes Compared to Normal Children

Jacobus H. Reitsma Edwin M. Ongkosuwito Peter H. Buschang Birte Prahl-Andersen

Cleft Palate Craniofacial Journal 2012; 49: 185-193 R1 Abstract R2

R3 Objective: To evaluate vertical and sagittal facial growth in children with Apert and Crouzon R4 syndromes and compare it to the growth patterns of a nonsyndromic control group. R5 R6 Design: Case-control study. R7 R8 R9 Setting: Department of Orthodontics, Children’s Hospital Erasmus Medical Centre, Sophia, R10 Rotterdam, The Netherlands. R11 R12 Patients, Participants: Sixty-two patients (37 patients with Crouzon syndrome and 25 patients R13 with Apert syndrome) born between 1971 and 2001 (age range 3.9 to 32 years) and 482 R14 nonsyndromic children as a control group. R15 R16 Interventions: Lateral cephalograms performed prior to any midfacial surgery of 62 patients and R17 482 nonsyndromic children were traced and horizontal and vertical measurements were digitized. R18 R19 Main Outcome Measures: Cephalometric measurements of SNA, SNB, ANB, NSMe, and SN/ R20 palatal plane angles and lower facial height ratio. R21 R22 Results: Horizontal measurements for the syndromic groups showed no change in SNA angle R23 R24 during growth. SNA angles were lower in patients with Apert syndrome compared to patients R25 with Crouzon syndrome. The syndromic groups showed smaller values for ANB angles compared R26 to the nonsyndromic group. Vertical measurements showed increased lower facial height ratios R27 for the syndromic groups compared to control subjects. There was an increasing counterclockwise R28 rotation of the palatal plane in relation to the anterior cranial base in syndromic patients. NSMe R29 angles among the three groups were not significantly different. R30 R31 Conclusions: Based on the growth differences identified, the sagittal and vertical jaw relationships R32 differ in patients with Crouzon syndrome, patients with Apert syndrome, and control subjects. R33 Syndromic patients show aggravation of midfacial underdevelopment and anterior rotation of R34 the mandible. R35 R36 R37 R38 R39

32 | Chapter 2 2.1 Introduction R1 R2

The prevalence of Apert syndrome is 1 in 100,000 births; Crouzon syndrome is seen more R3 R4 frequently, in 1 in 25,000 births (Cohen, 1986). Genetic mapping of syndromes with R5 craniosynostosis show that mutations in the fibroblast growth factor receptor 2 (FGFR2) gene 2 R6 are responsible for most phenotypes seen in these syndromes. The fact that the same mutation R7 can produce a wide range of phenotypic expressions highlights the complexity of anomalous R8 craniofacial developments (Carinci et al., 2005). Midface deficiency is a characteristic feature in R9 Crouzon and Apert syndromes; this skull deformity is caused by premature closure of the cranial R10 sutures. R11 Previous studies described the midface of Apert and Crouzon syndromes to be deficient in R12 all three planes of space: a sagittal severe midface deficiency compared to the cranial base, a R13 vertically short upper anterior face height, and a reduced maxillary width (Cohen, 1986; Kreiborg R14 and Aduss, 1986; Cohen and Kreiborg, 1996; Posnick and Ruiz, 2000). In contrast to Crouzon R15 syndrome, craniofacial involvement is always clearly identified at birth in Apert syndrome R16 patients, with brachycephaly associated with facial retrusion (Renier et al., 2000). Syndromic R17 midface deficiency is aggravated during growth and development (Reid, 2007). The maxilla grows R18 R19 anteriorly and inferiorly, but this growth is markedly less than that of control subjects (Bachmayer R20 et al., 1986). Two patterns of inferior maxillary growth have been observed. The first shows a R21 symmetrical descent of the anterior and posterior aspects of the palatal plane. The second growth R22 pattern is marked by a descent of the posterior part more than the anterior, which tilts the palatal R23 plane superiorly and anteriorly and in turn affects mandibular growth (Bachmayer et al., 1986). R24 In contrast to the maxilla, the mandible grows more normally in Apert and Crouzon syndromes, R25 exhibiting anterior rotation in relation to the anterior cranial base (Cohen, 1986; Kreiborg and R26 Aduss, 1986; Marsh et al., 1991; Cohen and Kreiborg, 1996; Posnick and Ruiz, 2000). R27 These two syndromes are different disorders with different craniofacial development (Kreiborg R28 and Cohen, 1998). Patients with Apert syndrome show a more abnormal craniofacial morphology R29 than patients with Crouzon syndrome (Turvey et al., 1996; Kreiborg and Cohen, 1998). Individual R30 variations in facial growth are observed, but prediction of facial growth in individual patients is R31 difficult. R32 Craniofacial dysmorphology causes increased intracranial pressure, visual impairment, and R33 R34 airway problems. To treat these functional difficulties, surgery of the immature skeleton is often R35 necessary (Bachmayer and Ross, 1986). Surgical treatment to correct the midface deficiency is R36 often performed later in life and is not recommended for the immature skeleton. New treatment R37 possibilities, including craniofacial distraction osteogenesis, may make intervention during early R38 R39

Facial Growth in Patients With Apert and Crouzon Syndromes Compared to Normal Children | 33 R1 infancy possible for the retruded midface. However, early surgical interventions are associated R2 with postsurgical relapse and possible inhibition of growth; in these situations, additional R3 surgery is required (Reid, 2007). Treatment of maxillary growth following early intervention is R4 controversial and is based on opinions, anecdotes, and inadequately designed human studies R5 in a small number of patients (Bachmayer et al., 1986). Timing, duration, and the amount of R6 displacement of the retruded midface in the growing child are essential factors affecting the R7 efficacy of treatment. Therefore, craniofacial growth reference data are important for orthodontic R8 R9 diagnosis, orthodontic treatment, and timing of surgical correction of the retruded midface R10 (Prahl-Andersen, 2005). R11 To predict facial development in patients with Crouzon and Apert syndromes, more R12 information is needed concerning the differences in craniofacial morphology of patients with R13 Apert syndrome, patients with Crouzon syndrome, and normal healthy controls. These data could R14 potentially be used in future research to predict the need for and ideal timing of midfacial surgery. R15 The aim of the present study was to compare normal vertical and sagittal facial growth patterns R16 to those seen in children with Apert and Crouzon syndromes. R17 R18 R19 2.2 Material and Methods R20 R21 2.2.1 Patients R22 Material used in this study consisted of data obtained from 37 patients with Crouzon syndrome R23 R24 (16 girls and 21 boys) and 25 patients with Apert syndrome (17 girls and eight boys) from the R25 Department of Orthodontics of the Erasmus Medical Centre of Rotterdam. Craniosynostosis in R26 syndromes related to the syndrome of Crouzon or Apert was excluded from the study because R27 of difficulty in comparison, insufficient data for patients with Pfeiffer syndrome, and the relatively R28 mild sagittal midface deformity in patients with the Saethre Chotzen, Carpenter, and Muenke R29 syndromes compared to patients with Apert and Crouzon syndromes. Clinical diagnosis of Apert R30 or Crouzon syndrome in all 62 patients had been confirmed genetically. All patients with Apert R31 syndrome had mutations in the gene encoding FGFR2. Most patients with Crouzon syndrome R32 had mutations in the gene encoding FGFR2; the remainder had mutations in the gene encoding R33 FGFR3. The hospital records, craniofacial team assessments, and cephalometric analyses were R34 reviewed retrospectively with approval from the Institutional Review Board at Sophia Children’s R35 Hospital, Erasmus Medical Centre. R36 A total of 177 sets of longitudinal cephalometric data obtained prior to any midface surgery R37 of patients born between 1979 and 2001 (age range 3.9 to 32 years) were collected at regular R38 R39

34 | Chapter 2 time intervals. These data were compared with a large mixed-longitudinal data set from the R1 Nijmegen Growth Study (Prahl-Andersen et al., 1979). This mixed-longitudinal growth study R2 included 482 nonsyndromic children, 4 to 15 years of age. Each child was followed for a period R3 R4 of 5 years. A final measurement was taken at 22 years of age for some control cohorts. The R5 cephalometric data came from existing mixed-longitudinal records obtained between 1971 and 2 R6 1976. Radiographs were taken annually from 4 to 9 years of age and semiannually from 9 to 15 R7 years of age. R8 R9 2.2.2 Cephalometric Landmarks and Measurements R10 Seven cephalometric points situated in the midsagittal plane were identified (Fig. 2.1). Comparison R11 of the three groups was based on six craniofacial measurements (Table 2.1) representing sagittal R12 and vertical jaw relationships and was done using Viewbox software (version 3.1.1.12; dHal R13 Orthodontic Software, Athens, Greece). The cranial base is important and serves as a reasonably R14 stable reference structure in roentgen cephalometric analyses. Two craniofacial measures (S-N R15 and Na-Me) served as reference for comparisons of the six craniofacial measurements (Table 2.6). R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31

Figure 2.1 Lateral skull with landmark points. ANS: anterior nasal spine. The anterior tip of the sharp bony R32 process of the maxilla at the lower margin of the anterior nasal opening. Me: Menton. The lowest point on R33 the symphyseal shadow of the mandible seen on a lateral cephalogram. N: Nasion. The most anterior point on R34 the frontonasal suture in the midsagittal plane. PNS: Posterior nasal spine. The posterior spine of the palatine bone constituting the hard palate. Point A: subspinale. The most posterior midline point in the concavity R35 between the ANS and the prosthion (the most inferior point on the alveolar bone overlying the maxillary R36 incisors). Point B: supramentale. The most posterior midline point in the concavity of the mandible between the most superior point on the alveolar bone overlying the mandibular incisors (infradentale) and Pogonion R37 (the most anterior point on the chin). S: Sella. The geometric center of the pituitary fossa. R38 R39

Facial Growth in Patients With Apert and Crouzon Syndromes Compared to Normal Children | 35 R1 Table 2.1 Description of cephalometric measurements. R2 ANS-Me Represents the lower anterior face height (LFH). R3 N-Me Represents the total anterior facial height. R4 LFH Ratio The ratio of the lower anterior facial height and the total anterior facial height. R5 NSMe angle Measures the angle from nasion to sella to menton. R6 SN/PP angle Measures the inclination of palatal plane to the anterior cranial base. R7 ANB angle The relative position of points A and B to each other. R8 SNA angle The anterior-posterior position of point A to the anterior cranial base. SNB angle The anterior-posterior position of point B to the anterior cranial base. R9 R10 R11 2.2.3 Statistics R12 2.2.3.1 Assessment of Interexaminer and Intraexaminer Variation R13 To calculate systematic and random errors, a subsample of 20 randomly selected radiographs was R14 retraced and redigitized by two examiners using Viewbox software; the angular and ratio variables, R15 as listed in table 2.1, were analyzed. Intraobserver duplicate measurement errors were calculated R16 (Fig. 2.1; Table 2.2) according to Dahlberg’s formula (Dahlberg, 1940), and reliability coefficients R17 between the first and second digitizing were calculated as Pearson’s correlation coefficients. An R18 intraclass correlation coefficient (ICC) was then calculated on the recorded measurements. The R19 same calculations were performed for interobserver errors. Statistical analyses were performed R20 using SPSS (version 15.0, SPSS, Chicago, IL). An ICC value greater than 0.75 represents a high R21 level of reliability, values between 0.4 and 0.75 indicate fair to moderate reliability, and a value R22 less than 0.4 represents poor reliability (Shrout and Fleiss, 1979). R23 R24 R25 Table 2.2 Intraobserver and interobserver agreement for digitization of the cephalometric landmarks. R26 Intraobserver reliability n Interobserver reliability n (digitization) (digitization) R27 = 20 = 20 R28 Correlation coefficient Correlation coefficient R29 SNA angle (degrees) 0.921 0.972 R30 SNB angle (degrees) 0.970 0.706 ANB angle (degrees) 0.847 0.872 R31 LFH ratio 0.984 0.742 R32 NSMe angle (degrees) 0.977 0.962 R33 SN/PP (degrees) 0.969 0.65 R34 R35 R36 R37 R38 R39

36 | Chapter 2 2.2.3.2 Growth Models R1 The program MLwiN (version 1.2, Centre for Multilevel Modelling, London, United Kingdom) was R2 used to model growth changes and compare the three groups. Two level models were used, with R3 R4 patients (i) at one level and age (j) nested within patients at the other level. For each y variable R5 (craniofacial measurement), a polynomial equation was estimated statistically. The y intercept was 2 R6 adjusted (intercept = age - 6) to 6 years of age to reduce the complexity of computations. Average R7 growth curves were estimated between 5 and 15 years of age. Because of expected differences R8 associated with syndrome and gender, separate models were fitted. A cubic model was first fitted R9 for each group, and the highest-order term was checked for statistical significance. If it was not R10 2 3 significant, it was removed andy ija =new β0ijconstant reduced + βmodel1tij + β 2twasij + fitted.β3tij The initial equation was: R11 R12 with 2 3 yij = β0ijconstant + β1tij + β2tij + β3tij R13 with R14 β0ij = u0j + e0ij with R15 R16 where the craniofacial growth measurement y was computed by adding the intercept (b0ij) to where the craniofacial growth measurement y was computed by adding the intercept (β0ij) to the β0ij = u0j + e0ij R17 the products of other fixed coefficientsb ( 1, b2, and b3) multiplied by age (t) at each occasion. products of other fixed coefficients (β1 , β2, and β3) multiplied by age (t) at each occasion. The u0j and R18 The u0j and e0ij comprise the random portion of the model and are assumed to have means equal where the craniofacial growth measurement y was computed by adding the intercept (β0ij) to the R19 to zero,e0ij comprise to be uncorrelated,the random portion and ofto the be model normally and aredistributed. assumed to The have level means 1 residualequal to ezero, represents to be 0ij R20 within-subjectproducts of other variation, fixed coefficients or the ‘‘error’’ (β1 , βterm,2, and while β3) multiplied the level by 2 age residual (t) at each u represents, occasion. The in uthis0j and case, uncorrelated, and to be normally distributed. The level 1 residual e0ij represents0j within-subject R21 between-subjecte0ij comprise the variation random portion(Goldstein, of the 1987). model and are assumed to have means equal to zero, to be variation, or the ‘‘error’’ term, while the level 2 residual u0j represents, in this case, between-subject R22 The polynomial model takes full advantage of each patient’s individual longitudinal growth uncorrelated, and to be normally distributed. The level 1 residual e0ij represents within-subject R23 variation (Goldstein, 1987). data and statistically evaluates the shape of the curve. Iterative generalized least squares were R24 variation, or the ‘‘error’’ term, while the level 2 residual u0j represents, in this case, between-subject used to estimate the model’s parameters (Goldstein, 1987). Two-level models were also used to R25 The polynomial model takes full advantage of each patient’s individual longitudinal growth estimatevariation the (Goldstein, groups’ adult 1987). stat status at 22 years of age (intercept = age - 22). R26 data and statistically evaluates the shape of the curve. Iterative generalized least squares were used to R27 The polynomial model takes full advantage of each patient’s individual longitudinal growth estimate the model’s parameters (Goldstein, 1987). Two-level models were also used to estimate the R28 2.3data Results and statistically evaluates the shape of the curve. Iterative generalized least squares were used to R29 groups’ adult stat status at 22 years of age (intercept = age - 22). estimate the model’s parameters (Goldstein, 1987). Two-level models were also used to estimate the R30 2.3.1 Assessment of Interexaminer and Intraexaminer Variation R31 groups’ adult stat status at 22 years of age (intercept = age - 22). ICC values for intraobserver reliability were excellent (Table 2.2). The ICC values for interobserver R32 R33 reliability2.3 Results were fair to excellent (Table 2.2): Fair to good reliability was found for measurements R34 concerning the inclination of the maxilla and point B relative to the cranial base and LFH, and all R35 the 2.32.3.1other Results Assessment measurements of Interexaminer showed excellent and Intraexaminerreliability. Variation R36 R37 2.3.1ICC values Assessment for intraobserver of Interexaminer reliability andwere Intraexaminerexcellent (Table Variation2.2). The ICC values for interobserver R38 reliability were fair to excellent (Table 2.2): Fair to good reliability was found for measurements R39 ICC values for intraobserver reliability were excellent (Table 2.2). The ICC values for interobserver concerning the inclination of the maxilla and point B relative to the cranial base and LFH, and all the reliability were fair toFacial excellent Growth in (Table Patients 2.2): With Fair Apert to and good Crouzon reliability Syndromes was Compared found forto Normal measurements Children | 37 other measurements showed excellent reliability. concerning the inclination of the maxilla and point B relative to the cranial base and LFH, and all the

other measurements showed excellent reliability.

2.3.2 Growth Models

2.3.2Control Growth Subjects Models

Control Subjects 47

R1 2.3.2 Growth Models R2 Control Subjects R3 Multilevel modeling (Table 2.3; Figs. 2.2 to 2.7) showed that the growth curves ranged from no R4 growth change (constant term only) to complex, third-order changes. The fixed terms of each R5 model were used to estimate the craniofacial values between 5 and 15 years of age. For example, R6 the SNB angle for control boys was 75.95 degrees at 10 years of age, computed as 70.59 + R7 (0.2157 x 4). The linear term 0.2157 (the yearly change) for control boys was multiplied by 4 R8 R9 instead of 10 because the intercept was set to 6 years of age. The SNA angle was not significantly R10 different between boys and girls and did not change significantly over time. The LFH ratio, which R11 also showed no statistically significant gender differences, decreased up to approximately 12 R12 years of age and then increased slightly until age 15. While the SN/PP angle for boys showed R13 no change over time, it increased slightly from 5 to 15 years of age in girls, at which point it R14 approximated the values seen for boys. The SNB angles increased for both genders, but girls R15 displayed a significantly greater yearly increase than boys. The ANB angle of girls decreased R16 steadily (0.18 deg/y), whereas the boys’ rate of decrease decelerated over time. Of all the angular R17 measurements, the ANB angle showed the greatest change during growth. R18 R19 Untreated Patients With Crouzon Syndrome R20 The patients with Crouzon syndrome showed statistically significant gender differences for all R21 measurements except for the LFH ratio (Table 2.4; Figs. 2.2 through 2.7), which was larger than R22 control values at all ages. The NSMe angle for patients with Crouzon syndrome, which remained R23 R24 constant for girls and decreased slightly for boys, remained within the normal limits seen in the R25 control participants. The SNA angle was significantly smaller in patients with Crouzon syndrome R26 than in controls; the female SNA angle increased slightly, and the male angle remained constant. R27 The SNB angle was larger in patients with Crouzon syndrome than in controls at all ages, with R28 boys increasing at a greater rate than girls. The ANB angle of patients with Crouzon syndrome R29 was significantly smaller than that of controls. The SN/PP angle was significantly smaller for R30 patients with Crouzon syndrome than controls, with this difference remaining constant for boys R31 and increasing for girls. R32 R33 R34 R35 R36 R37 R38 R39

38 | Chapter 2 R1 R2 R3 3.489e+0 2.812e+0 2.095e+0 3.263e+0 3.333e+0 3.576e+0 3.082e+0 SD 2.214e+0 3.228e+0 Between Subjects R4 R5 2 R6 ------R7 R8 R9 R10 ------Estimate SE Cubic - R11 R12 R13 ------R14 R15 R16 R17 - - - Estimate SE Quadratic R18 R19 R20 - - - R21 R22 R23 R24 Estimate SE Linear R25 R26 R27 R28 R29 R30 R31 7.070e+1 2.938e-1 9.641e-2 5.481e-2 -1.911e-2 5.807e-3 - 8.027e+0 2.363e-1 7.802e-2 2.132e-2 - 5.324e+0 1.776e-1 -1.794e-1 1.670e-2 - 7.459e+1 3.017e-1 3.230e-1 3.701e-2 - 8.048e+1 2.691e-1 - 7.071e+1 2.955e-1 -2.415e-3 6.504e-2 -3.635e-2 1.916e-2 4.031e-3 1.717e-3 3.447e+0 8.023e+1 3.050e-1 - 8.075e+0 2.499e-1 - Estimate SE 5.293e+0 2.084e-1 -3.347e-1 5.004e-2 2.022e-2 5.465e-3 - Constant 7.509e+1 3.334e-1 2.157e-1 4.847e-2 - R32 R33 R34

# R35 LFH Ratio 5.883e+1 1.961e-1 -5.089e-1 6.404e-2 2.258e-3 1.754e-2 4.044e-3 1.486e-3 2.224e+0 NSMe SN/PP ANB SNB LFH Ratio 5.928e+1 1.947e-1 -5.004e-1 5.554e-2 -1.875e-3 1.626e-2 3.657e-3 1.453e-3 2.165e+0 SNB NSMe SN/PP ANB R36 = 7.509e+1 + (2.157e-1 x 4) Multilevel models for growing untreated male and female controls. ♂ R37 R38 Females SNA Males SNA Gender Measurements Fixed Explanatory Variables* *Constant = age 6 years; - not statistically significant. #SNB10 Table 2.3 Table R39

Facial Growth in Patients With Apert and Crouzon Syndromes Compared to Normal Children | 39 R1 R2 R3 4.497e+0 4.912e+0 7.175e-1 5.999e+0 4.424e+0 4.990e+0 2.892e+0 5.708e+0 7.041e+0 4.831e+0 5.925e+0 5.675e+0 R4 Between Subjects R5 ------R6 - R7 R8 ------R9 Cubic R10 R11 ------R12 - R13 R14 ------Estimate SE Estimate SE SD R15 Quadratic R16 R17 R18 ------R19 R20 R21 Linear R22 Estimate SE R23 R24 R25 R26 R27 R28 R29 6.363e+1 1.298e+0 - 6.978e+1 1.405e+0 - 5.792e+0 2.263e+0 -8.928e-1 2.587e-1 - -7.693e+0 1.723e+0 - 7.852e+1 1.362e+0 2.880e-1 1.428e-1 - 7.159e+1 1.706e+0 4.334e-2 2.353e-1 - 6.369e+1 6.636e-1 - 7.125e+1 1.537e+0 -4.564e-1 1.561e-1 - 4.488e+0 1.615e+0 - -4.514e+0 1.356e+0 -7.167e-1 1.511e-1 - 7.630e+1 1.541e+0 6.958e-1 1.413e-1 - 7.165e+1 1.373e+0 - Constant R30 Estimate SE R31 R32 R33 R34 LFH Ratio NSMe SN/PP ANB SNB SNA LFH Ratio NSMe SN/PP ANB SNB SNA Measurements Fixed Explanatory Variables R35 R36 Multilevel models for growing untreated male and female patients with Crouzon syndrome. R37 R38 Females Males Gender Constant = age 6 years; - not statistically significant. R39 2.4 Table

40 | Chapter 2 R1 R2 R3 R4 R5 2 R6 R7 R8 R9 R10 R11 Figure 2.2a girls SNA angles for untreated patients with Apert (▲) and Crouzon (■) syndrome and control R12 subjects (●). R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24

Figure 2.2b boys SNA angles for untreated patients with Apert (▲) and Crouzon (■) syndrome and control R25 subjects (●). R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 Figure 2.3a girls SNB angles for untreated patients with Apert (▲) and Crouzon (■) syndrome and control R38 subjects (●). R39

Facial Growth in Patients With Apert and Crouzon Syndromes Compared to Normal Children | 41 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 Figure 2.3b boys SNB angles for untreated patients with Apert (▲) and Crouzon (■) syndrome and control R12 subjects (●). R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 Figure 2.4a girls ANB angles for untreated patients with Apert (▲) and Crouzon (■) syndrome and control subjects (●). R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 Figure 2.4b boys ANB angles for untreated patients with Apert (▲) and Crouzon (■) syndrome and control R37 subjects (●). R38 R39

42 | Chapter 2 R1 R2 R3 R4 R5 2 R6 R7 R8 R9 R10 Figure 2.5a girls SN/PP angles for untreated patients with Apert (▲) and Crouzon (■) syndrome and control R11 subjects (●). R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 Figure 2.5b boys SN/PP angles for untreated patients with Apert (▲) and Crouzon (■) syndrome and control R24 subjects (●). R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 Figure 2.6a girls NSMe angles for untreated patients with Apert (▲) and Crouzon (■) syndrome and control R37 subjects (●). R38 R39

Facial Growth in Patients With Apert and Crouzon Syndromes Compared to Normal Children | 43 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 Figure 2.6b boys NSMe angles for untreated patients with Apert (▲) and Crouzon (■) syndrome and control R12 subjects (●). R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 Figure 2.7a girls LFH ratio for untreated patients with Apert (▲) and Crouzon (■) syndrome and control R25 subjects (●). R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36

R37 Figure 2.7b boys LFH ratio for untreated patients with Apert (▲) and Crouzon (■) syndrome and control R38 subjects (●). R39

44 | Chapter 2 Untreated Patients With Apert Syndrome R1 Patients with Apert syndrome showed statistically significant gender differences for all R2 measurements except for SNA angle (Table 2.5; Figs. 2.2 through 2.7). SNA angle was significantly R3 R4 smaller than in controls at all ages, with the differences increasing with age. SNB angle in patients R5 with Apert syndrome was significantly larger than SNB angle in control participants, with these 2 R6 differences increasing during childhood and decreasing during adolescence. For both boys and R7 girls, differences in the ANB angle between patients with Apert syndrome and controls increased R8 over time, i.e., the Apert patients developed a more severe Angle Class III malocclusion. The SN/PP R9 angle in patients with Apert syndrome was significantly smaller than the SN/PP angle in controls, R10 with differences increasing between the ages of 5 to 15 years. The NSMe angle for patients with R11 Apert syndrome remained within the limits of the control subjects. The LFH ratio for patients R12 with Apert syndrome was significantly larger at all ages, with differences increasing in boys and R13 decreasing slightly in girls with increasing age. R14 R15 Comparison of Untreated Patients With Crouzon Syndrome and Untreated Patients With Apert R16 Syndrome R17 Growing patients with Apert syndrome showed more complex growth changes than patients R18 R19 with Crouzon syndrome (Tables 2.4 and 2.5; Figs. 2.2 through 2.7). The SNA, SNB, ANB, and SN/ R20 PP angles were all significantly smaller in patients with Apert syndrome than those with Crouzon R21 syndrome; the differences increased over time for all four angles. The LFH ratio was significantly R22 larger for patients with Apert syndrome than those with Crouzon syndrome. The NSMe angle R23 was larger for patients with Apert syndrome than for patients with Crouzon syndrome; these R24 differences were small but statistically significant. R25 R26 Comparison of Control Subjects With Untreated Adult Patients With Crouzon and Apert R27 Syndromes R28 Differences between adult controls and untreated adult syndromic patients were found for SNA, R29 ANB, SN/PP angles, and LFH ratio (Table 2.6). The SNA, ANB, and SN/PP angles showed higher R30 values for controls, while the LFH ratio was larger for syndromic patients. The NSMe and SNB R31 angles were not significantly different between controls and syndromic patients. Patients with R32 Crouzon syndrome had significantly larger SNA angles and smaller values for the LFH ratio than R33 R34 patients with Apert syndrome. Gender differences were observed only for the ANB and SN/PP R35 angles; male patients with Apert syndrome had significantly smaller ANB and SN/PP angles than R36 male patients with Crouzon syndrome. Female patients with Apert and Crouzon syndrome did R37 not differ. The SNB and NSMe angles showed no significant differences between the syndrome R38 groups. R39

Facial Growth in Patients With Apert and Crouzon Syndromes Compared to Normal Children | 45 R1 R2 R3 3.685e+0 3.578e+0 3.763e+0 2.400e+0 2.756e+0 3.300e+0 4.593e+0 4.290e+0 4.569e+0 5.190e+0 SD Between subjects R4 R5 R6 ------R7 - R8 R9 - - - - - Estimate SE R10 Cubic R11 R12 - - - - R13 - R14 R15 R16 Estimate SE Quadratic R17 R18 R19 R20 R21 R22 Estimate SE R23 Linear R24 R25 R26 R27 R28 R29 7.142e+1 9.659e-1 -5.612e-1 1.829e-1 6.658e-2 2.296e-2 - -8.351e+0 1.444e+0 -2.491e+0 4.009e-1 5.570e-1 1.448e-1 -3.286e-2 1.120e-2 5.081e+0 -8.436e+0 1.139e+0 -5.226e-1 1.304e-1 - 7.785e+1 7.976e-1 1.565e+0 3.052e-1 -3.652e-1 1.090e-1 2.246e-2 9.030e-3 2.440e+0 6.868e+1 9.560e-1 5.967e-1 3.752e-1 -1.192e-1 4.753e-2 - 7.286e+1 1.585e+0 -3.376e-1 1.555e-1 - -9.531e+0 2.120e+0 -7.351e-1 1.878e-1 - -5.153e+0 1.908e+0 -1.243e+0 1.592e-1 - 7.421e+1 1.264e+0 1.658e+0 5.297e-1 -1.325e-1 6.125e-2 - 6.891e+1 2.277e+0 4.399e-1 4.288e-1 -1.231e-1 5.082e-2 - Estimate SE R30 Constant R31 R32 R33 LFH ratio 7.377e+1 1.107e+0 3.302e-1 3.080e-1 -8.111e-2 3.881e-2 - NSMe SN/PP ANB SNB SNA LFH ratio 7.222e+1 1.340e+0 5.044e-1 1.345e-1 - NSMe SN/PP ANB SNB SNA R34 Measurement Fixed Explanatory Variables R35 R36 Multilevel models for growing untreated male and female patients with Apert syndrome. R37 R38 Females Males Gender Constant = age 6 years; - not statistically significant. R39 2.5 Table

46 | Chapter 2 Table 2.6 Multilevel models for untreated control, Crouzon and Apert adults. R1 Controls Crouzon Apert R2 Gender Measurements Estimate SD Estimate SD Estimate SD R3 SNA 8.127e+1 3.423e+0 6.993e+1 7.085 e+0 5.960e+1 3.586 e+0 R4 Males SNB 7.900e+1 3.361 e+0 8.016e+1 5.268 e+0 7.848e+1 2.880 e+0 R5 ANB 2.291e+0 2.689 e+0 -1.069e+1 4.011 e+0 -1.888e-1 3.685 e+0 SN/PP 8.498e+0 3.145 e+0 2.220e-1 9.680 e+0 -1.582e+1 3.314 e+0 2 R6 NSMe 6.857e+1 3.031 e+0 6.864e+1 4.454 e+0 7.164e+1 4.459 e+0 R7 LAFH 5.668e+1 2.647 e+0 6.341e+1 2.177 e+0 7.624e+1 3.384 e+0 R8 SN 7.487e+1 3.239e+0 5.253e+1 3.157e+0 5.547e+1 1. 570e+0 R9 TAFH 1.197e+2 6.393e+0 9.438e+1 4.229e+0 1.001e+2 5.567e+0 SNA 8.097e+1 3.981 e+0 8.097e+1 3.981 e+0 8.097e+1 3.981 e+0 R10 Females SNB 7.808e+1 3.785 e+0 7.808e+1 3.785 e+0 7.808e+1 3.785 e+0 R11 ANB 2.749e+0 2.610 e+0 2.749e+0 2.610 e+0 2.749e+0 2.610 e+0 R12 SN/PP 8.600e+0 3.407 e+0 8.600e+0 3.407 e+0 8.600e+0 3.407 e+0 R13 NSMe 6.855e+1 8.698 e+0 6.855e+1 8.698 e+0 6.855e+1 8.698 e+0 LAFH 5.694e+1 2.564 e+0 5.694e+1 2.564 e+0 5.694e+1 2.564 e+0 R14 SN 6.935e+1 2.459e+0 5.108e+1 1.633e+0 5.299e+1 9.689e+1 R15 TAFH 1.143e+2 5.029e+0 9.584e+1 1.810e+0 1.697e+0 4.137e+0 R16

Constant = age 22 years. R17 R18 R19 R20 2.4 Discussion R21 R22 Multilevel modeling is an important tool for the analysis of longitudinal cephalometric data. This R23 model has important advantages compared to other longitudinal statistical analysis procedures. It R24 can describe both individual and average growth curves; it is flexible because it uses polynomials, R25 which can describe growth curves of almost any form. Additionally, the model can handle missing R26 values very easily (without loss of complete cases). Finally, the model can be used with different R27 sample and research designs (Hoeksma and Van der Beek, 1991). R28 Premature fusion of craniofacial sutures results in midface retrusion in patients with Crouzon R29 and Apert syndromes. Lack of sutural growth of the maxilla and an abnormal remodeling pattern R30 result in a maxilla that is small in three planes of space (Kreiborg and Aduss, 1986). There is almost R31 a complete absence of anterior maxillary displacement in relation to the anterior cranial base R32 during growth (Kreiborg and Aduss, 1986). In this study, patients with Apert syndrome showed R33 R34 smaller SNA angle values compared to patients with Crouzon syndrome (Fig. 2.2; Tables 2.4 and R35 2.5); this finding is in agreement with other studies (Bachmayer et al., 1986; Kreiborg and Cohen, R36 1998; Kreiborg et al., 1999). More craniofacial sutures are fused at birth in patients with Apert R37 syndrome, whereas patients with Crouzon syndrome sometimes show open craniofacial sutures. R38 R39

Facial Growth in Patients With Apert and Crouzon Syndromes Compared to Normal Children | 47 R1 The synostosis of these sutures for Crouzon patients is often progressive during growth (Renier et R2 al., 2000; Connolly et al., 2004), which might influence sagittal growth in the syndromic patient. R3 The mandible in patients with Crouzon and Apert syndromes showed an anterior rotation R4 that produced an Angle Class III malocclusion (Figs. 2.3 and 2.4); this increasing mandibular R5 rotation during growth has been reported previously in cross-sectional studies (Bachmayer et R6 al., 1986; Cohen and Kreiborg, 1996; Kreiborg and Cohen, 1998; Kreiborg et al., 1999). The R7 sagittal growth of the mandible for the syndromic groups was similar to that seen in controls R8 R9 (Fig. 2.3). In contrast to the near absence of sagittal growth of the maxilla, the growth rate of the R10 mandible is fairly normal, resulting in a prognathic appearance in relation to the anterior cranial R11 base as a result of retrusion of the midface (Bachmayer et al., 1986; Kreiborg and Aduss, 1986); R12 this growth pattern increases the discrepancy between the maxilla and the mandible (Fig. 2.4). R13 However, controversy exists as to whether the mandible is normal in size and shape (Costaras- R14 Volarich and Pruzansky, 1984; Kreiborg and Aduss, 1986; Bachmayer et al., 1986; Carinci et al., R15 1994). A reduced mandible would result in a less severe Angle Class III malocclusion. R16 The palatal plane showed an increasing counterclockwise rotation in relation to the anterior R17 cranial base (Fig. 2.5). Other studies also found a relatively large amount of vertical maxillary R18 growth and virtually no sagittal growth (Bachmayer et al., 1986; Kreiborg and Aduss, 1986; R19 Carinci et al., 1994; Meazzini et al., 2005). Controversy exists concerning vertical maxillary R20 growth following early midfacial surgery (Fearon, 2005; Meazzini et al., 2005). Kreiborg and R21 Aduss showed large vertical maxillary growth in a small maxillary superimposition study (n = 8) R22 using metallic implants (Kreiborg and Aduss, 1986). However, the vertical growth was attributed R23 R24 to remodeling and appositional growth, whereas no sutural growth took place. R25 Conclusions should be drawn with care for several reasons. First, the low incidence of R26 patients with Crouzon and Apert syndromes makes it difficult to collect data from a large patient R27 population. Most studies evaluating presurgical growth have been cross-sectional in design; only R28 a few studies on craniofacial growth of Crouzon and Apert patients have examined samples R29 larger than 10 patients (Bachmayer et al., 1986; Cohen and Kreiborg, 1996; Kreiborg and Cohen, R30 1998; Kreiborg et al., 1999). From a statistical viewpoint, the sample size of the present study was R31 not large. However, given the prevalence of these syndromes and in comparison to other studies, R32 the sample size of untreated Crouzon and Apert syndrome patients is acceptable. R33 Second, the cranial base (basion [Ba]-S-N) in patients with Crouzon and Apert syndromes R34 is reported to be 12% to 15% shorter in all directions, with a shape comparable to that seen R35 in the normal population (Cohen, 1986; Kreiborg and Aduss, 1986). Sagittal shortening of the R36 cranial base is probably caused by diminished growth of the spheno-occipital synchondrosis and R37 sphenofrontal suture. The sphenoid bone, part of the anterior cranial base, is often reduced R38 R39

48 | Chapter 2 because of diminished growth of the sphenooccipital synchondrosis and sphenofrontal suture R1 (Kreiborg et al., 1999). The SN value was significantly smaller for patients with Crouzon and Apert R2 syndromes compared to controls (Table 2.6). A short cranial base means that the mandibular R3 R4 condyle is placed more forward and a skeletal Angle Class III. A relatively more distally placed R5 N will disguise a severe underlying skeletal Angle Class III. Other geometric effects of the used 2 R6 cephalometric points, like the vertical lengths N to A and N to B, will also distort an underlying R7 skeletal discrepancy (Jacobson, 1975; Cohen and Kreiborg, 1996; Posnick and Ruiz, 2000). R8 Third, the validity of any measurement obtained through a cephalometric radiograph depends R9 largely on the reproducibility of the cephalometric landmarks. Factors such as the quality of the R10 radiographs, the conditions under which they are measured, and the care and skill of the operator R11 will influence the magnitude of identification error. For this reason, it has been suggested that R12 every study should include an assessment of reproducibility, even though standard measurements R13 are used (Houston, 1983). The skeletal morphology of patients with Crouzon and Apert syndromes R14 is different from that of a normal population, but it has been shown that extreme variations in R15 skeletal morphology do not affect the accuracy of cephalometric evaluation (Wah et al., 1995). R16 In a meta-analysis of landmark identification and reproducibility in nonsyndromic patients, it was R17 concluded that 0.6 mm of total error in the x- or y-axis was acceptable (Trpkova et al., 1997). The R18 R19 cephalometric landmarks chosen in this study had even smaller total error for reproducibility in R20 the x- or y-axis (Fig. 2.1; Tables 2.1 and 2.2). R21 Fourth, intraobserver and interobserver reliability for digitization of cephalometric R22 measurements was sufficient, except for the interobserver reliability measurements of the SN/PP R23 angle. Difficulties in landmark identification for the palatal plane and point A may be a result of R24 tooth germs, erupting teeth, and the radiolucent immature skeleton (Hotz and Gnoinski, 1976). R25 Finally, early surgical treatment of the midface is sometimes performed because of functional R26 indications or a patient’s poor self-image (Reid, 2007). The paucity of data from patients who R27 undergo midfacial surgery at an early age (6 to 9 years of age) and the lack of adolescent data for R28 these syndrome patients may influence the data available in the literature. In this study, the few R29 data from adult syndromic patients were not considered to have much validity; however, it seems R30 that limited growth occurred after 15 years of age. R31 Given the aforementioned difficulties, caution with the interpretation of cephalometric R32 findings is advised. Multilevel modeling is useful for the construction of growth curves for R33 R34 patients with Apert and Crouzon syndromes to describe and predict development over time for R35 a particular outcome variable. The data for patients with Crouzon and Apert syndrome clearly R36 show growth at adolescence. Therefore, caution with midfacial surgical interventions in growing R37 patients should be exercised because of possible impairment of postsurgical facial growth. The R38 R39

Facial Growth in Patients With Apert and Crouzon Syndromes Compared to Normal Children | 49 R1 prediction accuracy for the measurements used in this study might improve with the collection R2 of more data. Individual variations in growth in syndromic patients are observed; however, there R3 is a lack of knowledge concerning the prediction of facial skeletal growth development in the R4 individual patient. R5 R6 R7 2.5 Conclusion R8 R9 R10 The craniofacial growth analysis data presented here showed marked and significant differences R11 in sagittal and vertical growth in patients with Apert and Crouzon syndromes. In general, R12 abnormal craniofacial morphology was more severe in Apert syndrome than in Crouzon R13 syndrome. The maxilla in syndromic patients is more retruded and restrained in sagittal than R14 in vertical growth. Fairly normal mandibular growth results in an anterior rotation and a more R15 severe maxillomandibular discrepancy during adolescence. However, vertical maxillary growth is R16 not restrained by growth; therefore a counterclockwise rotation of the palatal plane in relation to R17 the anterior cranial base can be expected. R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

50 | Chapter 2 2.6 References R1 R2 Bachmayer DI, Ross RB, Munro IR. Maxillary growth following LeFort III advancement surgery in Crouzon, R3 Apert, and Pfeiffer syndromes. Am J Orthod Dentofacial Orthop. 1986;90:420–430. R4 Bachmayer DI, Ross RB. Stability of Le Fort III advancement surgery in children with Crouzon’s, Apert’s, and Pfeiffer’s syndromes. Cleft Palate J. 1986;23(suppl 1):69–74. R5 Carinci F, Avantaggiato A, Curioni C. Crouzon syndrome: cephalometric analysis and evaluation of 2 R6 pathogenesis. Cleft Palate Craniofac J 1994;31:201–209. R7 Carinci F, Pezzetti F, Locci P, Becchetti E, Carls F, Avantaggiato A, Becchetti A, Carinci P, Baroni T, Bodo R8 M. Apert and Crouzon syndromes: clinical findings, genes and extracellular matrix. J Craniofac Surg. 2005;16:361–368. R9 Cohen MM Jr, ed. Craniosynostosis: Diagnosis, Evaluation, and Management. New York: Raven Press; 1986. R10 Cohen MM Jr, Kreiborg S. A clinical study of the craniofacial features in Apert syndrome. Int J Oral Maxillofac R11 Surg. 1996;25:45–53. R12 Connolly JP, Gruss J, Seto ML, Whelan MF, Ellenbogen R, Weiss A, Buchman SR, Cunningham ML. Progressive R13 postnatal craniosynostosis and increased intracranial pressure. Plast Reconstr Surg. 2004;113:1313– 1323. R14 Costaras-Volarich M, Pruzansky S. Is the mandible intrinsically different in Apert and Crouzon syndromes? Am R15 J Orthod. 1984;85:475–487. R16 Dahlberg G. Statistical Methods for Medical and Biological Students. New York: Interscience Publications; R17 1940. R18 Fearon JA. Halo distraction of the Le Fort III in syndromic craniosynostosis: a long-term assessment. Plast Reconstr Surg. 2005;115:1524–1536. R19 Goldstein H. Multilevel Models in Educational and Social Research. London: Oxford University Press; 1987. R20 Hoeksma JB, van der Beek MC. Multilevel modelling of longitudinal cephalometric data explained for R21 orthodontists. Eur J Orthod. 1991;13:197–201. R22 Houston WJ. The analysis of errors in orthodontic measurements. Am J Orthod. 1983;83:382–390. R23 Hotz M, Gnoinski W. Comprehensive care of cleft lip and palate children at Zürich: a preliminary report. Am J Orthod. 1976;70:481–504. R24 Jacobson A. The ‘‘Wits’’ appraisal of jaw disharmony. Am J Orthod. 1975;67:125–138. R25 Kreiborg S, Aduss H. Pre- and postsurgical facial growth in patients with Crouzon’s and Apert’s syndromes. R26 Cleft Palate J. 1986;23(suppl 1):78–90. R27 Kreiborg S, Cohen MM Jr. Is craniofacial morphology in Apert and Crouzon syndromes the same? Acta R28 Odontol Scand. 1998;56:339–341. Kreiborg S, Aduss H, Cohen MM Jr. Cephalometric study of the Apert syndrome in adolescence and adulthood. R29 J Craniofac Genet Dev Biol. 1999;19:1–11. R30 Marsh JL, Galic M, Vannier MW. The craniofacial anatomy of Apert syndrome. Clin Plast Surg. 1991;18:237– R31 249. R32 MeazziniMC, Mazzoleni F, Caronni E, Bozetti A. Le Fort III advancement osteotomy in the growing child affected by Crouzon’s and Apert’s syndromes: presurgical and postsurgical growth. J Craniofac Surg. R33 2005;16:369–377. R34 Posnick JC, Ruiz RL. The craniofacial synostosis syndromes: current surgical thinking and future directions. R35 Cleft Palate Craniofac J. 2000;37:433. R36 Prahl-Andersen B, Kowalski CJ, Heyendaal PHJM. A Mixed-Longitudinal Interdisciplinary Study of Growth and Development. New York: Academic Press; 1979. R37 R38 R39

Facial Growth in Patients With Apert and Crouzon Syndromes Compared to Normal Children | 51 Prahl-Andersen B. Controversies in the management of craniofacial malformations. Semin Orthod. R1 2005;11:67–75. R2 Reid RR. Facial skeletal growth and timing of surgical intervention. Clin Plast Surg. 2007;34:357–367. R3 Renier D, Lajeunie E, Arnaud E, Marchac D. Management of craniosynostosis. Childs Nerv Syst. 2000;16:645– R4 658. R5 Shrout PE, Fleiss JL. Intraclass correlations: uses in assessing rater reliability. Psychol Bull. 1979;86:420–428. R6 Trpkova B, Major P, Prasad N, Nebbe B. Cephalometric landmarks identification and reproducibility: a meta- analysis. Am J Orthod Dentofac Orthop. 1997;112:165–170. R7 Turvey TA, Vig KWL, Fonseca RJ. Facial Clefts and Craniosynostosis: Principles and Management. Philadelphia: R8 WB Saunders; 1996:630–631. R9 Wah PL, Cooke MS, Hägg U. Comparative cephalometric errors for orthodontic and surgical patients. Int J R10 Adult Orthodon Orthognath Surg. 1995;10:119–126. R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

52 | Chapter 2 Chapter 3

Mandibular Asymmetry in Patients With the

Syndrome of Crouzon or Apert

Poejan Elmi Jacobus H. Reitsma Peter H. Buschang Eppo B. Wolvius Edwin M. Ongkosuwito

Cleft Palate Craniofacial Journal (submitted) R1 Abstract R2

R3 Purpose: The aim of this study was to describe directional and fluctuating mandibular asymmetry R4 in children with Crouzon or Apert syndrome over time. R5 R6 Patients and Methods: Mandibular asymmetry of children between 7.5 and 14 years of age R7 with the Crouzon syndrome (n = 35) and Apert syndrome (n = 24) were compared with controls R8 R9 (n = 327). From panoramic radiographs, mandibular directional and fluctuating asymmetry R10 was determined for the three groups. Multilevel statistical techniques were used to describe R11 mandibular asymmetry changes over time. R12 R13 Results: Patients with Crouzon and Apert syndromes showed statistically significant more R14 fluctuating asymmetry for mandibular measures than controls. Between the Crouzon and Apert R15 syndromes, no statistical differences were found in directional and fluctuating asymmetry. The R16 control group showed statistically significant more directional asymmetry than patients with R17 Crouzon or Apert syndrome. Controls showed for condylar-ramal height no change over time for R18 directional asymmetry, while the directional asymmetry for the gonial angle increased. Patients R19 with Crouzon syndrome showed only side dominance for the condylar-ramal height, whereas R20 patients with Apert syndrome did not show dominance for any of the measurements. R21 R22 Conclusions: Apert and Crouzon syndromes showed developmental instability in contrast to the R23 R24 controls. No statistically significant longitudinal differences were found for both directional and R25 fluctuating asymmetry between Crouzon and Apert syndromes. Findings for fluctuating and R26 directional asymmetry for both syndromes may indicate an inability to cope with genetic and R27 environmental stress during development and treatment compared to nonsyndromic individuals. R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

54 | Chapter 3 3.1 Introduction R1 R2

Development of facial symmetry in children with premature closure of one or more craniofacial R3 R4 sutures (craniosynostosis) has not been well studied. Facial symmetry is most commonly R5 associated with a state of facial equilibrium, in which there is correspondence in size, shape, and R6 arrangement of facial landmarks on both sides of the face (Peck et al., 1991). Many studies have R7 demonstrated a certain asymmetry of structures as a naturally biological occurring phenomenon R8 (Woo, 1931; Thompson, 1943; Melnik, 1992). Asymmetry is measured as the left minus the 3 R9 right value of a structure. Some authors suggest that a difference of sides between 3-5 percent R10 may be a normal population mean (Skvarilova 1993, Farkas and Cheung 1981). The point where R11 normal asymmetry becomes abnormal cannot easily be defined because no standard outcome R12 measurements for normal and abnormal asymmetry exists (Liukkonen et al., 2005; Kambylafkas R13 et al., 2006). Asymmetry from bilateral structures can be distinguished in two different R14 categories (Fig. 3.1, Table 3.1) (Van Valen, 1962). The first category includes two different types R15 of asymmetry; directional asymmetry and antisymmetry. For directional asymmetry there is a R16 systematic difference, with one side being consistently larger or dominant than the other (Fig. 1a, R17 Table 1) (Van Valen, 1962; Liukkonen et al., 2005). Most individuals are asymmetrical either to the R18 R19 left or right side (>95%). In contrast, antisymmetry is when the left and right side of individuals R20 are almost equally present in a sample. The mean of the total population is centered around R21 zero (Fig. 3.1b, Table 3.1) (Van Valen, 1962). Presumably these two types of asymmetry produce R22 growth discrepancies and have a genetic basis (Van Valen, 1962). R23 In contrast, fluctuating asymmetry can also occur (Fig. 3.1c) (Van Valen, 1962). Fluctuating R24 asymmetry (the second category of asymmetry), refers to random deviations from perfect symmetry R25 in bilateral structures and is frequently used as a measurement of developmental instability (Van R26 Valen, 1962; Adams and Niswander, 1967; DeLeon and Richtsmeier, 2009; Swaddle, 2003). R27 The degree of fluctuating asymmetry during growth and medical treatment may reflect R28 developmental instability caused by stress (Van Valen, 1962; Adams and Niswander, 1967; R29 DeLeon and Richtsmeier, 2009; Swaddle, 2003). The amount of stress experienced by individuals R30 during growth may increase by physical impact or mental limitations (Adams and Niswander, R31 1967; Van Valen, 1962). Both the directional and fluctuating asymmetry of craniofacial structures R32 have been measured (Melnik, 1992; DeLeon and Richtsmeier, 2009). R33 R34 R35 R36 R37 R38 R39

Mandibular Asymmetry in Patients With the Syndrome of Crouzon or Apert | 55 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 Fluctuating asymmetry is characterized perfect symmetry by small deviation from is frequently FA in bilateral structures. of developmental used as a measurement caused by minor instability during the growth or genetic deviations environmental = | L - R / [(L + R) 2] FA between the left is the absolute difference FA of The differences and right side of a character. the right and left sides having a mean of zero with normal variation Only positive values possible R12 Fluctuating asymmetry (FA) R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 Anitsymmetry is a different rare type of DA. rare Anitsymmetry is a different around AS is characterized by being centred is almost there However, a mean of zero. a equally distribution of left- and right side population in the same group, AS = (L – R) / [(L + 2] The mean of left minus right side is zero in normal population with non-normal distribution (usually bimodal) Positive or negative values possible R23 Antisymmetry (AS) R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 DA = (L – R) / [(L + 2] or a The mean of left minus right side is zero, either left or right side in small deviation toward normal population Positive or negative values possible Directional asymmetry is characterized by a Directional around symmetry distribution that is not centred either on but is biased significantly toward zero used the left or right side. DA is frequently of developmental precision as a measurement and is caused primarily by genetic deviations R35 asymmetry (DA) Directional

R36 antisymmetry and fluctuating. L = left side, R right side Definition and distribution of directional asymmetry, R37 R38 Formula Distribution Values Definition R39 3.1 Table

56 | Chapter 3 During growth in normal children, both increases and decreases in directional asymmetry of R1 the mandible have been observed (Melnik, 1992). Dominance of both the left and right sides of R2 the mandible have been described (Vig and Hewitt, 1975; Peck et al., 1991). In normal children R3 R4 with developmental homeostatis, fluctuating asymmetry should be minimal (Fig. 3.1c, Table 3.1). R5 Decreased fluctuating asymmetry indicates that development is relatively stable and unaffected R6 by genetic or environmental distortions over time (Van Valen, 1962; Palmer and Strobeck, R7 1986; DeLeon and Richtsmeier, 2009). Developmental homeostasis can sometimes be distorted R8 during growth by minor developmental problems, resulting in increased fluctuating asymmetry. 3 R9 Developmental instability during normal growth is small if sufficient homeostasis or buffering R10 occurs (Palmer and Strobeck, 1986). R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 Figure 3.1 Three types of asymmetry: a) directional asymmetry, b) antisymmetry, c) fluctuating asymmetry R29 (Palmer and Strobeck, 1986). R30 Craniosynostosis associated with Crouzon syndrome (1 in 25,000 live births) and Apert R31 syndrome (1 in 60,000 live births) results in severe craniofacial dysmorphology (Cohen and R32 Kreiborg, 1992; Kreiborg and Cohen, 1998; Reardon et al., 1994). The craniosynostosis in these R33 R34 syndromes could indirectly influence the mandibular development and create asymmetries R35 (Costaras-Volarich and Pruzansky, 1984; Boutros et al., 2007). However, limited growth data R36 are available from patients with Crouzon or Apert syndrome due to their very low prevalence R37 (Costaras-Volarich and Pruzansky, 1984; Kreiborg and Cohen, 1998). More information about R38 R39

Mandibular Asymmetry in Patients With the Syndrome of Crouzon or Apert | 57 R1 asymmetry in patients with Crouzon or Apert syndrome is needed in order to better understand R2 how these patients react to environmental and genetic influences during growth. Therefore, the R3 aim of this study was to evaluate and to describe the development of directional and fluctuating R4 asymmetry in patients with Crouzon or Apert syndrome over time. R5 R6 R7 3.2 Materials and Methods R8 R9 R10 Sample preparation and radiographic scans R11 Panoramic radiographic data of 72 Caucasian patients (age range 3-33 years) with Crouzon R12 syndrome (25 boys and 17 girls) or Apert syndrome (11 boys and 19 girls) were collected from the R13 Craniofacial Center of the Erasmus MC, Sophia Children’s Hospital in Rotterdam, The Netherlands. R14 The clinical diagnosis of the syndromes was genetically confirmed (Table 3.2). From these data R15 only radiographs between 7.5 and 14 years of age were selected in order to compare the same R16 age range in nonsyndromic controls. The syndromic patients had undergone various surgical R17 and orthodontic interventions (no mandibular surgical procedures), both prior to the observation R18 period. The panoramic radiographs were taken according to the team protocol. Only radiographs R19 of diagnostic quality, taken before any mandibular surgery was performed, were used. At least R20 two panoramic radiographs from each patient were included. 35 panoramic radiographs were R21 excluded due to poor exposure. This resulted in a sample of 152 panoramic radiographs from 24 R22 patients with Apert syndrome (8 boys and 16 girls) and 35 patients with Crouzon syndrome (18 R23 R24 boys and 17 girls) born between 1970 – 2004. The patients had an average of 2.5 radiographs R25 (min. 2, max. 5, median 2) and the time-interval between the radiographs varied between 6.1 R26 months and 2.2 years. The use of data from human subjects followed an approved protocol and R27 satisfied the requirement of the IRB (approval number MEC-2010-304). R28 Control panoramic radiographs were obtained from normal children evaluated between R29 1971 and 1976 who participated in the mixed-longitudinal Nijmegen Growth Study. Only control R30 children with similar ages to the syndromic patients were used as controls (Prahl-Andersen et R31 al., 1979). The controls consist of three mixed-longitudinal cohorts who were followed for 5 R32 years, from 4 to 14 years of age. At the start of the study, the children were 4, 7, or 9 years of R33 age. A total of 2151 panoramic radiographs of 327 children (157 boys and 170 girls, age range R34 7.5-14 years) were selected. On average 6.5 radiographs (range 2 - 12, median 8) were used for R35 each individual, with a time interval of 6 months between every two radiographs. The control R36 radiographs were collected using a standardized procedure, using different panoramic machines: R37 Philips OrthOralix; Siemens Orthopantomograph and Siemens Orthophos. The magnification R38 R39

58 | Chapter 3 factor varied between 1.28 - 1.33. The conventional panoramic radiographs were scanned and R1 digitized for further analysis. R2 R3 R4 Table 3.2. Overview of the diagnostic genetic mutations in patients with Crouzon and Apert syndromes. Apert (n = 30) Crouzon (n = 42) R5 FGFR2 R6 P253R 12 R7 S252W 18 R8 A362T 3 R9 C278F 5 3 C342R 2 R10 C342T 2 R11 C342W 3 R12 C342Y 8 R13 G271V 1 G338R 1 R14 Q289P 3 R15 S267P 3 R16 S354C 2 R17 W290R 4 Y105C 1 R18 Y340H 3 R19 FGFR3 R20 A391 E 1 R21 R22 R23 3.2.1 Measurements R24 Twelve landmarks were digitized using Viewbox software (v3.1.1.14, D. Hal 1995-2006, Athens, R25 Greece) (Figs. 2a and 2b). Only angular and ratio measurements were used due to magnification R26 differences. An established method for measuring condylar and ramal asymmetry on panoramic R27 radiographs was used (Habets et al., 1987; Habets et al., 1988). The measurements have been R28 used for quantifying both directional and fluctuating asymmetry (Van Valen, 1962; Melnik, 1992; R29 Liukkonen et al., 2005) (Fig. 2). Condylar-ramal heights and the gonial angles were used to R30 calculate mandibular asymmetry based on the differences between the left (L) and right (R) sides. R31 Directional and fluctuating asymmetry were calculated according to the formulae in table 3.1. R32 R33 R34 R35 R36 R37 R38 R39

Mandibular Asymmetry in Patients With the Syndrome of Crouzon or Apert | 59 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 Figure 3.2 Mandibular landmarks, lines and measurements used for asymmetry (Habets et al., 1987). R14 Landmarks and lines: Co: most superior point of the condylar image; O1: most superior point of the condyle; O2: most lateral point of the ascending ramus; Go: Gonion; A point on the bony contour of the R15 mandibular angle determined by bisecting the line of the posterior border of the mandibular ramus and R16 the line of the lower border of the mandibular body angle; M1: most inferior point of the angulus on the R17 tangential line of the lower border of the mandibular body; M2: most inferior point of the ascending lower border of the mandible; RL-line: tangential line of the posterior border of the mandibular ramus trough the R18 points O1 and O2; ML-line: tangential line of the lower border of the mandibular body trough the points M1 R19 and M2. Measurements: 1,2. Condylar-ramal height left (L) and right (R); the distance between landmarks Condylion and Gonion; 3,4. Gonial angle left (L) and right (R); Angle in degrees between tangential line of R20 the posterior border of the mandibular ramus and tangential line of the lower border of the mandibular body R21 R22 3.2.2 Statistical Analysis R23 R24 Intra reliability R25 One investigator performed all of the measurements. Intra-examiner error for reproducibility R26 of the measurements was determined by retracing panoramic radiographs from 23 syndromic R27 patients (n = 107) and 20 control children (n = 122), with an interval of two weeks between R28 replicates. Interclass correlation coefficients were calculated (Shrout and Fleiss, 1979). For the R29 statistical analyses the SPSS software package (version 15.0, SPSS, Chicago, USA) was used. R30 R31 Growth Models R32 Orthogonal polynomials were used to model directional and fluctuating asymmetry over time. R33 The mathematical description of the procedure is given by Grizzle and Allen (Grizzle and Allen, R34 1969), and extended by Goldstein (Goldstein, 1986). The program MLwiN (version 2.1, Centre for R35 Multilevel Modelling, London, United Kingdom) was used to model growth changes and compare R36 the three groups. For each y variable (asymmetry measurement), a polynomial equation was R37 estimated for the patient (i) on the age of measurement (j). For each y variable of directional and R38 R39

60 | Chapter 3 fluctuating asymmetry (condylar-ramal height (Co-Go) and gonial angle (Gonang)) a polynomial R1 equation was estimated. The y intercept was adjusted to ten years of age (intercept = age 10) R2 to provide a comparison in the middle of the age range and to reduce the complexity of the R3 R4 computations. Average growth curves were estimated between 7.5 and 14 years of age. Due to R5 expected group differences, separate models were fitted for each group. A cubic model was first R6 fitted for each group and the highest-order term was checked for statistical significance, by using R7 the t-test. Statistical significance was determined by the standard errors of the estimates using a R8 0.05 level for statistical significance. If the term was not significant, it was removed and a new 3 R9 reduced model was fitted. As there were no statistically significant differences between the two R10 2 3 sexes, boys and girls were pooled.yij = The β0ij constantinitial equation + β1tij + βwas:2tij + β3tij R11 R12 with 2 3 yij = β0ijconstant + β1tij + β2tij + β3tij R13 with R14 β0ij = u0j + e0ij with R15 R16 The asymmetry growth measurement, y was computed by adding the intercept (b0ij) to the where the craniofacial growth measurement y was computed by adding the intercept (β0ij) to the β0ij = u0j + e0ij R17 products of other fixed coefficientsb ( 1, b2, and b3) multiplied by age (t) at each occasion. The u0j products of other fixed coefficients (β1 , β2, and β3) multiplied by age (t) at each occasion. The u0j and R18 and e0ij comprise the random portion of the model and are assumed to have means equal to zero, where the craniofacial growth measurement y was computed by adding the intercept (β0ij) to the R19 to bee0ij uncorrelatedcomprise the random and normally portion of distributed. the model and The are level assumed 1 residual to have e means represents equal to within-subjectzero, to be 0ij R20 variation,products or of the other “error” fixed coefficientsterm, while (β the1 , β level2, and 2 β residual3) multiplied u represents by age (t) at in each this occasion. case between-subject The u0j and uncorrelated, and to be normally distributed. The level 0j 1 residual e0ij represents within-subject R21 variatione0ij comprise (Goldstein, the random 1986). portion of the model and are assumed to have means equal to zero, to be variation, or the ‘‘error’’ term, while the level 2 residual u0j represents, in this case, between-subject R22

uncorrelated, and to be normally distributed. The level 1 residual e0ij represents within-subject R23 variation (Goldstein, 1987). The polynomial model takes full advantage of each patient’s individual longitudinal growth data R24 variation, or the ‘‘error’’ term, while the level 2 residual u0j represents, in this case, between-subject and statistically evaluates the shape of the curve. Iterative generalized least squares were used to R25 The polynomial model takes full advantage of each patient’s individual longitudinal growth estimatevariation the (Goldstein, model’s parameters1987). (Goldstein, 1986). R26 data and statistically evaluates the shape of the curve. Iterative generalized least squares were used to R27 The polynomial model takes full advantage of each patient’s individual longitudinal growth 3.3estimate Results the model’s parameters (Goldstein, 1987). Two-level models were also used to estimate the R28 data and statistically evaluates the shape of the curve. Iterative generalized least squares were used to R29 groups’ adult stat status at 22 years of age (intercept = age - 22). 3.3.1estimate Measurement the model’s errorparameters (Goldstein, 1987). Two-level models were also used to estimate the R30 The interclass correlation coefficient for intra-investigator reliability varied from 0.95 to 0.99 for R31 groups’ adult stat status at 22 years of age (intercept = age - 22). condylar-ramal height and gonial angle, respectively. R32 R33 2.3 Results R34 3.3.2 Growth models R35 Controls2.32.3.1 Results Assessment of Interexaminer and Intraexaminer Variation R36 The multilevel procedures showed that the growth followed simple models, ranging from ICC values for intraobserver reliability were excellent (Table 2.2). The ICC values for interobserver R37 constant2.3.1 Assessment(i.e. no growth) of Interexaminer to linear changes and Intraexaminer over time. The Variationfixed terms of each model were used R38 reliability were fair to excellent (Table 2.2): Fair to good reliability was found for measurements R39 ICC values for intraobserver reliability were excellent (Table 2.2). The ICC values for interobserver concerning the inclination of the maxilla and point B relative to the cranial base and LFH, and all the reliability were fair to excellent (TableMandibular 2.2): Asymmetry Fair to good in Patients reliability With the was Syndrome found forof Crouzon measurements or Apert | 61 other measurements showed excellent reliability. concerning the inclination of the maxilla and point B relative to the cranial base and LFH, and all the

other measurements showed excellent reliability.

2.3.2 Growth Models

2.3.2Control Growth Subjects Models

Control Subjects 47

R1 to estimate the values for fluctuating and directional asymmetry between 7.5 and 14 years of R2 age. For instance, the directional asymmetry for the gonial angle in the control group showed R3 ratio 0.00965 at the age of 12 years, computed as 0.00783 + (0.00091 * 2) (Table 3.3b). The R4 linear term 0.00091 (the yearly change) was multiplied by 2 instead of 12 because the intercept R5 was set to 10 years of age. R6 Multilevel growth models for fluctuating asymmetry in the control group showed no change R7 over time for condylar-ramal height and showed a slight increase for the gonial angle (Figs. 3.3a R8 R9 and 3.3b). For the directional asymmetry, condylar-ramal height showed to have a dominance for R10 the right side and showed no change over time (Fig. 3.4a). However, for the gonial angle, the R11 controls showed an increase of directional asymmetry, with a dominance to the mandibular left R12 side (Fig. 3.4b). R13 R14 Patients with Crouzon syndrome R15 Fluctuating asymmetry measurements for condylar-ramal height decreased between 7.5 to 14 R16 years of age (Fig. 3.3a). At 10 years of age, statistically significant more fluctuating asymmetry R17 for condylar-ramal height was found compared to controls (Tables 3.3a and 3.4a). Fluctuating R18 asymmetry for the gonial angle did not change during growth (Fig. 3.3b) and no differences with R19 controls were seen at the age of 10 years. For patients with Crouzon syndrome, the condylar-ramal R20 height had a dominance for the right side (Fig. 3.4a) and the directional asymmetry decreased R21 between 7.5 and 14 years of age (Fig. 3.4a). At the age of 10 years the condylar-ramal height R22 showed statistically significant more directional asymmetry compared to the controls (t = -2.300, R23 R24 p<0.05) (Tables 3.3b and 3.4b). The gonial angle of the patients with Crouzon syndrome showed R25 dominance for the mandibular left side (Fig. 3.4b) and no statistically significant differences were R26 found with controls (Tables 3.3b and 3.4b). R27 R28 Patients with Apert syndrome R29 Measurements for fluctuating asymmetry (condylar-ramal height and gonial angle) were statistically R30 significantly higher in Apert patients compared to the controls (Table 3.3a). Measurements for R31 fluctuating asymmetry did not change in the period between 7.5 and 14 years of age (Figs. R32 3.3a and 3.3b). Patients with Apert syndrome showed no statistically significant directional R33 asymmetry for the condylar-ramal height and gonial angle (Table 3.3b), and these measurements R34 did not change over time (Figs. 3.4a and 3.4b). The controls showed statistically significant more R35 directional asymmetry for gonial angle compared to Apert patients (t = 2.328, p<0.05) (Table R36 3.3b). No statistically significant differences were found for the condylar-ramal height between R37 these two groups (Table 3.3b). R38 R39

62 | Chapter 3 t-value R1 t-value R2 R3 R4 R5 Linear R6 Linear R7

t-value Estimate (SE) R8

t-value Estimate (SE) 3 R9 R10 R11 R12 Controls Intercept 2.233e-2 (7.588e-4) 30.706*** 7.302e-4 (2.884e-4) 2.532* R13 Control Intercept 7.833e-3 (1.341e-3) 5.841*** 9.066e-4 (3.885e-4) 23.340*** R14 R15 t-value Estimate (SE)

t-value Estimate (SE) R16 R17 R18 R19 R20 Linear

Linear R21 R22

t-value Estimate (SE) R23 t-value Estimate (SE) R24 R25 R26 R27 Crouzon Intercept R28 Crouzon Intercept -2.840e-2 (6.507e-3) -4.365*** 5.164e-3 (2.248e-3) 2.297* -1.064e-2 (1.650e-3) -6.448*** R29 R30 t-value Estimate (SE) t-value Estimate (SE) R31 R32 R33 R34 R35 Intercept Estimate (SE) Intercept 4.244e-2 (5.020e-3) 8.454*** 4.554e-2 (4.114e-3) 11.080***3.468e-2 (5.060e-3) -5.418e-3 (1.665e-3) 6.854*** -3.254** 2.761e-2 (2.526e-3) 3.193e-2 (8.737e-4) 10.930*** 36.546*** Estimate (SE) -1.297e-2 (1.003e-2) -1.293 R36 Directional asymmetry; estimated intercepts and linear coefficient at the age of 10 years in three groups (Crouzon, Apert and Control subjects). Directional asymmetry; estimated intercepts and linear coefficient at the age of 10 years in three groups (Crouzon, Apert Control subjects). Fluctuating asymmetry; estimated intercepts and linear coefficient at the age of 10 years in three groups (Crouzon, Apert and Control subjects). Fluctuating asymmetry; estimated intercepts and linear coefficient at the age of 10 years in three groups (Crouzon, Apert Control subjects). R37 R38 Measures Apert Measures Apert Condylar-ramal Condylar-ramal height Gonial Angle Condylar-ramal Condylar-ramal height Gonial Angle -4.172e-3 (8.605e-3) -0.485 3.931e-3 (4.893e-3) 0.803 Table 3.3b Table * p<0.05; ** p<0.01; *** p<0.001 Table 3.3a Table * p<0.05; ** p<0.01; *** p<0.001 R39

Mandibular Asymmetry in Patients With the Syndrome of Crouzon or Apert | 63 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 Figure 3.3a Ratios of fluctuating asymmetry for condylar-ramal height for control subjects (●), patients with R18 the syndrome of Crouzon (■) and Apert (▲). R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35

R36 Figure 3.3b Ratios of fluctuating asymmetry for gonial angle for control subjects ●( ), patients with the R37 syndrome of Crouzon (■) and Apert (▲). R38 R39

64 | Chapter 3 Patients with Crouzon syndrome compared with patients with Apert syndrome R1 Multilevel modelling showed different tendency of growth over time (constant vs linear curves) R2 for patients with Crouzon syndrome compared to patients with Apert syndrome (Figs. 3a and 4a). R3 R4 Although the two groups showed different growth models, no statistically significant differences R5 were found between the two syndromes for either directional or for fluctuating asymmetry R6 (Tables 3.3a and 3.3b). R7 R8 3 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 Figure 3.4a Ratios of directional asymmetry for condylar-ramal height for control subjects (●), patients with the syndrome of Crouzon (■) and Apert (▲). R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 Figure 3.4b Ratios of directional asymmetry for gonial angle height for control subjects (●), patients with the R38 syndrome of Crouzon (■) and Apert (▲). R39

Mandibular Asymmetry in Patients With the Syndrome of Crouzon or Apert | 65 R1

R2 p<0.05;

R3 * t-value R4 t-value R5 R6

R7 Apert minus Crouzon R8 R9

R10 Estimate (SE) 1.232e-2 (1.114e-2)-8.271e-3 (9.267e-3) 1.081 -0.893 R11 Apert minus Crouzon Intercept -1.729e-3 (6.378e-3)7.394e-3 (5.241e-3) -0.271 1.411 R12 R13 t-value R14 t-value Estimate (SE) R15 R16 R17 R18 R19 R20 Crouzon minus Control Crouzon Intercept 8.760e-3 (3.351e-3)4.464e-3 (2.568e-3) 2.614* 1.807 Estimate (SE) -1.360e-2 (5.913e-3)-4.638e-3 (4.439e-3) -2.300* -1.056 R21 minus Control Crouzon Constant R22 R23 R24 t-value Estimate (SE) R25 t-value R26 R27 R28 R29 R30 R31 Apert minus Control Intercept Estimate (SE) 1.049e-2 (4.153e-3)1.169e-2 (3.228e-3) 2.526* 3.621** -1.298e-2 (5.575e-3) -2.328* Estimate (SE) Apert minus Control Constant R32 R33 R34 R35 Differences in the directional asymmetry between groups (Crouzon, Apert and Control subjects); estimates differences, SE t-values. * p<0.05;

R36 asymmetryin the fluctuating Differences estimates differences, SE and t-values. between groups (Crouzon, Apert and Control subjects); R37 R38 Measures Condylar-ramal height Condylar-ramal Gonial Angle Condylar-ramal heightCondylar-ramal Gonial Angle -8.7806e-4 (7.2784e-3) -1.206 Measures Table 3.4b Table ** p<0.01; *** p<0.001 ** p<0.01; *** p<0.001 R39 3.4a Table

66 | Chapter 3 3.4 Discussion R1 R2

The most important finding in this study was that fluctuating asymmetry was larger in patients R3 R4 with Apert syndrome than in controls and patients with Crouzon syndrome. Increased fluctuating R5 asymmetry for condylar-ramal height and for the gonial angle may imply more developmental R6 instability in patients with Apert syndrome (Table 3.3a, Figs. 3.3a and 3.3b). Previous studies R7 showed increased fluctuating asymmetry in other syndromes or anomalies, such as Down R8 syndrome and cleft lip and palate (Adams and Niswander, 1967; Barden, 1980; Laspos et al., 3 R9 1997; Kurt et al., 2010). Patients with Crouzon syndrome showed less developmental instability R10 based on condylar-ramal height and gonial angle compared to patients with Apert syndrome R11 (Table 3.3a). Craniofacial discrepancies in both syndromes hardly change with growth and R12 development, probably because of genetic influences (Parsons, 1992). Differences in craniofacial R13 morphology between Crouzon and Apert syndromes showed more severe abnormal growth R14 pattern among the latter group, which concurs with previously reported results (Costaras-Volarich R15 and Pruzansky, 1984; Kreiborg and Cohen, 1998). R16 Fluctuating asymmetry in growth patients with syndromic craniosynsotosis is influenced by R17 genetic and environmental factors. There is evidence showing that genetic and environmental R18 R19 disturbances contribute to increased fluctuating asymmetry (Parsons, 1992). These patients R20 are confronted with physical, emotional, and social problems, probably partly caused by their R21 craniofacial disfigurement (Campis, 1991; Furlow et al., 1997; De Jong et al., 2012). Also several R22 surgical and other medical interventions like long-term orthodontic treatment during growth R23 could be a major stress factor for these patients. The overall effect may be an explanation for R24 the higher degree of fluctuating asymmetry of the mandible found for patients with Crouzon or R25 Apert syndromes. R26 Directional asymmetry in a growing patient with syndromic craniosynostosis was expected. A R27 dominant side of a structure can be explained by growth discrepancies due to craniosynostosis and R28 other etiological factors. Etiologic factors that could explain mandibular asymmetry of Crouzon R29 and Apert syndromes include condylar pathologies, functional habits or dental malocclusions R30 (Costaras-Volarich and Pruzansky, 1984; Kreiborg and Cohen, 1998). The controls showed a R31 dominant side (left or right side) for directional asymmetry (Table 3.3b, Figs. 3.4a and 3.4b), R32 which is in line with previous studies (Peck et al., 1991; Melnik, 1992). The Apert and Crouzon R33 R34 syndromes showed a higher degree of directional asymmetry for condylar-ramal height over time R35 compared than the controls. Premature unilateral synostoses of calvarial sutures may explain the R36 directional asymmetry that occurs in these syndromic patients (Cohen and Kreiborg, 1990) and R37 may indirectly influence the growing mandible (Costaras-Volarich and Pruzansky, 1984). R38 R39

Mandibular Asymmetry in Patients With the Syndrome of Crouzon or Apert | 67 R1 Significantly more directional asymmetry was found for the condylar-ramal height of the R2 patients with Crouzon syndrome than for controls. However, for the other measurements of the R3 syndromic patients, only a tendency of directional asymmetry was found in contrast to controls R4 (Table 3.3b). The small average value of directional asymmetry close to zero could be misleading R5 (Fig. 3.1a). It is reasonable to consider that in Crouzon and Apert syndromes the more rare type R6 antisymmetry may occur (Fig. 3.1b). In contrast to directional asymmetry where the direction of R7 asymmetry is either left or right, antisymmetry shows right- and left-sided bimodal distribution R8 R9 (Fig. 3.1b). Antisymmetry may show a wide range of individual asymmetry in patients. A possible R10 explanation for the present results in this study could be the wide range of asymmetry in patients R11 demonstrated by a large standard error found for both syndromes (Palmer and Strobeck, 1986) R12 (Table 3.3b). However, after analyzing scatterplots for the actual distribution of the results, the R13 syndromic patients showed no bimodal distribution for the condylar-ramal height or for the R14 gonial angle. Further research is needed to study the possible role of bimodal distribution in the R15 facial symmetry of bilateral structures in these syndromic patients. New technological methods R16 like three-dimensional reconstructions of computed tomography (CT) images or laser surface R17 scanning methods could therefore be a helpful tool (DeLeon and Richtsmeier, 2009; Djordjevic R18 et al., 2001). R19 For reliable and accurate measurements on panoramic radiograph, some recommendations R20 from the literature were used in this study. Reliable vertical and angular measurements were R21 used instead of inaccurate horizontal measurements (Habets et al., 1987; Kambylafkas et al., R22 2006; Elslande et al., 2008). Ratios instead of absolute values were used to prevent positioning, R23 R24 distortion or magnification errors due to the use of different panoramic x-ray machines (Fig. R25 3.2) (Habets et al., 1988; Kjellberg et al., 1994). In addition, regarding the adopted statistical R26 methodology, multilevel models offer an important tool for describing longitudinal asymmetry R27 with limited data of rare syndromes like Crouzon or Apert. Both individual and average growth R28 curves can be described; it is a flexible model because it uses polynomials, which can describe R29 growth curves of almost any form (Goldstein, 1986). Conventional procedures, including cross- R30 sectional descriptions and analyses of yearly velocities from two measurement occasions provide R31 less optimal use of the available material. Moreover, other polynomial methods would have R32 required elimination of most of the subjects, due to missing observations, and adjustment of R33 values to exact ages (Goldstein, 1986). R34 R35 R36 R37 R38 R39

68 | Chapter 3 3.5 Conclusion R1 R2

The following conclusions can be made from this study: R3 R4 (1) Fluctuating asymmetry in patients with the Apert syndrome was statistically significant higher R5 compared to controls. R6 (2) No statistically significant differences were found for longitudinal directional and fluctuating R7 asymmetry between patients with Crouzon or Apert syndrome. R8 (3) Findings of fluctuating and directional asymmetry may illustrate the influence of genetic and 3 R9 environmental factors in growth and development of children with Crouzon and Apert syndromes. R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

Mandibular Asymmetry in Patients With the Syndrome of Crouzon or Apert | 69 R1 3.6 References R2 R3 Adams MS, Niswander JD. Developmental ‘noise’ and congenital malformation. Genet Res. 1967;10:313- R4 317. Barden HS. Fluctuating dental asymmetry: a measure of developmental instability in Down syndrome. Am J R5 Phys Anthropol. 1980;52:169-173. R6 Boutros S, Shetye PR, Ghali S, Carter CR, McCarthy JG, Grayson BH. Morphology and growth of the mandible R7 in Crouzon, Apert, and Pfeiffer syndromes. J Craniofac Surg. 2007;18:146-150. R8 Campis LB. Children with Apert syndrome: developmental and psychologic considerations. Clin Plast Surg. 1991;18:409-416. R9 Cohen MM Jr, Kreiborg S. The central nervous system in the Apert syndrome. Am J Med Genet. 1990;35:36- R10 45. R11 Cohen MM Jr, Kreiborg S. New indirect method for estimating the birth prevalence of the Apert syndrome. R12 Int J Oral Maxillofac Surg. 1992;21:107-109. R13 Costaras-Volarich M, Pruzansky S. Is the mandible intrinsically different in Apert and Crouzon syndromes?. Am J Orthod. 1984;85:475-487. R14 De Jong T, Maliepaard M, Bannink N, Raat H, Mathijssen IMJ. Health-related problems and quality of life in R15 patients with syndromic and complex craniosynostosis. Childs Nerv Syst. 2012;28:879-882. R16 DeLeon VB, Richtsmeier JT. Fluctuating asymmetry and developmental instability in sagittal craniosynostosis. R17 Cleft Palate Craniofac J. 2009;46:187-196. R18 Djordjevic J, Pirttiniemi P, Harila V, Heikkinen T, Toma AM Zhurov AI, Richmond S. Three-dimensional longitudinal assessment of facial symmetry in adolescents. Eur J Orthod. 2011;35:143-151. R19 Farkas LG, Cheung G. Facial asymmetry in healthy North American Caucasians. An anthropometrical study. R20 Angle Orthod. 1981;51(1):70-77. R21 Furlow FB, Armijo-Prewitt T, Gangestad SW, Thornhill R. Fluctuating asymmetry and psychometric intelligence. R22 Proc Biol Sci. 1997;264:823-829. Goldstein H. Efficient statistical modelling of longitudinal data. Ann Hum Biol. 1986;13:129-141. R23 Grizzle JE, Allen DM. Analysis of growth and dose response curves. Biometrics. 1969;25:357-381. R24 Habets LL, Bezuur JN, Van Ooij CP, Hansson TL. The orthopantomogram, an aid in diagnosis of R25 temporomandibular joint problems. I. The factor of vertical magnification. J Oral Rehabil. 1987;14:475- R26 480. R27 Habets LL, Bezuur JN, Naeiji M, Hansson TL. The Orthopantomogram, an aid in diagnosis of temporomandibular joint problems. II. The vertical symmetry. J Oral Rehabil. 1988;15:465-471. R28 Kambylafkas P, Murdock E, Gilda E, Tallents RH, Kyrkanides S. Validity of panoramic radiographs for measuring R29 mandibular asymmetry. Angle Orthod. 2006;76:388-393. R30 Kjellberg H, Ekestubbe A, Kiliaridis S, Thilander B. Condylar height on panoramic radiographs. A methodologic R31 study with a clinical application. Acta Odontol Scand. 1994;52:43-50. R32 Kreiborg S, Cohen MM Jr. Is craniofacial morphology in Apert and Crouzon syndromes the same?. Acta Odontol Scand. 1998;56:339-341. R33 Liukkonen M, Sillanmäki L, Peltomäki T. Mandibular asymmetry in healthy children. Acta Odontol Scand. R34 2005;63:168-172. R35 Mathijssen IMJ. Craniosynostosis: clinical and fundamental aspects. Rotterdam: Erasmus University; 2000. Dissertation. R36 Melnik AK. A cephalometric study of mandibular asymmetry in a longitudinally followed sample of growing R37 children. Am J Orthod Dentofacial Orthop. 1992;101:355-366. R38 R39

70 | Chapter 3 Palmer AR, Strobeck C. Fluctuating asymmetry: measurement, analysis, patterns. Annu Rev Ecol Syst. 1986;17:391-421. R1 Parsons PA. Fluctuating asymmetry: a biological monitor of environmental and genomic stress. Heredity. R2 1992;68:361-364. R3 Peck S, Peck L, Kataja M. Skeletal asymmetry in esthetically pleasing faces. Angle Orthod. 1991;61:43-48. R4 Prahl-Andersen B, Kowalski CJ, Heyendaal PHJM. A mixed-longitudinal interdisciplinary study of growth and R5 development. Academic Press. 1979. R6 Reardon, W, Winter RM, Rutland P, Pulleyn LJ, Jones BM Malcolm S. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet. 1994;8:98-103. R7 Shrout PE, Fleiss JL. Intraclass correlations: uses in assessing rater reliability. Psychol Bull. 1979;86:420-428. R8 Skvarilova B. Facial asymmetry: type, extent and range of normal values. Acta Chir Plast. 1993;35:173-180. 3 R9 Swaddle JP. Fluctuating Asymmetry, Animal Behavior, and Evolution. Advances in the Study of Behavior. R10 2003;32:169-205. R11 Thompson JR. Asymmetry of the face. J Am Dent Assoc. 1943;30:1859-1871. R12 Van Elslande DC, Russett SJ, Major PW, Flores-Mir C. Mandibular asymmetry diagnosis with panoramic imaging. Am J Orthod Dentofacial Orthop. 2008;134:183-192. R13 Van Valen L. A study of fluctuating asymmetry. Evolution. 1962;16:125-142. R14 Vig PS, Hewitt AB. Asymmetry of the human facial skeleton. Angle Orthod. 1975;45:125 129. R15 Wilkie AO, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, Hayward RD, David DJ, Pulleyn LJ, R16 Rutland P et al., Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995;9:165-172. R17 Woo TL. On the asymmetry of the human skull. Biometrika. 1931;22:324-352. R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

Mandibular Asymmetry in Patients With the Syndrome of Crouzon or Apert | 71

Chapter 4

Dental Maturation in Children With the

Syndrome of Crouzon or Apert

Jacobus H. Reitsma Inge H. Balk-Leurs Edwin M. Ongkosuwito Evert Wattel Birte Prahl-Andersen

Cleft Palate Craniofacial Journal 2013; doi:10.1597/13-071 R1 Abstract R2

R3 Purpose: Developing teeth are used to assess maturity and estimate age in a number of disciplines. R4 The purpose of this investigation was to study the dental maturation in children with Crouzon or R5 Apert syndrome compared with nonsyndromic controls. R6 R7 Patients and Methods: Records of 40 children with Crouzon syndrome (18 boys and 22 girls, R8 R9 aged 4.0 to 17.9 years) and 28 children with Apert syndrome (10 boys and 18 girls, aged 3.9 to R10 15.1 years) were referred to the Department of Orthodontics, Cleft Palate Team and Craniofacial R11 Team, Erasmus MC–Sophia. Data from syndromic children were compared with data from R12 451 nonsyndromic children (225 boys and 226 girls, aged 2.9 to 16.9 years). From panoramic R13 radiographs, dental maturation was determined for patients with Crouzon and Apert syndromes R14 and compared with data collected from control children. Logistic functions were constructed for R15 dental maturation over time for syndromes and gender. R16 R17 Results: Statistically significant gender differences in dental maturation scores were found R18 for girls with Crouzon (P < .05) and Apert syndrome (P < .05). Patients with Apert syndrome R19 demonstrated a significantly delayed dental maturation (P < .05), while patients with Crouzon R20 syndrome showed a nonsignificant delay. R21 R22 Conclusions: Dental maturation in patients with Apert syndrome was more delayed than in R23 R24 patients with Crouzon syndrome. The delay of tooth formation in patients with Crouzon or Apert R25 syndrome suggests a possible common genetic association. R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

74 | Chapter 4 4.1 Introduction R1 R2

Dental maturity or dental age is a method for biological age determination (Demirjian et al., R3 R4 1973). Clinicians have studied dental development in relation to chronological age and regard R5 this to be superior to the use of other biological age determinations as indicators for chronological R6 age (Moorrees et al., 1963; Anderson et al., 1976; Nik-Hussein et al., 2011). Developing tooth R7 calcification has been shown to be less susceptible to environmental influences than skeletal R8 development (Prahl-Andersen and Van der Linden, 1972; Prahl-Andersen et al., 1979; Mörnstad R9 et al., 1995; Liversidge, 1999). Identification of key genes for tooth formation may show that R10 disrupted dental development is caused by several independent defective genes, acting alone R11 or in combination with other genes. Exploring these genes involved in different interacting R12 molecular pathways may explain the wide variety in dental development patterns but can also 4 R13 explain their possible association with additional craniofacial anomalies (Wilke et al., 1997; R14 DeMoerlooze et al., 2000; Bachler and Neubüser, 2005; De Coster et al., 2007). This may clarify R15 tooth anomalies seen in patients with craniosynostosis as the genes involved in odontogenesis are R16 also partly involved in craniosynostosis syndromes (De Coster et al., 2007; Nieminen et al., 2011). R17 Mutations in the gene encoding of the fibroblast growth factor receptor (FGFR) were found in R18 R19 most syndromes with craniosynostosis (Wilke et al., 1997). The list of genes that are involved in R20 craniosynostosis includes those coding for FGFR1, FGFR2, and FGFR3 but also genes encoding R21 transcription factors, such as MSX2 and TWIST (Wilke et al., 1997; Bachler and Neubüser, 2005; R22 Nieminen et al., 2011). R23 The fibroblast growth factors (FGFs) are a family of intercellular signaling molecules that are R24 important factors controlling bone development, growth, remodeling, and repair (De Coster et al., R25 2007). The FGF and the FGFR also have been shown to play an important role in tooth formation R26 and regeneration (Kettunen and Thesleff, 1988; Kettunen et al., 2000; Nieminen et al., 2011). R27 The FGFs Fgf-4, -8, and -9 have been implicated as epithelial signals regulating mesenchymal R28 gene expression and cell proliferation during tooth initiation and later during epithelial folding R29 morphogenesis and the establishment of tooth shape. Fgf-10 expression is observed in the R30 presumptive dental epithelium and mesenchyme during tooth initiation, whereas Fgf-3 expression R31 appeared in the dental mesenchyme at the bud stage. During the cap and bell stage, both Fgf-3 R32 and Fgf-10 were intensely expressed in the dental papilla mesenchymal cells both in incisors and R33 R34 molars. Fgf-3 participates in signaling functions of primary enamel knot. The dynamic expression R35 patterns of different Fgfs in dental epithelium and mesenchyme and their interactions suggest R36 existence of regulatory signaling cascades between epithelial and mesenchymal FGFs during R37 tooth development (Kettunen and Thesleff, 1988; Miletich and Sharpe, 2003; Lin et al., 2009; R38 Nieminen et al., 2011). R39

Dental Maturation in Children With the Syndrome of Crouzon or Apert | 75 R1 Mutations of FGFR2 or FGFR3 are causal to retarded craniofacial growth and development in R2 Crouzon and Apert syndromes (Wilke et al., 1997; Bachler and Neubüser, 2005). The involvement R3 of FGFR2 in dentogenesis in animal studies may suggest that mutated FGFR2 genes may influence R4 dental development seen in these syndromes (Wilke et al., 1997). Determining dental maturation R5 of patients with Crouzon and Apert syndromes yields information not only about the general R6 development of the dentition but also about the general development of the individual, thus R7 giving an indication for the involvement of the mutated FGFR2 or FGFR3 in the unique growth R8 R9 pattern seen in these syndromes. The aim of this study is to compare dental maturation of R10 patients with Crouzon and Apert syndromes with nonsyndromic Dutch children and to develop R11 new standards for these syndromes. R12 R13 R14 4.2 Materials and Methods R15 R16 A retrospective longitudinal design was conducted with data of 96 panoramic radiographs R17 from 28 patients (10 boys and 18 girls) with Apert syndrome and 135 panoramic radiographs R18 from 40 patients (18 boys and 22 girls) with Crouzon syndrome from Erasmus MC Craniofacial R19 Center, Sophia Children’s Hospital, in Rotterdam, The Netherlands. The median age at which the R20 panoramic radiographs were taken was 9.2 years for patients with Crouzon syndrome, with a R21 range from 4.0 to 17.9 years. The median age at which the panoramic radiographs were taken R22 was 9.5 years for patients with Apert syndrome, with a range from 3.9 to 15.1 years. The use of R23 R24 data from human subjects followed an approved protocol and satisfied the requirement of the R25 institutional review board (approval MEC-2010-304). R26 The control group consisted of 451 normal Dutch children (225 boys and 226 girls) included R27 in a previously published study (Leurs et al., 2005). The median age of the controls at which the R28 panoramic radiographs were taken was 7.7 years, with a range from 2.9 to 16.9 years. R29 The clinical diagnosis of Crouzon or Apert syndrome was confirmed with genetic testing to R30 detect a mutation in the FGFR2 or FGFR3 gene. R31 The subjects for this study had panoramic radiographs taken according to the protocol R32 for treatment planning and treatment of Caucasian patients with Crouzon or Apert syndrome R33 between 1980 and 2011. When one left mandibular tooth was missing, the contralateral right R34 mandibular tooth was used. When mandibular teeth were missing bilaterally, the panoramic R35 radiographs were excluded because no dental maturity score can be determined in these cases. R36 Dental agenesis, identified on radiographs, was verified by analysis of dental records, to exclude R37 premature extractions. Panoramic radiographs with a maturity score of 100 were excluded R38 R39 because the dentition has matured.

76 | Chapter 4 4.2.1 Statistical Analysis of Dental Maturity Scores R1 The dental development scores for patients with Crouzon and Apert syndromes were compared R2 with the scores of control children using a logistic curve-fitting procedure (Leurs et al., 2005). The R3 R4 function used for the 50th percentile curve of the data was Y = 100*{1/ (1 + e-v (x-m))}, in which R5 v stands for velocity of the mean dental maturation over time and m for mean age at the 50th R6 dental maturation percentile. Several logistic functions were estimated and graphed: R7 R8 -0.559(x-5.586) 1. For control children (boys and girls), Y = 100*{1/(1+ e )} (Leurs et al., 2005) R9 2. For patients with Crouzon syndrome (boys and girls) R10 3. For patients with Apert syndrome (boys and girls) R11 R12 For dental development to be determined over time, at least two consecutive panoramic 4 R13 radiographs are needed. For logistic curve fitting, at least three measurements are necessary. R14 The patients with one or two radiographic measurements were used to improve the earlier- R15 established logistic curves for estimating the logistic population mean. The data derived from one R16 or two panoramic radiographs do not directly contribute to the calculation of velocity but are R17 substantial to the level of the curve at a certain age. To calculate the 5th and 95th percentiles for R18 R19 the norm logistic curve, the SD was added and subtracted 1.96 times. R20 R21 4.2.2 Dental Development Scores R22 The developmental stages of the seven left permanent mandibular teeth were assessed according R23 to the method proposed by Demirjian et al. (1973). Each tooth of the mandible was given a score R24 from A to H. These scores were converted into numbers and summed, referred to as the maturity R25 score (Demirjian et al., 1973). Two examiners were trained by means of a tutorial program, R26 available on CD-ROM (Demirjian, 1993–1994). R27 R28 4.2.3 Measurement Error R29 Intra- and interexaminer reliability is expressed by the intraclass correlation coefficient (ICC) for R30 the dental maturity score. To assess intra- and interexaminer reliability, two examiners randomly R31 rescored 35 panoramic radiographs. The ICC is comparable to the kappa coefficient. ICC values R32 range from 0 to 1. An ICC of .61 to .80 is interpreted as substantial agreement and an ICC of R33 R34 .81 to 1.00 as an almost perfect agreement. Calculations were performed with the statistical R35 software package SPSS version 11.5 (SPSS Inc., Chicago, IL). R36

R37 R38 R39

Dental Maturation in Children With the Syndrome of Crouzon or Apert | 77 R1 4.3 Results R2

R3 4.3.1 Measurement Error R4 The ICC for intraexaminer reliability was .96 (95% confidence interval [CI], .94 to .99). The ICC R5 for interexaminer reliability was .97 (95% CI, .96 to .99). Both scores indicate high reliability. R6 R7 4.3.2 Dental Development Scores R8 R9 Differences in dental development between patients with craniosynostosis and Dutch controls R10 were found. The dental maturation of patients with Apert syndrome is significantly delayed (Table R11 4.1). Also, patients with Crouzon syndrome had delayed dental maturation scores compared with R12 controls; these differences were not statistically significant (Fig. 4.1; Table 4.1). Compared with R13 the Dutch norm, gender differences were also found. Female patients with Crouzon and Apert R14 syndromes were statistically significantly delayed compared with controls (Figs. 4.1 and 4.2). R15 Dental maturation of male patients with Crouzon and Apert syndromes was less mature than R16 that of control subjects. A slight acceleration occurred between 9 and 12 years of age for male R17 patients with Crouzon syndrome compared with controls. R18 Female patients with Crouzon syndrome at all ages were less matured than boys, although R19 these differences were not statistically significant (Fig. 4.3). In patients with Crouzon syndrome, R20 male patients showed delayed dental development before 6 to 7 years of age compared with R21 female patients with Crouzon syndrome (Fig. 4.4). From this age on, female patients with Crouzon R22 syndrome were less matured dentally compared with boys. R23 R24 R25 Table 4.1 Mean difference for the logistic fits for the syndrome of Crouzon and Apert for gender. N is R26 number of OPTs; mean difference is mean maturity score difference; SD is the standard deviation for the R27 mean difference; SE is the standard error for the mean difference; P-value for mean difference compared to R28 the Dutch control children. R29 N mean diff SD SE p-value R30 Crouzon Boys 81 0.467 1.347 0.1497 N.S. Apert Boys 85 -0.347 1.112 0.1206 N.S. R31 Crouzon Girls 64 -1.082 1.611 0.2014 p<0.05 R32 Apert Girls 26 -1.617 0.829 0.1628 p<0.05 R33 Crouzon Total 145 -0.216 1.655 0.1374 N.S. R34 Apert Total 111 -0.645 1.393 0.1120 p<0.05 R35 R36 R37 R38 R39

78 | Chapter 4 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 4 R13 R14 R15 R16 R17 Figure 4.1 Dental maturation for male controls and male patients with Crouzon and Apert syndromes. The R18 5th, 50th, and 95th percentile lines for controls are indicated. R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 Figure 4.2 Dental maturation for Dutch female controls and female patients with Crouzon and Apert R38 syndromes. The 5th, 50th, and 95th percentile lines for controls are indicated. R39

Dental Maturation in Children With the Syndrome of Crouzon or Apert | 79 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 Figure 4.3 Dental maturation for male and female patients with Crouzon syndrome. R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 Figure 4.4 Dental maturation for male and female patients with Apert syndrome. R39

80 | Chapter 4 4.4 Discussion R1 R2

The dental maturation in Dutch patients with Crouzon and Apert syndromes was compared with R3 R4 the dental maturation in a nonsyndromic control group of the same ethnicity. In both syndromes, R5 disturbances in the gene expression show abnormal skeletal growth and probably could also have R6 influence on dental development (Wilke et al., 1997; De Coster et al., 2007). The correction of R7 facial deformities in patients with craniosynososis syndromes is complex because of the esthetic R8 and functional difficulties associated with these disorders. Management of these patients requires R9 knowledge and understanding of craniofacial growth and development (Renier et al., 2000). An R10 important role is determining the type and timing of orofacial interventions in which gender- and R11 syndrome specific data for dental maturation may attribute. R12 This study showed that the early dental maturation in syndromic patients is severely delayed 4 R13 (Table 4.1). Also, dental maturation in patients with Crouzon and Apert syndromes is abnormally R14 distributed when compared with the nonsyndromic Dutch control group. The development R15 over time at the 50th percentile was delayed compared with normal values (Figs. 4.1 and 4.2). R16 One study in the literature investigated the relationship between dental maturity and Apert R17 syndrome (Kaloust et al., 1997). This study showed a delayed dental maturity in patients with R18 R19 Apert syndrome, with a trend of increasing delay with increased age compared with a control R20 group. The authors suggested a positive correlation between increased age and increased delay, R21 extending equally the general growth of Apert children (Kaloust et al., 1997). However, gender R22 differences were not accounted for. R23 Remarkable gender differences in dental maturation were found in patients with Crouzon R24 and Apert syndromes. Girls with Crouzon and Apert syndromes showed statistically significant R25 delayed dental maturation compared with boys. A large study of a normal sample (n = 1031) R26 showed independent gender scores of dental maturity, which were always more advanced for R27 girls (Chaillet et al., 2005). Girls were advanced already at 2 years of age until 12 years of age. R28 Acceleration of dental maturation in boys started at 12 to 13 years, at the beginning of their R29 puberty, and continued strongly until 18 years of age (Chaillet et al., 2005). Control Dutch boys R30 and girls in the present study confirmed these findings. Gender differences in dental maturation R31 for patients with craniosynostosis and control subjects (Field et al., 1991; Cohen and Kreiborg, R32 1993; Chaillet et al., 2005) might be related to variability due to the limited sample size of R33 R34 syndromic patients. R35 There is evidence to suggest that tooth agenesis is related to dental maturation in patients R36 with Crouzon and Apert syndromes (Kaloust et al., 1997; Lin et al., 2009). Dental maturation of R37 permanent teeth in nonsyndromic children (n = 108) is delayed with dental agenesis (Ruiz-Mealin R38 R39

Dental Maturation in Children With the Syndrome of Crouzon or Apert | 81 R1 et al., 2012), and the severity of dental agenesis affects the magnitude of the delay (Ruiz-Mealin R2 et al., 2012). The prevalence of tooth agenesis in patients with Crouzon and Apert syndromes is R3 much higher than reported for the general population (Polder et al., 2004; Stavropoulos et al., R4 2011; Stavropoulos et al., 2012). High prevalence of tooth agenesis in patients with Crouzon and R5 Apert syndromes might negatively influence delayed maturation in the present study, although R6 the literature contains no consensus concerning delayed tooth development in patients with R7 dental agenesis (Ruiz-Mealin et al., 2012). R8 R9 The ability to determine dental maturity is important to those involved in treatment of patients R10 with Crouzon or Apert syndrome (Kaloust et al., 1997). The oral surgeon plays an important role R11 in determining the type and timing of orofacial interventions partly determined by the dental R12 development (Cohen and Kreiborg, 1993; Kaloust et al., 1997). Dental development is particularly R13 useful to the orthodontist when planning the treatment of different types of malocclusions in R14 relation to surgical intervention. Dental maturation may also be of interest to molecular biologists, R15 because genetic mutations may alter dental morphogenesis (Kaloust et al., 1997). R16 Dental maturity assessed by the Demirjian method (Demirjian et al., 1973) is considered to R17 be the most precise and accurate method (Hägg and Matsson, 1985). Most methods determine R18 dental maturation according to the degree of dental calcification observed in x-rays of the jaws R19 (Schour and Massler, 1941; Garn et al., 1959; Haavikko, 1970; Moorrees et al., 1963; Prahl- R20 Andersen and Van der Linden, 1972; Gustafson and Koch, 1974; Anderson et al., 1976). This is in R21 contrast to Demirjian’s method of estimating dental maturity by the development stage of seven R22 teeth in the left side of the mandible. R23 R24 Further, the method developed by Demirjian et al. (1973) avoids magnification considerations R25 and the need for direct measurements. Therefore, it is one of the simplest, practical, and widely R26 used methods (Garamendi et al., 2005). R27 After the age of 15 years, the accuracy of Demirjian’s age prediction decreases because most R28 subjects reach dental maturity scores of 100. Adding the third molar might increase the possibility R29 of prediction until 18 years of age. However, the high variability of third molar development R30 (Mesotten et al., 2002; Gunst et al., 2003; Chaillet et al., 2005), a 20% chance of third molar R31 agenesis (Polder et al., 2004), and small sample sizes make accuracy of dental maturation at an R32 older age low. R33 R34 R35 R36 R37 R38 R39

82 | Chapter 4 4.5 Conclusion R1 R2

To calculate the dental maturation for patients with Crouzon and Apert syndromes, scoring can R3 R4 be carried out according to the system of Demirjian et al. (1973). Girls and boys with Crouzon R5 and Apert syndromes were delayed compared with dental maturation in normal Dutch children R6 (Leurs et al., 2005). Gender differences between the syndromes showed that girls with Crouzon R7 and Apert syndromes had a statistically significant less mature dental maturity compared with R8 controls. Dental maturation in patients with Apert syndrome was more delayed than in patients R9 with Crouzon syndrome. The delay of tooth formation in patients with Crouzon and Apert R10 syndromes suggest a possible common genetic association. R11 R12 4 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

Dental Maturation in Children With the Syndrome of Crouzon or Apert | 83 R1 4.6 References R2 R3 Anderson DL, Thompson GW, Popovich F. Age of attainment of mineralization stages of the permanent R4 dentition. J Forensic Sci.1976;21:191–200. Bachler M, Neubüser A. Expression of members of the Fgf family and their receptors during midfacial R5 development. Mech Dev. 2001;100:313–316. R6 Chaillet N, Nyström M, Demirjian A. Comparison of dental maturity in children of different ethnic origins: R7 international maturity curves for clinicians. J Forensic Sci. 2005;50:1164–1174. R8 Cohen MM Jr, Kreiborg S. An updated pediatric perspective on Apert syndrome. Am J Dis Child. 1993a;147:989–993. R9 Cohen MM Jr, Kreiborg S. Growth pattern in the Apert syndrome. Am J Med Genet. 1993b;47:617–623. R10 De Coster PJ, Mortier G, Marks LA, Martens LC. Cranial suture biology and dental development: genetic and R11 clinical perspectives. J Oral Pathol Med. 2007;36:447–455. R12 Demirjian A. Dental development [CD-ROM]. Montreal, Canada: Silver Platter Education, University of R13 Montreal; 1993–1994. R14 Demirjian A, Goldstein AH, Tanner JM. A new system of dental age assessment. Hum Biol. 1973;45:211–227. De Moerlooze L, Spencer-Dene B, Revest JM, Hajihosseini M, Rosewell I, Dickson C. An important role for the R15 IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal epithelial signalling during R16 mouse organogenesis. Development. 2000;127:483–492. R17 Field CR, Leiber A, Toniges C. Case report: Crouzon syndrome with short stature. Am J Med Sci. 1991;302:101– R18 102. Garamendi PM, Landa MI, Ballesteros J, Solano MA. Reliability of the methods applied to assess age minority R19 in living subjects around 18 years old: a survey on a Moroccan origin population. Forensic Sci Int. R20 2005;154:3–12. R21 Garn SM, Lewis AB, Polacheck DL. Variability of tooth formation. J Dent Res. 1959;38:135–148. R22 Gunst K, Mesotten K, Carbonez A, Willems G. Third molar root development in relation to chronological age: a large sample sized retrospective study. Forensic Sci Int. 2003;136:52–57. R23 Gustafson G, Koch G. Age estimation up to 16 years of age based on dental development. Odontol Revy. R24 1974;25:297–306. R25 Haavikko K. The formation and the alveolar and clinical eruption of the permanent teeth: an R26 orthopantomographic study. Suom Hammaslaak Toim. 1970;66:103–170. R27 Hägg U, Matsson L. Dental maturity as an indicator of chronological age: the accuracy and precision of three methods. Eur J Orthod. 1985;7:25–34. R28 Kaloust S, Ishii K, Vargervik K. Dental development in Apert syndrome. Cleft Palate Craniofac J. 1997;34:117– R29 121. R30 Ketunnen P, Laurikkala J, Itäranta P, Vainio S, Itho N, Thesleff I. Associations of FGF-3 and FGF-10 with R31 signalling networks regulating tooth morphogenesis. Dev Dyn. 2000;219:322–332. R32 Kettunen P, Thesleff I. Expression and function of FGFs-4,-8 and -9 suggest functional redundancy and repetitive use as epithelial signals during tooth morphogenesis. Dev Dyn. 1998;211:256–268. R33 Leurs IH, Wattel E, Aartman IHA, Etty E, Prahl-Andersen B. Dental age in Dutch children. Eur J Orthod. R34 2005;27:309–314. R35 Lin Y, Cheng YS, Qin C, Lin C, D’Souza R, Wang F. FGFR2 in the dental epithelium is essential for development and maintenance of the maxillary cervical loop, a stem cell niche in mouse incisors. Dev Dyn. R36 2009;238:324–330. R37 Liversidge HM. Dental maturation of 18th and 19th century British children using Demirjian’s method. Int J R38 Paediatr Dent. 1999;9:111–115. R39

84 | Chapter 4 Mesotten K, Gunst K, Carbonez A, Willems G. Dental age estimation and third molars: a preliminary study. Forensic Sci Int. 2002;129:110–115. R1 Miletich I, Sharpe PT. Normal and abnormal dental development. Hum Mol Genet. 2003;12:R69–R73. R2 Moorrees CFA, Fanning EA, Hunt EE. Age variation of formation stages for ten permanent teeth. J Dent Res. R3 1963;42:1490–1502. R4 Mörnstad H, Reventlid M, Teivens A. The validity of four methods for age determination by teeth in Swedish R5 children: a multicenter study. Swed Dent J. 1995;19:121–130. R6 Nik-Hussein NN, Kee KM, Gan P. Validity of Demirjian and Willems methods for dental age estimation for Malaysian children aged 5–15 years old. Forensic Sci Int. 2011;30:204(1–3):208.e1–208.e6. R7 Polder BJ, Van’t Hof MA, Van der Linden FPGM, Kuijpers-Jagtman AM. A meta-analysis of the prevalence of R8 dental agenesis of permanent teeth. Community Dent Oral Epidemiol. 2004;32:217–226. R9 Prahl-Andersen B, Kowalski CJ, Heydendael PHJM. A Mixed-Longitudinal Interdisciplinary Study of Growth R10 and Development. San Diego, CA: Academic Press; 1979. Prahl-Andersen B, Van der Linden FPGM. The estimation of dental age. Trans Eur Orthod Soc. 1972:535–541. R11 Renier D, Lajeunie E, Arnaud E, Marchac D. Management of craniosynostoses. Childs Nerv Syst. 2000;16:645– R12 658. 4 R13 Ruiz-Mealin EV, Parekh S, Jones SP, Moles DR, Gill DS. Radiographic study of delayed tooth development in R14 patients with dental agenesis. Am J Orthod Dentofacial Orthop. 2012;141:307–314. R15 Schour I, Massler M. The development of the human dentition. J Am Dent Assoc. 1941;28:1153–1160. R16 Stavropoulos D, Bartzela T, Bronkhorst E, Mohlin B, Hagberg C. Dental agenesis patterns of permanent teeth in Apert syndrome. Eur J Oral Sci. 2011;119:198–203. R17 Stavropoulos D, Bartzela T, Tarnow P, Mohlin B, Kahnberg KE, Hagberg C. Dental agenesis patterns in Crouzon R18 syndrome. Swed Dent J. 2012;35:195–201. R19 Wilke TA, Gubbels S, Schwartz J, Richman JM. Expression of fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3) in the developing head and face. Dev Dyn. 1997;210:41–52. R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

Dental Maturation in Children With the Syndrome of Crouzon or Apert | 85

Chapter 5

Patterns of Tooth Agenesis in Patients

With the Syndrome of Crouzon or Apert

Jacobus H. Reitsma Edwin M. Ongkosuwito Arjen J. van Wijk Birte Prahl-Andersen

Cleft Palate Craniofacial Journal 2014; 51: 178-183 R1 Abstract R2

R3 Purpose: Dental agenesis is the most common anomaly of dental development and can be a R4 component of a congenital syndrome. The purpose of this study was to evaluate the prevalence of R5 agenesis and to describe patterns of tooth agenesis in patients with Crouzon or Apert syndrome R6 compared with nonsyndromic controls. R7 R8 R9 Patients and Methods: Longitudinal records of 67 patients with Crouzon syndrome (n = 39) or R10 Apert syndrome (n = 28) from the Erasmus Medical Centre were examined. Syndromic patients R11 were compared with patients in a nonsyndromic control group (n = 284). R12 R13 Results: Prevalence of tooth agenesis in patients with Crouzon syndrome (35.9%) and patients R14 with Apert syndrome (46.4%) was significantly higher than the prevalence in control subjects R15 (27.5%) (P < .005). In all groups third molars were the most likely to be agenetic. Tooth agenesis R16 excluding third molars was significantly higher in syndromic patients than in control subjects R17 (P < .001). Bilateral agenesis of mandibular second premolars occurred significantly more often in R18 patients with Crouzon and Apert syndrome than in control subjects (P < .001). R19 R20 Conclusions: Tooth agenesis is more prevalent in patients with Crouzon or Apert syndrome than R21 in control subjects. Tooth agenesis and mandibular symmetrical patterns of second premolar R22 agenesis are more prevalent in syndromic patients. R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

88 | Chapter 5 5.1 Introduction R1 R2

Tooth agenesis, the most common dental anomaly, is described in different ways: congenitally R3 R4 missing teeth, hypodontia (a few teeth are missing), oligodontia (several teeth are missing), and R5 anodontia (all teeth are missing) (De Coster et al., 2009). In this article, the term tooth agenesis R6 encompasses all of these terms. Excluding the third molars, agenesis of permanent teeth in the R7 general population ranges from 3.2% to 7.6% (Polder et al., 2004). The prevalence of tooth R8 agenesis varies per tooth. Third molar agenesis is the most common, with a prevalence around R9 20% in population studies (Vastardis, 2000; Polder et al., 2004). The teeth with second most R10 prevalence of agenesis are the lateral maxillary incisor or mandibular second premolar (Polder et R11 al., 2004). R12 Tooth agenesis can be a nonsyndromic trait or a component of an inherited syndrome R13 (Vastardis, 2000; De Coster et al., 2007). Many syndromes are associated with tooth anomalies, R14 which suggests that common molecular mechanisms are responsible for dental and organ R15 development (Bailleul-Forestier et al., 2008). Tooth agenesis has been reported in syndromic 5 R16 craniosynostosis (premature fusion of the craniofacial sutures), such as in patients with Crouzon R17 or Apert syndrome (Cohen and MacLean, 2000; De Coster et al., 2007). These rare syndromes R18 R19 share common clinical features, genetic features, and craniofacial abnormalities (Wilke et al., R20 1997; Cohen and MacLean, 2000). R21 Previous studies describing tooth agenesis often use frequencies to describe which individual R22 tooth is missing in a certain population (Polder et al., 2004). This means that only one tooth at R23 the time is addressed and not the overall pattern of absent teeth. The recently introduced Tooth R24 Agenesis Code (TAC) can be used to describe the number and location of missing teeth (Van R25 Wijk and Tan, 2006). TAC scores of different studies could eventually be combined to describe R26 the overall pattern in tooth agenesis for a specific condition. Therefore, the purpose of this study R27 was to evaluate the prevalence of tooth agenesis and to describe patterns of tooth agenesis in R28 patients with Crouzon or Apert syndrome compared with those in nonsyndromic control subjects. R29 R30 R31 5.2 Materials and Methods R32 R33 R34 5.2.1 Participants R35 The sample consisted of 39 patients with Crouzon syndrome (20 boys and 19 girls) and 28 R36 patients with Apert syndrome (10 boys and 18 girls) from the Erasmus MC Craniofacial Center, R37 Sophia Children’s Hospital in Rotterdam, The Netherlands. A large mixed-longitudinal data set R38 R39

Patterns of Tooth Agenesis in Patients With the Syndrome of Crouzon or Apert | 89 R1 from the Nijmegen Growth Study was used as a control group (Prahl et al., 1979). From these R2 data a random selection of 284 nonsyndromic children was made (125 boys and 157 girls). R3 R4 5.2.2 Design R5 This study had a retrospective cross-sectional design. Longitudinal standardized panoramic R6 radiographs of sufficient quality taken in the protocol of diagnosis and treatment of these patients R7 between 1980 and 2011 were analyzed. The clinical diagnosis of Crouzon or Apert syndrome R8 R9 was genetically confirmed. Only Caucasian patients with one or more panoramic radiographs R10 were included. Patients and control subjects were between 11 and 22 years old at the time R11 of the panoramic radiograph examination. If a patient showed no third molar on a panoramic R12 radiograph at a certain age, agenesis was scored when the root length of the second molar R13 was at least equal to crown height on a panoramic radiograph (Liversidge, 2008). Chronological R14 age of at least 15.0 years (if available) (Richardson, 1980) was used as third criterion to score R15 third molar agenesis. Third molar agenesis could not always be determined because some of the R16 syndromic patients or control subjects were younger than 15 years, and third molars were still R17 absent. The use of data from human subjects followed an approved protocol and satisfied the R18 requirement of the Institutional Review Board (approval number MEC-2010-304). R19 R20 5.2.3 Patterns of Tooth Agenesis R21 The TAC (Van Wijk and Tan, 2006) was used to identify patterns of tooth agenesis. The TAC R22 consists of four numbers (q1, q2, q3, and q4) that describe the number and location of missing R23 R24 teeth in each quadrant. Within each quadrant the teeth are numbered 1 to 8 (Peck and Peck, R25 1996). Each tooth has a tooth value that can be determined by calculating 2(n-1), in which n = R26 tooth number. TAC values are derived by calculating the sum of tooth values for the missing teeth R27 in each quadrant (Fig. 5.1). R28 R29 5.2.4 Procedure R30 Tooth agenesis was diagnosed by one of two authors (E.O. or B.P-A.) based on clinical examination R31 and after studying the panoramic radiographs, plaster casts, and intraoral photographs. All R32 diagnoses were confirmed twice by one author (J.H.R.) by retrospectively studying the patients’ R33 dental charts and panoramic radiographs with an interval between the first and second assessment R34 of at least 1 week. In three patients, discrepancies between the authors were identified and R35 discussed until consensus was achieved. Cohen’s kappa showed high intraobserver (1.0) and R36 interobserver (0.96) reliability. Both scores are considered very high. R37 R38 R39

90 | Chapter 5 Right upper jaw (Q1) Left upper jaw (Q2) R1 A 18 17 16 15 14 13 12 11 21 22 23 24 25 26 27 28 R2 B 128 64 32 16 8 4 2 1 1 2 4 8 16 32 64 128 R3 A 48 47 46 45 44 43 42 41 31 32 33 34 35 36 37 38 R4 Right lower jaw (Q4) Left lower jaw (Q3) R5 R6 Figure 5.1 Schematic representation of the human dentition that can be used to determine Tooth Agenesis Code (TAC) values. To calculate TAC values [Q1, Q2, Q3, and Q4], simply calculate the R7 sum of the values associated with the missing elements in each quadrant. A, tooth numbering R8 according to the FDI tooth numbering system (22); B, values associated with missing teeth. FDI, (French) translates World Dental Federation; Q1, quadrant 1; Q2, quadrant 2; Q3, quadrant 3; R9 Q4, quadrant 4. R10 R11 5.2.5 Statistical Analysis R12 The Statistical Package for the Social Sciences (version 18.0; SPSS Inc., Chicago IL) was used for R13 data analysis. TAC values were analyzed using a website that was specifically developed for this R14 purpose (http://www.toothagenesiscode.com). A chi-square test and independent-samples t test R15 were used for statistical analysis. 5 R16 R17 R18 5.3 Results R19 R20 R21 5.3.1 Prevalence of Tooth Agenesis and Tooth Agenesis Patterns in Patients with Crouzon R22 Syndrome R23 Prevalence of tooth agenesis ( ≥ 1) in patients with Crouzon syndrome, including the third molar, R24 was 35.9% (upper jaw 10.3%, lower jaw 7.7%, upper and lower jaw 17.9%) (Table 5.1). The R25 number of missing teeth ranged from one to six. Patients showing tooth agenesis had an average R26 of 2.8 (SD = 1.3) missing teeth; for the upper and lower jaw the averages were was 1.8 (SD = R27 0.72) and 1.9 (SD = 0.30), respectively. The most commonly missing teeth were the third molars R28 (TAC value 128), followed by the second premolars (TAC value 16) and lateral incisors (TAC value R29 2) (Table 5.1). For the upper jaw, four patterns were found in q1 and three in q2 (Table 5.2). The R30 whole maxilla showed seven different patterns. The only symmetrical maxillary pattern was a R31 single bilateral third molar (TAC value 128). For the mandible, five different patterns were found R32 (Table 5.3). Except for one patient (TAC value 16 found in q4), all other patients with agenesis R33 R34 (n = 9) presented symmetrical patterns of one single tooth. R35 R36 R37 R38 R39

Patterns of Tooth Agenesis in Patients With the Syndrome of Crouzon or Apert | 91 R1 Total Total Total R2 R3 R4 q4 q4 q4 0 0 1 5 50 10 R5 21 20 10 6 2 3 0 20 0 16 1 10 100 37 R6 0 00 0 0 1 0 1 R7 00 00 0 00 0 0 5 2 0 2 4.6 3 2 2.4 19.8 2.3 6 14.0 7 11 100 7 100 31 100 43 100 166 62.525.0 512.5 1 71.4 1 14.3 13 14.3 14 2 87.8 34 79.1 136 0 R8 0 100 44.4 22.2 11.1 22.2

R9 n % n q3 q3 q3 0 5 2 1 0 8 1 4 0 0 0 R10 0 41 36 0 4 0 R11 2 1 2 9 % n % n R12 %

R13 0 % n % n 5.0 5.0 5.0 5.0 7.5 100 80.0

R14 n 0 0 0 100 R15 28.6 71.4 n 0 0 0 20 10 70 R16 100 n q2 q2 q2 R17 2 1 1 1 0 3 % 40 32 R18 0 2 5 0 0 7 R19 0 2 1 0 7 0 % 10 R20 % Apert syndrome Apert syndrome R21 subjects Control n 0 0 Crouzon syndrome syndrome Crouzon 7.0 2.4 4.8 4.8 100 R22 81.0 0 100 R23 11.1 11.1 66.7 11.1 n 0 0 q1 100 12.5 R24 12.5 62.5 12.5 n q1 R25 q1 1 1 6 0 1 9 3 0 1 2 0 2 % R26 34 42 R27 % 1 8 0 0 1 5 1 R28 % R29 R30 2

R31 n 2 1 +I + P 3 3 3 +P 2 2

R32 n 2 I Tooth type Tooth M C P P M M R33 n

R34 2 2 2 +P +M

R35 3 3 3 2 2 +P M M M P I 3 3 +C 2 2 1 2 I R36 I Patterns of missing teeth in each quadrant for sample. R37 R38 1 2 128 M 20 P TAC Tooth type 2 16 P 144Total M TAC Tooth type 128 144 192 TAC 16 Total 130 4 16 24 128 144 Total 2 R39 5.1 Table

92 | Chapter 5 R1 Total Total Total 5.3.2 Prevalence of Tooth Agenesis and Tooth Agenesis Patterns in Patients with Apert Syndrome R2 Prevalence of tooth agenesis ( ≥1) in patients with Apert syndrome, including the third molar, R3 R4 q4 q4 q4 was 46.4% (upper jaw 14.3%, lower jaw 10.7%, upper and lower jaw 21.4%) (Table 5.1). The 0 0 1 5 50 10 21 20 10 6 2 3 0 20 0 16 1 R5 10 100 37 number of missing teeth ranged from one to six. Patients who showed tooth agenesis had an R6 average of 2.6 (SD = 1.5) missing teeth. For the upper and lower jaw the averages were 1.3 0 00 0 0 1 0 1 00 00 0 00 0 0 5 2 0 2 4.6 3 2 R7 2.4 19.8 2.3 6 14.0 7 11 100 7 100 31 100 43 100 166 62.525.0 512.5 1 71.4 1 14.3 13 14.3 14 2 87.8 34 79.1 136 (SD = 0.43) and 1.7 (SD = 0.47), respectively. The most commonly missing teeth were the third 0 0 R8 100 44.4 22.2 11.1 22.2 molars (TAC value 128), followed by the second premolars (TAC value 16). For the upper jaw,

n % n R9 q3 q3 q3 four unilateral patterns of agenesis were found in the first quadrant (q1) and two patterns in the 0 5 2 1 0 8 1 4 0 0 0 0 R10 41 36 second quadrant (q2) (Table 5.2). The maxilla showed six different patterns (Table 5.2). Half of 0 4 0 2 1 2 9 R11 % n % n these maxillary patterns showed a symmetrical single tooth pattern of agenesis. Agenesis of the R12 % third molars (TAC value 128; 63.6%) was found bilaterally or unilaterally in q1 (Tables 5.1 and 5.2).

0 R13 % n % n 5.0 5.0 5.0 5.0 7.5 100 80.0

n R14 0 0 0 For the lower jaw, three patterns were found in the third quadrant (q3) and fourth quadrant (q4) 100 28.6 71.4 R15 n 0 0 0 (Table 5.3). The mandible showed nine different patterns of agenesis. In six patients a symmetrical 20 10 70 100 R16 n mandibular pattern of a single tooth was found. In all of these patients the mandibular agenesis q2 q2 q2 5 R17 2 1 1 1 0 3 % 40 32 was found in the second premolars and third molars (TAC values 16 and 128). R18 0 2 5 0 0 7 R19 0 2 1 0 7 0 % 10 5.3.3 Prevalence of Tooth Agenesis and Tooth Agenesis Patterns in Control Subjects R20 % The prevalence of tooth agenesis ( ≥1) in control subjects, including the third molar, was 27.5% Apert syndrome Apert syndrome Control subjects Control R21 n 0 0 Crouzon syndrome syndrome Crouzon 7.0 2.4 4.8 4.8 100

81.0 (upper jaw 8.8%, lower jaw 10.6%, upper and lower jaw 8.1%) (Table 5.1). The number of R22 0 100 11.1 11.1 66.7 11.1 missing teeth ranged from one to seven. Patients who had tooth agenesis had an average of 2.2 R23 n 0 0 q1 100 12.5 12.5 62.5 12.5 (SD = 1.4) missing teeth. For the upper and lower jaw the averages were 1.6 (SD = 0.48) and 1.4 R24 n q1 q1 (SD = 0.50), respectively. The most commonly missing teeth were the third molars, followed by R25 1 1 6 0 1 9 3 0 1 2 0 2 % 34 42 the second premolars and upper lateral incisors. Five agenesis patterns were found in q1 and six R26 % in q2 (Table 5.2). In the maxilla, 11 different patterns were found. In 64.6% of the symmetrical R27 1 8 0 0 1 5 1 % patients a single bilateral tooth symmetry was found in TAC value 128 (n = 28) and TAC value 2 (n R28 = 3). Of the patients with agenesis, 88.5% was found in the lateral incisors or third molars (TAC R29 value 2 or 128). Unilateral patterns of agenesis were found in q3 (n = 3) and q4 (n = 4) (Table 5.3). R30 2 n R31 2 1 The mandible showed eight different patterns of agenesis, most often in the second premolars +I + P 3 3 3 +P 2 2

n R32 2 I Tooth type Tooth M C P P M M and third molars (TAC values 16 and 128). n R33

2 R34 2 2 +P +M

3 3 3 R35 2 2 +P M M M P I 3 3 +C 2 2 1 2 I I R36 Patterns of missing teeth in each quadrant for sample. R37 R38 2 1 128 M 20 P TAC Tooth type 2 16 P 144Total M 128 144 192 TAC 16 Total TAC Tooth type 130 4 16 24 128 144 Total 2 Table 5.1 Table R39

Patterns of Tooth Agenesis in Patients With the Syndrome of Crouzon or Apert | 93 R1 R2 2 (3.8%) 1 (1.9%) 1 (1.9%) q3 & q4 R3 31 1 (2.1%) 1 (2.1%) 1 (2.1%) 1 (2.1%) q1 & q2 2 (4.2%) 34 R4 R5 R6 q4 1 (1.9%) 4 (7.5%) 12 q2 1 (2.1%) 2 (4.2%) 6 R7 R8 R9 Control 10 Control 1 (2.1%) R10 8 R11 R12 1 (9.1%) 1 (9.1%) q1 & q2 q1 1 (9.1%) 7 q3 & q4 q3 2 (20%) 10(18.9%) 11(20.8%) 23(43.4%) 9 R13 2 (20%) 1 (10%) R14 R15 1 (9.1%) q2 2 (18.2%) 4 (36.4%) 7 (14.6%) 5 (10.4%) 26(54.2%) 3 1 R16 1 (10%) 4 (40%) R17

R18 Crouzon Crouzon 1 R19 R20 q3 & q4 q3 q4 6 1 (7.7%) R21 1 (7.7%) q1 & q2 q1 4 (30.8%) 1 (7.7%) 6 R22 R23 q4 1 q2 1 R24 1 (7.7%) 1 (7.7%) 1 (9.1%) R25 R26 q3 2 1 (7.7%)1 (7.7%) 1 (7.7%) 4 (30.8%) q1 1 (7.7%) 2 (15.4%) R27 3 R28 R29 (q2) 3

R30 (q2) (q2) (q2) (q2) 3 3 2 3 (q2) 2 (q2) 1

R31 +P (q2) 1 (q2) 2 R32 3 (q1) and M (q1) and M R33 2 (q1) and M 2 (q1) and M (q1) and P (q1) and I 2 2 2 2 2 2 +I (q1) and I (q1) and P +I +P +M 3 3 3 3 3 3 3 +P +P

R34 +P 3 3 3 2 1 (q1) and M 1 2 2 2 M M P C+P I I C P M M 1 2 I P I R35 M M

R36 Mandibular patterns of tooth agenesis for patients with the syndrome Crouzon, Apert and control subjects. Maxillary patterns of tooth agenesis for patients with the syndrome Crouzon, Apert and control subjects. R37 R38 144.128 M 128.2 130.128 M 128.24 24.16 16.128 P 20.1 Total 2 144.128 M 1 2 TAC valuesTAC missing teeth Corresponding Apert valuesTAC missing teeth Corresponding Apert 16 1 128 144 4 16 130 Total 192.128 M 128 Table 5.2 Table R39 5.3 Table

94 | Chapter 5 5.3.4 Comparison of Patients With Crouzon and Apert Syndrome With Control Subjects R1 Differences between control subjects and patients with Crouzon and Apert syndrome were R2 found in the prevalence of tooth agenesis. Prevalence of agenesis including the third molar was R3 R4 significantly higher in that patients with Apert syndrome χ( 2[1] = 4.4; P = .035), but no difference R5 was found for patients with Crouzon syndrome compared with control subjects (χ2[1] = 1.2; R6 P = .27). The prevalence of agenesis, excluding the third molar, among patients with Crouzon R7 syndrome (23.1%) and Apert syndrome (25.0%) was significantly higher than that for control R8 2 subjects (6.0%) (χ [2] = 23.8; P <.001). The mean number of missing teeth was significantly R9 higher in patients with Crouzon syndrome compared with control subjects (t[315] = 2.51; P = R10 .013). Among patients with tooth agenesis, symmetrical maxillary patterns were found more R11 frequently in control subjects than in patients with Crouzon or Apert syndrome, (χ2[2] = 3.23; R12 P = .019). Symmetrical mandibular patterns were found more frequently in patients with Crouzon R13 and Apert syndrome than in control subjects, but these differences were not statistically significant R14 (χ2[2] = 5.04; P =.081) (Tables 5.2 and 5.3). In syndromic patients, agenesis of a bilateral second R15 mandibular premolar occurred significantly more often in syndromic patients than in control 5 R16 subjects (χ2[2] = 24.62; P <. 001). R17 R18 R19 R20 5.4 Discussion R21 R22 5.4.1 Prevalence of Tooth Agenesis R23 The prevalence of agenesis among patients with Crouzon and Apert syndromes was significantly R24 higher than in control subjects and was in agreement with an earlier finding that these syndromes R25 are associated with tooth agenesis (Bailleul-Forestier et al., 2008). The prevalence of third molar R26 agenesis in the present study is very similar to that found in other studies (Kazanci et al., 2010; R27 Celikoglu et al., 2011). Third molar agenesis in patients with Apert syndrome was statistically R28 significant higher than that for control subjects. Third molar agenesis might correlate with an R29 increased prevalence of other missing teeth (Celikoglu et al., 2011). In addition, agenesis of the R30 third molars exhibited maxillary lateral incisor microdontia more frequently and showed higher R31 prevalence of other dental anomalies than in control subjects (De Coster et al., 2009; Celikoglu R32 et al., 2011). R33 R34 Previous reports (Garn et al., 1962; Gravely, 1965) suggested that the upper age limit for third R35 molar agenesis is 13 years. Additionally, some studies reported that third molar development R36 was as late as age 14 or 15 years (Richardson, 1980). Besides age, third molar agenesis can also R37 be predicted from second molar formation. The probability of a third molar crypt developing R38 R39

Patterns of Tooth Agenesis in Patients With the Syndrome of Crouzon or Apert | 95 R1 decreases as the adjacent second molar root matures. When the root of the second molar is R2 halfway, it is very unlikely for individuals to develop a third molar crypt at a later stage (Liversidge, R3 2008). R4 In this study, the prevalence of agenesis, excluding third molars, in control subjects was R5 within the same range as found in other studies (Polder et al., 2004), whereas the prevalence R6 found in patients with Crouzon or Apert syndrome showed much greater prevalence. The second R7 most commonly absent tooth was the mandibular second premolar in all groups, although the R8 R9 prevalence was significantly higher in patients with Crouzon and Apert syndrome than in control R10 subjects. R11 R12 5.4.2 Patterns of Tooth Agenesis R13 Among patients with tooth agenesis, a trend of symmetrical maxillary patterns was found more R14 often in control subjects than in patients with Crouzon or Apert syndrome (Tables 5.1 and 5.2). R15 In contrast, symmetrical mandibular patterns were found significantly more frequently in patients R16 with Crouzon or Apert syndrome compared with control subjects (Tables 5.1 and 5.3). This finding R17 is surprising as tooth agenesis was shown to be more or less equally distributed between maxilla R18 and mandible in each of the three groups. Prevalence of bilateral mandibular second premolar R19 agenesis was significantly higher in syndromic patients than control subjects. In two patients, R20 a combination of TAC values were found, whereas all other symmetrical patterns in mandible R21 or maxilla were combinations of missing bilaterally single teeth (Tables 5.2 and 5.3). Although R22 sample sizes are small, it might suggest that there are common molecular mechanisms of the R23 R24 same genetic defect for tooth agenesis and syndromic development (De Coster et al., 2007). R25 Two Swedish studies also revealed higher prevalence of tooth agenesis in patients with R26 Crouzon syndrome (42.3%; n = 26) (Stavropoulos et al., 2012) or Apert syndrome (34.8%; R27 n = 23) (Stavropoulos et al., 2011), although third molars were excluded. A variety of patterns, R28 mainly asymmetric, were found for patients with Crouzon syndrome (Stavropoulos et al., 2012) R29 in contrast to the mainly symmetrical patterns found in this study. In contrast, the other Swedish R30 study showed mainly symmetrical dental agenesis patterns in patients with Apert syndrome R31 (Stavropoulos et al., 2011). Bilateral tooth agenesis patterns were found for second mandibular R32 premolars and lateral maxillary incisors in patients with Apert syndrome (Stavropoulos et al., R33 2011). However, in this study the prevalence of maxillary incisors in patients with Apert syndrome R34 was very low (Table 5.1). It was also apparent that in the Swedish study agenesis occurred in R35 either the maxilla or mandible and not in both arches (Stavropoulos et al., 2011). The prevalence R36 of the second mandibular premolar agenesis was in agreement with this study. Ethnic population R37 differences and the number of patients might explain differences found in this study and the R38 R39 Swedish studies.

96 | Chapter 5 5.5 Conclusion R1 R2 R3 • Prevalence of agenesis excluding the third molar is significantly higher in syndromic R4 patients than in control subjects. R5 • Tooth agenesis including the third molar is more prevalent in patients with Apert R6 syndrome than in patients with Crouzon syndrome and control subjects. R7 Symmetrical maxillary patterns of tooth agenesis were found more often in control • R8 subjects than in syndromic subjects. R9 • Symmetrical mandibular patterns of tooth agenesis seem to occur more often in patients R10 with Crouzon or Apert syndrome often than in control subjects. R11 • Prevalence of bilateral tooth agenesis of second mandibular premolars is higher in R12 syndromic patients than in control subjects. R13 R14 R15 5 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

Patterns of Tooth Agenesis in Patients With the Syndrome of Crouzon or Apert | 97 R1 5.6 References R2 R3 Bailleul-Forestier I, Berdal A, Vinckier F, de Ravel T, Fryns JP, Verloes A. The genetic basis of inherited anomalies of the teeth. Part 2: syndromes with significant dental involvement. Eur J Med Genet. 2008;51:383– R4 408. R5 Celikoglu M, Bayram M, Nur M. Patterns of third-molar agenesis and associated dental anomalies in an R6 orthodontic population. Am J Orthod Dentofacial Orthop. 2011;140:856–860. R7 Cohen MM, MacLean RE. Craniosynostosis: Diagnosis, Evaluation, and Management. New York: Oxford University Press; 2000:316–365. R8 De Coster PJ, Marks LA, Martens LC, Huysseune A. Dental agenesis: genetic and clinical perspectives. J Oral R9 Pathol Med. 2009;38:1–17. R10 De Coster PJ, Mortier G, Marks LA, Martens LC. Cranial suture biology and dental development: genetic and R11 clinical perspectives. J Oral Pathol Med. 2007;36:447–455. R12 Garn SM, Lewis AB, Vicinus JH. Third molar agenesis and reduction in the number of other teeth. J Dent Res. 1962;41:717. R13 Gravely JF. A radiographic survey of third molar development. Br Dent J. 1965;119:397–401. R14 Kazanci F, Celikoglu M, Miloglu O, Oktay H. Third-molar agenesis among patients from the East Anatolian R15 region of Turkey. J Contemp Dent Pract. 2010;11:E033–E040. R16 Liversidge H. Predicting mandibular third molar agenesis from second molar formation. Acta Stomatol Croat. 2008;42:311–317. R17 Peck S, Peck L. Tooth numbering progress. Angle Orthod. 1996;66:83–84. R18 Polder BJ. Van‘t Hof MA, Van der Linden FP, Kuijpers-Jagtman AM. A meta-analysis of the prevalence of dental R19 agenesis of permanent teeth. Community Dent Oral Epidemiol. 2004;32:217–226. R20 Prahl-Andersen B, Kowalski CJ, Heyendaal PHJM. A Mixed-Longitudinal Interdisciplinary Study of Growth and R21 Development. New York: Academic Press; 1979. R22 Richardson M. Late third molar genesis: its significance in orthodontic treatment. Angle Orthod. 1980;50:121– 128. R23 Stavropoulos D, Bartzela T, Bronkhorst E, Mohlin B, Hagberg C. Dental agenesis patterns of permanent teeth R24 in Apert syndrome. Eur J Oral Sci. 2011;119:198–203. R25 Stavropoulos D, Bartzela T, Tarnow P, Mohlin B, Kahnberg KE, Hagberg C. Dental agenesis patterns in Crouzon R26 syndrome. Swed Dent J. 2012;35:195–201. Van Wijk AJ, Tan SP. A numeric code for identifying patterns of human tooth agenesis: a new approach. Eur R27 J Oral Sci. 2006;114:97–101. R28 Vastardis H. The genetics of human tooth agenesis: new discoveries for understanding dental anomalies. Am R29 J Orthod Dentofacial Orthop. 2000;117:650–656. R30 Wilke TA, Gubbels S, Schwartz J, Richan JM. Expression of fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3) in the developing head and face. Dev Dyn. 1997;210:41–52. R31 R32 R33 R34 R35 R36 R37 R38 R39

98 | Chapter 5 Chapter 6

A Longitudinal Study of Dental Arch Morphology in Children With the Syndrome of Crouzon or Apert

Jacobus H. Reitsma Poejan Elmi Edwin M. Ongkosuwito Peter H. Buschang Birte Prahl-Andersen

European Journal of Oral Sciences 2013; 121: 319-327 R1 Abstract R2

R3 Objective: The aim of this study was to compare changes in dental arch morphology between R4 patients with Crouzon syndrome or Apert syndrome and controls. R5 R6 Patients and Methods: Children between 4 and 14 yr of age with Crouzon syndrome (n = 40) or R7 Apert syndrome (n = 28) were compared with nonsyndromic controls (n = 457) in terms of arch R8 R9 widths, depths, and length dimensions. Multilevel statistical modeling techniques were used to R10 evaluate changes over time. R11 R12 Results: Dental arch dimensions were found to be smaller in patients with Crouzon syndrome or R13 Apert syndrome compared with control subjects. Maxillary intercanine width for patients with R14 Apert syndrome were increased, whilst other arch width variables showed no change. Patients R15 with Crouzon syndrome showed increases in maxillary intercanine width, whilst intermolar width R16 showed no change over time. R17

R18 Conclusions: Dental arch dimensions in syndromic patients were thus found to be consistently R19 smaller than in control subjects between 4 and 14 yr of age, implying that patients with Crouzon R20 syndrome and Apert syndrome had a diminished growth potential. R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

100 | Chapter 6 6.1 Introduction R1 R2

Longitudinal reference data of dental arch dimensions during childhood and adolescence in R3 R4 patients with Crouzon syndrome or Apert syndrome are scarce. Such data would make it easier R5 to predict abnormal tooth movement and help the often challenging orthodontic treatment R6 planning in these patients. Children born with Crouzon syndrome or Apert syndrome suffer R7 from a marked craniofacial skeletal deformity that may also affect the overlying soft tissues and R8 underlying structures. Crouzon syndrome is characterized by shallow orbits, ocular proptosis, a R9 variable degree of maxillary hypoplasia, and a Class III malocclusion. Patients with Apert syndrome R10 have a craniofacial appearance comparable with that of patients with Crouzon syndrome, but the R11 deformity has generally been characterized as more severe. The premature closure of craniofacial R12 sutures (craniosynostosis), seen in both syndromes, indirectly influences tooth eruption and R13 dental arch dimensions (Cohen and Kreiborg, 1996; Kreiborg, 1981; Kreiborg and Björk, 1982). R14 Dental arches in the syndromic patients are often distorted because the morphology of the dental R15 arch is determined by the supporting basal maxillary and mandibular bones (Kreiborg and Björk, R16 1982; Costaras-Volarich and Pruzansky, 1984). Craniosynostosis severely decreases dental arch R17 dimensions as a result of the lack of maxillary growth, which might be expected to produce R18 R19 tooth size arch discrepancies in patients with Crouzon syndrome or Apert syndrome (Kreiborg 6 R20 and Cohen, 1998). Increased prevalence of dental agenesis and delayed dental maturation in R21 Crouzon syndrome or Apert syndrome may decrease dental arch dimensions even more (Reitsma R22 et al., 2013; Stavropoulos et al., 2011; Stavropoulos et al., 2011a). R23 The development of the human dentition is normally a continuous process (Moorrees, 1959). R24 Individual variation in dental arch dimensions may be explained by the supporting bone, genetic R25 background, tooth movement, oral habits, dental caries, periodontal disease, oral musculature, R26 age, or gender (Moorrees, 1959; Buschang et al., 1987; Thilander, 2009; Moorrees et al., 1969). R27 The maxilla and mandible are consistently larger in boys than in girls (Thilander, 2009; Moorrees et R28 al., 1969; Ward et al., 2006). Knowledge of these kinds of change of different variables affecting R29 dental arch dimensions may be useful for individualized predictions of dental arch development R30 (Buschang et al., 1987). R31 Dental arch dimensions change during the period of intensive growth and less so in R32 adulthood (Ward et al., 2006; Bishara et al., 1996; Carter and McNamara, 1998). Intercanine R33 R34 width, intermolar width, dental arch depth, and arch length are the dental arch dimensions most R35 often described (Thilander, 2009; Bishara et al., 1996). In healthy children, width dimensions in R36 both arches remain static between 3 and 5 yr of age (Moorrees et al., 1969; Ward et al., 2006; R37 Bishara et al., 1996). The intercanine width increases between 6 and 10 yr of age, associated R38 R39

A Longitudinal Study of Dental Arch Morphology in Children With the Syndrome of Crouzon or Apert | 101 R1 with the eruption of the permanent incisors and canines (Moorrees, 1959; Prahl-Andersen et al., R2 1979). From 10 to 11 yr of age, the maxillary intercanine width increases up to the age of 16 yr, R3 whilst the mandibular intercanine width decreases between 10 and 16 yr of age (Thilander, 2009; R4 Moorrees et al., 1969; Prahl-Andersen et al., 1979). The mandibular intermolar width increases R5 between 9 and 14 yr of age and remains constant after 14 yr of age (Moorrees, 1959, Ward et al., R6 2006, Prahl-Andersen et al., 1979). These changes in width are related to the growth period and R7 to the timing and direction of eruption of the permanent teeth (Ward et al., 2006). The maxillary R8 R9 and mandibular arch lengths decrease between 9 and 14 yr of age and remain constant after the R10 age of 14. The main causes of these changes are the closure of posterior interproximal spaces as a R11 result of the replacement of the deciduous molars with the permanent premolars, lingual tipping R12 of the anterior teeth, and the interproximal contacts made by the permanent teeth (Moorrees R13 et al., 1969). In the early mixed dentition, the dental arch depth increases with the eruption of R14 the permanent incisors in a proclined position. In the late mixed dentition, the dental arch depth R15 decreases owing to the mesial drift of the first molars into leeway spaces and sometimes because R16 of incisor crowding (Moorrees, 1959; Bishara et al., 1997). R17 To date, the dental features of patients with Crouzon syndrome and Apert syndrome have R18 been poorly described and characterized. They have been reported mainly in isolated case reports R19 (Dalben et al., 2006). Longitudinal dental arch measurements of patients with Crouzon syndrome R20 or Apert syndrome are currently lacking. It is essential to provide information on the dental R21 arch changes and, more importantly, on the variability in the observed changes. It is particularly R22 important to have a better understanding of the sagittal and transversal growth changes that R23 R24 occur between primary and late mixed dentitions in the maxillary and mandibular arches in both R25 syndromic and nonsyndromic children. R26 Therefore, the aim of this study was to investigate longitudinal changes in dental arch R27 dimensions during the growth of patients with Crouzon syndrome or Apert syndrome. R28 R29 R30 6.2 Material and methods R31 R32 6.2.1 Patient sample R33 Between 1980 and 2007, all Caucasian patients diagnosed with Crouzon or Apert syndrome with R34 available dental casts were used from the Erasmus Medical Center Rotterdam, the Netherlands. R35 Data from patients, 4 -14 yr of age, with Crouzon syndrome (18 girls and 22 boys) or Apert R36 syndrome (16 girls and 12 boys) were obtained from the Department of Orthodontics, Sophia R37 Children’s Hospital, Erasmus MC, in Rotterdam, the Netherlands. The clinical diagnosis of the R38 R39

102 | Chapter 6 syndromes was genetically confirmed. Dental casts of patients with Crouzon syndrome or Apert R1 syndrome were transformed into digital models (Ortho-Proof, Nieuwegein, The Netherlands). The R2 impressions and the wax bite were scanned using a Flash CT scanner (model FCT-1600; Hytec, Los R3 R4 Alamos, NM, USA) at 160 kV with a voxel resolution of 0.05 mm. R5 Patients were diagnosed early and most often had a fronto-orbital advancement or cranial R6 remodeling between 6 and 12 months after birth to prevent brain and optic nerve damage. As R7 patients were diagnosed and treated (or operated on) at different ages, only patients who had R8 no previous surgical midfacial advancement, orthodontic treatment, or extractions of permanent R9 teeth were selected. Syndromic data were analyzed and compared with a longitudinal data set R10 from the Nijmegen Growth Study (Prahl-Andersen et al., 1979). This longitudinal growth study R11 comprised a total of 457 Dutch nonsyndromic children (241 girls and 216 boys) between 4 R12 and 14 yr of age. The sample selection was based on longitudinal records, with no malformed, R13 extracted teeth, no previous orthodontic treatment, and all points to be measured being clearly R14 identifiable. In the present study, the prevalence of dental agenesis of permanent teeth, excluding R15 third molars, occurred in patients with Crouzon syndrome (maxilla 12.8%; mandible 20.5%), R16 Apert syndrome (maxilla 14.3%; mandible 25.0%), and healthy children (maxilla 3.5%; mandible R17 3.2%). In patients with dental agenesis, only dental casts with the remaining primary teeth were R18 R19 used. This resulted in 70 dental casts [median (range) = 2 (1–5)] from 40 patients with Crouzon 6 R20 syndrome, 64 dental casts [2 (1–6)] from 28 patients with Apert syndrome, and 3.667 dental R21 casts [9 (1–12)] from 486 healthy children. The hospital records of the syndromic patients were R22 retrospectively reviewed after ethical approval from the Institutional Review Board at Sophia R23 Children’s Hospital, Erasmus Medical Centre (MEC-2010-304). R24 R25 6.2.2 Outcome variables R26 To examine the morphological changes of dental arches, eight measurements (Fig. 6.1) were R27 taken, four in the mandible and four in the maxilla. One investigator made all the measurements R28 for further statistical analysis. R29 (i) Intercanine width, measured as the distance between the cusp tips of deciduous and R30 permanent canines. In the case of attrition, the measuring point was determined as the R31 middle of the facet. R32 (ii) Intermolar width, measured as the distance between the center point of the occlusal R33 R34 surface of the right and left first permanent molars. Intermolar width was measured R35 from the first appearance of permanent first molars between 7 and 14 yr of age. R36 (iii) Arch depth, measured as the perpendicular distance from the labial surface of the R37 central incisors to the mesial surface of the first permanent molar or the distal surface R38 of the second deciduous molar or permanent second premolar. R39

A Longitudinal Study of Dental Arch Morphology in Children With the Syndrome of Crouzon or Apert | 103 R1 (iv) Arch length, the sum of the right and left distances between the mesial surface R2 of the first permanent molars or the distal surface of the second deciduous molar or R3 permanent second premolar and the interproximal contact point of the central incisors R4 or the midpoint of the central diastema when present. R5 R6 6.2.3 Intra- and inter-reliability R7 Measurements on 20 randomly selected dental casts were repeated after 2 months to determine R8 R9 the intraclass correlation coefficient (Shrout and Fleiss, 1979). The inter-reliability was tested by R10 two examiners on the same selected dental casts. R11 R12 6.2.4 Growth models R13 The data were analyzed using multilevel modeling of longitudinal data (Goldstein, 1987). Multilevel R14 models are statistical models of parameters that vary at more than one level. A multilevel model R15 attempts to model all the components in a hierarchy of nested effects (Goldstein, 1987). The R16 program, MLwiN (version 1.2; Centre for Multilevel Modelling, London, UK), was used to model R17 growth changes and compare the three groups. For each y variable (the dental arch measurement), R18 a polynomial equation was estimated for the child (i) on the age of the measurement (j). The y R19 intercept was adjusted to 10 yr of age (intercept = age - 10) to provide a comparison in the middle R20 of the age range. Average growth curves were estimated mathematically. Owing to expected R21 differences associated with the syndromes, separate models were fitted. Multiple tests for each R22 variable were run for the separate groups and for possible differences between groups. Despite R23 R24 multiple testing, it was decided not to correct alpha because the accompanying reduction in R25 statistical power would not be beneficial given the relatively small sample sizes of the syndromic R26 groups. A cubic model was first fitted for each group and the highest-order term was checked R27 for statistical significance; if it was not statistically significant (P < 0.05) it was eliminated and the 2 3 R28 lower-order model was tested. Theyij = initialβ0ijconstant equation + β1t ijwas: + β2tij + β3tij R29

with 2 3 R30 yij = β0ijconstant + β1tij + β2tij + β3tij R31 with β0ij = u0j + e0ij R32 with R33 The dental arch measurement, y, was computed by adding the intercept (b0ij) to the products where the craniofacial growth measurement y was computed by adding the intercept (β0ij) to the R34 β0ij = u0j + e0ij of other fixed coefficients (b1, b2, and b3) multiplied by age (t) at each occasion. u0j and e0ij R35 β β β compriseproducts the of otherrandom fixed portion coefficients of the ( 1 ,model 2, and and 3) multipliedare assumed by age to ( t)have at each means occasion. equal The to u 0jzero, and to R36 where the craniofacial growth measurement y was computed by adding the intercept (β0ij) to the be euncorrelated,0ij comprise the and random normally portion distributed. of the model Theand arelevel assumed 1 residual, to have e means, represents equal to within-subjectzero, to be R37 0ij variation,products or of the other ‘error’ fixed coefficientsterm, whilst (β 1 the, β2 , leveland β 23) multipliedresidual, uby, agerepresents, (t) at each inoccasion. this case, The ubetween-0j and R38 uncorrelated, and to be normally distributed. The level 1 residual0j e0ij represents within-subject R39 e0ij comprise the random portion of the model and are assumed to have means equal to zero, to be variation, or the ‘‘error’’ term, while the level 2 residual u0j represents, in this case, between-subject

uncorrelated, and to be normally distributed. The level 1 residual e0ij represents within-subject variation (Goldstein, 1987). 104 | Chapter 6 variation, or the ‘‘error’’ term, while the level 2 residual u0j represents, in this case, between-subject The polynomial model takes full advantage of each patient’s individual longitudinal growth variation (Goldstein, 1987). data and statistically evaluates the shape of the curve. Iterative generalized least squares were used to The polynomial model takes full advantage of each patient’s individual longitudinal growth estimate the model’s parameters (Goldstein, 1987). Two-level models were also used to estimate the data and statistically evaluates the shape of the curve. Iterative generalized least squares were used to groups’ adult stat status at 22 years of age (intercept = age - 22). estimate the model’s parameters (Goldstein, 1987). Two-level models were also used to estimate the

groups’ adult stat status at 22 years of age (intercept = age - 22).

2.3 Results

2.32.3.1 Results Assessment of Interexaminer and Intraexaminer Variation

2.3.1ICC values Assessment for intraobserver of Interexaminer reliability andwere Intraexaminerexcellent (Table Variation2.2). The ICC values for interobserver reliability were fair to excellent (Table 2.2): Fair to good reliability was found for measurements ICC values for intraobserver reliability were excellent (Table 2.2). The ICC values for interobserver concerning the inclination of the maxilla and point B relative to the cranial base and LFH, and all the reliability were fair to excellent (Table 2.2): Fair to good reliability was found for measurements other measurements showed excellent reliability. concerning the inclination of the maxilla and point B relative to the cranial base and LFH, and all the

other measurements showed excellent reliability.

2.3.2 Growth Models

2.3.2Control Growth Subjects Models

Control Subjects 47

47 subject variation (Goldstein, 1987). The fixed parameters from the different models for the R1 various groups were used to construct growth curves for the different dental arch measurements. R2 Initial multilevel modeling showed no gender differences for syndromic patients, in contrast to R3 R4 healthy children. Therefore, the data from all boys and girls were pooled. The polynomial model R5 takes full advantage of each patient’s individual longitudinal growth data, easily handles missing R6 data, and statistically evaluates the shape of the curve. Iterative generalized least squares were R7 used to estimate the model’s parameters (Goldstein, 1987). R8 R9 R10 6.3 Results R11 R12 6.3.1 Measurement error R13 The intraclass correlation coefficient values for intraobserver reliability varied from 0.897 to 0.984 R14 for dental arch measurements. The intraclass correlation coefficient values for interobserver R15 reliability varied from 0.875 to 0.988. An interclass correlation coefficient value larger than 0.75 R16 represents a high level of reliability (Fleiss, 1986). R17 R18 R19 6.3.2 Nonsyndromic control subjects 6 R20 Multilevel statistical/mathematical modeling showed that the growth curves ranged from linear R21 changes to second-order changes. The second-order changes or quadratic coefficient of the R22 model refers to changes in growth velocity. The fixed terms of each model were used to estimate R23 the dental arch values in subjects between 4 and 14 yr of age (Table 6.1). For example, the R24 mandibular intermolar width for control subjects was 42.20 mm at 12 yr of age, computed as R25 41.30 + (0.4514 x 2). Note that the linear term 0.4514 (the yearly change) for control subjects R26 was multiplied by two instead of by 12, because the intercept had been set to 10 yr of age. R27 The multilevel statistical models showed statistical group differences for 18 of the 24 variables R28 evaluated (Table 6.2). The multilevel models of the control subjects showed that mandibular and R29 maxillary intermolar widths (Fig. 6.2) followed linear patterns of growth between 4 and 14 yr of R30 age (i.e. the widths increased by approximately the same amounts each year). All of the other R31 arch dimensions followed quadratic growth curves, with rates of growth increasing initially and R32 then decreasing. Maxillary intercanine width increased 6 mm; and mandibular intercanine width R33 R34 increased approximately 4 mm between 4 and 12 yr of age, and then decreased slightly (Fig. R35 6.3). Arch depths increased slightly during the first 4 yr, and decreased between 8 and 14 yr of R36 age (Fig. 6.4). Maxillary arch length increased between 4 and 12 yr of age, and then decreased R37 slightly (Fig. 6.5a); mandibular arch length increased, with little or no change after 12 yr of age R38 (Fig. 6.5b). R39

A Longitudinal Study of Dental Arch Morphology in Children With the Syndrome of Crouzon or Apert | 105 R1 R2 R3

R4 Linear R5 R6 R7 R8 6.585e+1 1.468e+0 -8.645e-1 3.379e-1 2.097e+1 8.423e-1 2.356e+1 7.167e-1 2.502e+1 6.157e-1 3.758e+1 1.015e+0 9.274e-1 1.991e-1 3.870e+1 9.842e-1 Constant R9 Apert R10 R11 R12 R13 Estimate SE Quadratic R14 R15 R16 R17 Estimate SE R18 Linear R19 R20 R21 4.027e+1 6.382e-1 4.012e+1 8.212e-1

R22 Estimate SE Crouzon Constant R23 R24 R25 R26 Estimate SE R27 Quadratic R28 R29 R30 R31 Estimate SE Linear R32 R33 R34 R35 9.786e+1 2.341e-1 1.621e-0 -5.491e-2 -6.448e-1 1.390e-2 6.783e+1 1.160e+0 8.840e+1 2.459e-1 9.081e-1 4.525e-2 -1.813e-1 1.778e-2 6.690e+1 8.739e-1 -6.687e-1 1.924e-1 -1.363e-1 5.735e-2 6.500e+1 1.035e+0 -9.391e-1 1.720e-1 2.841e+1 9.806e-2 -3.337e-1 1.181e-22.354e+1 -7.524e-2 1.015e+0 -5.163e-1 2.855e-3 1.040e-2 2.259e+1 -4.793e-2 5.113e-1 3.717e-3 2.352e+1 3.452e-1 -4.312e-1 8.127e-2 -6.763e-2 2.395e-2 2.210e+1 4.555e-1 -6.811e-1 8.369e-2 2.630e+1 8.490e-2 1.991e-1 1.141e-2 -8.682e-2 2.824e-3 2.309e+1 5.016e-1 6.092e-1 1.126e-1 4.130e+1 1.178e-1 4.514e-1 1.195e-2 3.188e+1 9.463e-2 6.214e-1 1.266e-2 -2.655e-2 3.007e-3 2.979e+1 6.209e-1 4.163e-1 1.374e-1 4.432e+1 4.376e-2 2.776e-1 2.427e-2 Estimate SE R36 Constant R37 Multilevel models for untreated control, Crouzon and Apert children. R38 Maxillary arch Maxillary arch length (mm) Mandibular length arch (mm) Maxillary arch Maxillary arch depth (mm) Mandibular depth arch (mm) Mandibular intercanine width (mm) Mandibular intermolar width (mm) Maxillary intercanine width (mm) Maxillary intermolar width (mm) Measures Control

R39 6.1 Table

106 | Chapter 6 R1 R2 R3

Linear Estimate SE R4 R5 R6 R7 R8 Difference Crouzon vs Apert Crouzon Difference Constant Estimate SE 1.262e+0 1.419e+0 1.4273e+0 1.285e+0 -3.657e+0 8.022e-1 -8.798e-1 9.036e-1 9.512e-1 8.556e-1 -1.005e+0 5.353e-1 4.285e-1 1.004e-1 3.936e-1 1.767e+0 R9 R10 R11 R12 R13 Linear Estimate SE R14 R15 R16 R17 R18 Difference Control vs Apert Control Difference Constant Estimate SE -7.584e+0 1.119e+0 9.135e-1 2.576e-1 -2.841e+0 8.031e-1 -4.553e+0 4.843e-1 -3.872e+0 4.319e-1 -7.523e+0 1.302e+0 -1.358e+0 5.540e-1 -2.734e+1 1.488e+0 -4.244e+0 3.344e-1 R19 6 R20 R21 R22

Quadratic Estimate SE R23 R24 R25 R26 R27 Linear Estimate SE R28 R29 R30 R31 R32 Difference Control vs Crouzon Control Difference Constant Estimate SE -4.096e+0 5.319e-1 -1.358e+0 5.540e-1 -1.954e+0 4.332e-1 -2.5759e-1 7.865e-2 -2.649e+0 3.596e-1 1.887e-1 5.463e-2 -5.140e+0 4.163e-1 -2.075e+1 1.068e+0 -2.176e+1 1.273e+0 -1.964e+0 3.470e-1 4.311e-1 1.015e-1 -1.949e+1 1.426e+0 -3.977e+0 3.242e-1 -1.030e+0 1.286e+0 6.142e-1 2.273e-1 R33 R34 R35 R36 Comparison between multilevel models for untreated control, Crouzon and Apert children. * bold indicates statically significant difference. R37 R38 Measurements Maxillary intermolar width (mm) Mandibular intermolar width (mm) Maxillary intercanine width (mm) Maxillary intercanine Mandibular intercanine width (mm) Maxillary arch depth (mm) Maxillary arch Mandibular arch depth (mm)Mandibular arch -1.850e-1 4.137e-1 1.300e-1 6.555e-2 3.949e-3 2.063e-2 Maxillary arch length (mm) Maxillary arch Mandibular arch length (mm) Mandibular arch

Table 6.2 Table R39

A Longitudinal Study of Dental Arch Morphology in Children With the Syndrome of Crouzon or Apert | 107 R1 6.3.3 Crouzon syndrome patients R2 Compared with the controls, patients with Crouzon syndrome followed entirely different R3 (simpler) growth patterns for six of the eight variables measured; only mandibular arch depths R4 and lengths followed the same quadratic pattern of the controls. The mandibular and maxillary R5 intermolar width (Fig. 6.2) for patients with Crouzon syndrome showed no change over time, R6 whereas mandibular and maxillary intercanine widths increased (Fig. 6.3). The intercanine and R7 intermolar widths of the dentition in patients with Crouzon syndrome were statistically smaller R8 R9 at 10 yr of age compared with those of control subjects (Tables 6.1 and 6.2). The growth model R10 for mandibular arch depth for patients with Crouzon syndrome was not statistically different R11 from that for control subjects (Fig. 6.4 and Tables 6.1 and 6.2). Maxillary arch depth showed no R12 change at the given age range; these variables were statistically smaller than in control subjects. R13 Maxillary and mandibular dental arch lengths measured for patients with Crouzon syndrome R14 were statistically smaller than in control subjects (Fig. 6.5). Dental arch length did not change in R15 the maxilla, but it decreased slightly in the mandible. R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 Figure 6.1 Diagram showing dental arch measurements. (1) Intercanine width. (2) Intermolar width. (3) Arch R31 depth. (4) Arch length. R32

R33 6.3.4 Apert syndrome patients R34 Compared with the controls, the growth patterns of patients with Apert syndrome were entirely R35 different for all variables measured. Patients with Apert syndrome showed no change over time R36 for mandibular intermolar width (Fig. 6.2a), or for maxillary and mandibular intercanine width R37 variables (Fig. 6.3). The maxillary intermolar width increased between 7 and 14 yr of age (Fig. R38 R39

108 | Chapter 6 6.2b). All width variables were statistically smaller than in control subjects. Dental arch depth in R1 the maxilla decreased over time, whilst mandibular dental arch depth showed no change over R2 time (Fig. 6.4). The arch depth in the maxilla was statistically smaller than in control subjects at R3 R4 10 yr of age, whilst the mandibular arch depth showed no difference. Maxillary and mandibular R5 arch lengths in syndromic patients were statistically smaller than in control subjects and decreased R6 slightly from 4 to 14 yr of age (Fig. 6.5 and Tables 6.1, 6.2). R7 R8 6.3.5 Comparison of patients with Crouzon syndrome and Apert syndrome R9 Growth curves for patients with Crouzon syndrome showed changes ranging from constant to R10 acceleration, while those for patients with Apert syndrome ranged from constant to linear (Table R11 6.1). The mandibular arch depth, arch length, and maxillary intercanine width were all statistically R12 smaller in patients with Apert syndrome than in patients with Crouzon syndrome (Table 6.2). R13 Mandibular intercanine and intermolar width, maxillary intermolar width, arch depth, and arch R14 length showed no statistical differences (Table 6.2). R15 R16 R17 R18 R19 6 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

A Longitudinal Study of Dental Arch Morphology in Children With the Syndrome of Crouzon or Apert | 109 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 Figure 6.2 Growth curves of mean maxillary (a) and mandibular (b) intercanine width for male and female R31 control subjects (SD) (●), and for patients with Crouzon syndrome (■) and Apert syndrome (▲). R32 R33 R34 R35 R36 R37 R38 R39

110 | Chapter 6 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 6 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 Figure 6.3 Growth curves of mean maxillary (a) and mandibular (b) intermolar width for male and female control subjects (SD) (●), and for patients with Crouzon syndrome (■) and Apert syndrome (▲). R31 R32 R33 R34 R35 R36 R37 R38 R39

A Longitudinal Study of Dental Arch Morphology in Children With the Syndrome of Crouzon or Apert | 111 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 Figure 6.4 Growth curves of mean maxillary (a) and mandibular (b) arch depth for male and female control R31 subjects (SD) (●), and for patients with Crouzon syndrome (■) and Apert syndrome (▲). R32 R33 R34 R35 R36 R37 R38 R39

112 | Chapter 6 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 6 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 Figure 6.5 Growth curves of mean maxillary (a) and mandibular (b) arch length for male and female control subjects (SD) (●), and for patients with Crouzon syndrome (■) and Apert syndrome (▲). R31 R32 R33 R34 R35 R36 R37 R38 R39

A Longitudinal Study of Dental Arch Morphology in Children With the Syndrome of Crouzon or Apert | 113 R1 6.4 Discussion R2

R3 Multilevel models offer an important tool for describing longitudinal dental arch changes R4 with limited data in rare syndromes such as Crouzon or Apert. Both individual and average R5 growth curves can be described; it is a flexible model because it uses polynomials, which can R6 describe growth curves of almost any form and they do not require complete longitudinal data R7 or observations taken at the same time points (Buschang et al., 1989). Moreover, traditional R8 R9 polynomial methods would have required elimination of most of the subjects as a result of missing R10 observations and adjustment of values to exact ages (Buschang et al., 1989, Goldstein, 1986). R11 Conventional procedures, including cross-sectional descriptions and analyses of yearly velocities R12 from two measurement occasions, would have provided less illustrative and informative results. R13 It is important, when analyzing longitudinal dental arch changes of small samples of R14 syndromic subjects, to compare these outcomes with a representative large sample of unaffected R15 individuals. To our knowledge, this is the first study to analyze longitudinal data of dental R16 arch changes in patients with Crouzon syndrome or Apert syndrome with the aid of multilevel R17 modeling. Abnormal arch development in syndromes where ceased growth does not reach its full R18 potential is very easily picked up compared with normal arch development. In patients without R19 any surgical or orthodontic treatment in the midface or mandible, or dental extractions, Crouzon R20 or Apert syndrome showed a higher prevalence of dental agenesis, excluding third molars, R21 compared with healthy controls (Reitsma et al., 2013; Stavropoulos et al., 2011; Stavropoulos R22 et al., 2011a). Dental agenesis may account for smaller dental arch dimensions in syndromic R23 R24 patients. When dental agenesis occurred, the remaining primary teeth were used to calculate R25 dental arch dimensions. Maxillary lateral incisors and mandibular second premolars were the R26 most frequently missing teeth in all three groups (Reitsma et al., 2013; Stavropoulos et al., R27 2011; Stavropoulos et al., 2011a), although were more prevalent in syndromic patients. The R28 arch development changes, in control subjects, for dental arch width, in the literature (Moorrees, R29 1959; Thilander, 2009; Moorrees et al., 1969; Bishara et al., 1996; Bishara et al., 1997). Arch R30 width and depth increases have been previously reported to occur between 4 and 14 yr of age R31 (Bishara et al., 1997, Moorrees and Reed, 1965; Moyers et al., 1976). Importantly, approximately R32 73% of the total maxillary intercanine width increases, and 84% of the total maxillary intermolar R33 width increases occurred between 6 and 9 yr of age (Bishara et al., 1997, Moorrees and Reed, R34 1965; Moyers et al., 1976). The increases of dental arch widths, particularly the intermolar width, R35 were more likely to be related to dental eruption than to growth. R36 Patients with Crouzon syndrome exhibited severe constriction of dental arch development, R37 especially during the transition from primary to permanent dentition. In contrast to normal R38 R39

114 | Chapter 6 development, arch dimensions for dental arch width, depth, and length in patients with Crouzon R1 syndrome hardly changed with growth and transition from primary to permanent dentition (Figs R2 6.1-6.4). Premature fusion of craniofacial sutures in patients with Crouzon syndrome influences R3 R4 growth and development of the maxilla and mandible (Kreiborg and Cohen, 1998; Marsh et R5 al., 1991; Reitsma et al., 2012), with major consequences for the development of the dentition R6 and the occlusion. The limited craniofacial growth potential explains the changes in dental arch R7 measurements seen in these patients (Kreiborg and Cohen, 1998; Cohen and Kreiborg, 1993). R8 Patients with Apert syndrome tended to have smaller arch dimensions than patients with R9 Crouzon syndrome. Longitudinal dental arch changes between Crouzon and Apert syndrome R10 differ, and the corresponding values for patients with Apert syndrome were even smaller than R11 for those with Crouzon syndrome (Table 6.2). Although both syndromes share clinical features, R12 differences in craniofacial growth and development have been observed (Costaras-Volarich and R13 Pruzansky, 1984; Reitsma et al., 2012). A more abnormal growth pattern was seen in patients R14 with Apert syndrome, which was confirmed by earlier reports (Tables 6.1, 6.2) (Kreiborg, 1981; R15 Kreiborg and Cohen, 1998, Avantaggiato et al., 1996). The premature arrest of maxillary sutural R16 growth in Crouzon syndrome had usually already occurred during the first years of life (Kreiborg, R17 1981) and is probably earlier and more severe in Apert syndrome. The maxillary intermolar width R18 R19 in patients with Apert syndrome showed an increase over time, although the measurements 6 R20 were much smaller compared with those for control subjects. This increase in intermaxillary R21 arch width may be related to ectopic eruption of maxillary first molars in a transversally reduced R22 maxilla (Kreiborg and Cohen, 1992). Maxillary dental arch depths measured in syndromic patients R23 were smaller than in control subjects and showed no change over time (Fig. 6.4). Besides space R24 deficiency for the permanent canines, the frequent mesial eruption of the maxillary first molars R25 might be related to the small maxillary dental arch depth. This may result in first molar retention R26 and resorption of the distal root of the adjacent primary molar and its premature loss, aggravating R27 the space deficiency. R28 A Class III skeletal relationship caused by retruded midfacial growth in patients with Crouzon R29 syndrome or Apert syndrome is associated with maxillary posterior crossbites. Although upper R30 and lower dental arch width dimensions in both syndromes were severely reduced (Fig. 6.2), the R31 upper arch was relatively smaller. In patients with craniosynostosis, transverse discrepancies are R32 usually the result of maxillary constriction. In these cases, the suture fusion is not limited to the R33 R34 skull and cranial base but may also involve facial sutures and cartilages. Maxillary constriction may R35 be part of the pathophysiology of obstructive sleep apnea (Luna-Paredes et al., 2012). Subjects R36 with maxillary constriction have increased nasal airway resistance and resultant mouth breathing R37 (Langford et al., 2003). An abnormal muscular balance, such as a low tongue posture, seen R38 R39

A Longitudinal Study of Dental Arch Morphology in Children With the Syndrome of Crouzon or Apert | 115 R1 in patients with Crouzon or Apert syndrome, may contribute to the underdevelopment of the R2 maxillary arch dimensions (Kreiborg and Cohen, 1998). The direction of eruption of mandibular R3 teeth could therefore be influenced by the narrow hypoplastic maxilla, leading to a more lingual R4 direction of tooth eruption than normal and thereby enhance the already decreased mandibular R5 arch width dimensions (Krarup et al., 2005). R6 Because of the complexity of the functional and structural abnormalities, the care of a patient R7 with craniosynostosis should be managed and treated by a multidisciplinary team of experts. The R8 R9 focus in such a center is on general oral health needs, orthodontic and surgical management, as R10 well as psycho-social needs, which should give better overall treatment results. Different types of R11 intervention are often necessary to prevent brain damage, possible blindness, or obstructive sleep R12 apnea (Oberoi et al., 2012). R13 The lack of maxillary growth and development caused by craniosynostosis in these syndromes R14 results in crowding, impaction, premature loss of primary teeth, delayed tooth eruption, and R15 ectopic eruption. These oral features are found in both arches, but are more severe in the maxilla R16 (Cohen and Kreiborg, 1996; Reitsma et al., 2012). Probably, the mandible is indirectly influenced R17 by the absence of primary and secondary displacement of the bones of the maxillary complex R18 and the cranial base. The goal of orthodontic treatment in the mixed dentition is to resolve issues R19 related to aberrant eruption of the permanent teeth. Knowledge about the sequence of tooth R20 eruption in patients with Crouzon or Apert syndrome is necessary for dental and orthodontic R21 management. In a future study, dental maturation may be better predicted by assessing R22 mineralization and eruption stages. It should be stressed that better prediction of dental arch R23 R24 dimensions might be expected using the multilevel method in a relatively small, but well-defined, R25 group, although some variation was left unexplained in this study. Extreme small arch dimensions R26 in these patients require early intervention and referral to a specialized team. R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

116 | Chapter 6 6.5 References R1 R2 Cohen MM Jr, Kreiborg S. A clinical study of the craniofacial features in Apert syndrome. Int J Oral Maxillofac R3 Surg. 1996;25:45–53. R4 Kreiborg S. Craniofacial growth in plagiocephaly and Crouzon syndrome. Scand J Plast Reconst Surg. 1981;15:187–197. R5 Kreiborg S, Björk A. Description of a dry skull with Crouzon syndrome. Scand J Plast Reconstr Surg. R6 1982;16:245–253. R7 Costaras-Volarich M, Pruzansky S. Is the mandible intrinsically different in Apert and Crouzon syndromes? Am R8 J Orthod. 1984;85:475–487. R9 Kreiborg S, Cohen MM Jr. Is craniofacial morphology in Apert and Crouzon syndromes the same? Acta Odontol Scand. 1998;56:339–341. R10 Reitsma JH, Ongkosuwito EM, Van Wijk AJ, Prahl-Andersen B. Patterns of tooth agenesis in patients with the R11 syndrome of Crouzon or Apert. Cleft Palate Craniofac J. 2014; 51: 178-183. R12 Stavropoulos D, Bartzela T, Tarnow P, Mohlin B, Kahnberg KE, Hagberg C. Dental agenesis patterns in Crouzonnsyndrome. Swed Dent J. 2011;35:195–201. R13 Stavropoulos D, Bartzela T, Bronkhorst E, Mohlin B, Hagberg C. Dental agenesis patterns of permanent teeth R14 in Apert syndrome. Eur J Oral Sci. 2011a;119:198–203. R15 Moorrees CFA. The dentition of the growing child. Cambridge, MA: Harvard University Press, 1959. Buschang R16 PH, Demirjian A, Tanguay R, Charbonneau C. Multivariate patterns of variation in dental arch morphology of French-Canadians. Hum Biol. 1987;59:911–920. R17 Thilander B. Dentoalveolar development in subjects with normal occlusion. A longitudinal study between the R18 ages of 5 and 31 years. Eur J Orthod. 2009;31:109–120. R19 Moorrees CFA, Gron AM, Lebret LM, Yen PK, Fröhlich FJ. Growth studies of the dentition: a review. Am J 6 R20 Orthod. 1969;55:600–616. R21 Ward DE, Workman J, Brown R, Richmond S. Changes in arch width. A 20-year longitudinal study of orthodontic treatment. Angle Orthod. 2006;76:6–13. R22 Bishara SE, Bayati P, Jakobsen JR. Longitudinal comparisons of dental arch changes in normal and untreated R23 Class II, Division 1 subjects and their clinical implications. Am J Orthod Dentofac Orthop. 1996;110:483– R24 489. R25 Carter GA, McNamara JA Jr. Longitudinal dental arch changes in adults. Am J Orthod Dentofacial Orthop. 1998;114:88–99. R26 Prahl-Andersen B, Kowalski CJ, Heyendaal PHJM. A mixed-longitudinal interdisciplinary study of growth and R27 development. New York: Academic Press, 1979. R28 Bishara SE, Jakobsen JR, Treder J, Nowak A. Arch width changes from 6 weeks to 45 years of age. Am J R29 Orthod Dentofacial Orthop. 1997;111:401–409. R30 Dalben GDA S, Das Neves LT, Gomide MR. Oral findings in patients with Apert syndrome. J Appl Oral Sci. 2006;14:465–469. R31 Ferraro NF. Dental, orthodontic, and oral/maxillofacial evaluation and treatment in Apert syndrome. Clin Plast R32 Surg. 1991;18:291–307. R33 Letra A, De Almeida AL, Kaizer R, Esper LA, Sgarbosa S, Granjeiro JM. Intraoral features of Apert’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103:e38–e41. R34 Nurko C, Quinones R. Dental and orthodontic management of patients with Apert and Crouzon syndromes. R35 Oral Maxillofac Surg Clin North Am. 2004;16:541–553. R36 Shrout PE, Fleiss JL. Intraclass correlations: uses in assessing rater reliability. Psychol Bull. 1979;86:420–428. R37 Goldstein H. Multilevel models in educational and social research. London: Oxford University Press, 1987. R38 R39

A Longitudinal Study of Dental Arch Morphology in Children With the Syndrome of Crouzon or Apert | 117 Fleiss JL. The design and analysis of the clinical experiments. New York: Wiley, 1986. R1 Buschang PH, Tanguay R, Demirjian A, LaPalme L, Goldstein H. Modeling longitudinal mandibular growth: R2 percentiles for gnathion from 6 to 15 years of age in girls. Am J Orthod Dentofac Orthop. 1989;95:60– R3 66. R4 Goldstein H. Efficient statistical modelling of longitudinal data. Ann Hum Biol. 1986;13:129–141. R5 Moorrees CFA, Reed RB. Changes in dental arch dimensions expressed on the basis of tooth eruption as measure of biologic age. J Dent Res. 1965;44:129–141. R6 Moyers RE, Van Der Linden FPGM, Riolo ML, McNamara JA. Standards of human occlusal, development. R7 Monograph 5. Craniofacial growth series. Ann Arbor, MI: Center of Human Growth and Development. R8 University of Michigan, 1976. R9 Marsh JL, Galic M, Vannier MW. The craniofacial anatomy of Apert syndrome. Clin Plast Surg. 1991;18:237– 249. R10 Reitsma JH, Ongkosuwito EM, Buschang PH, Prahl-Andersen B. Facial growth in patients with apert and R11 crouzon syndromes compared to normal children. Cleft Palate Craniofac J. 2012;49:185–193. R12 Cohen MM Jr, Kreiborg S. Growth pattern in the Apert syndrome. Am J Med Genet. 1993;47:617–623. R13 Avantaggiato A, Carinci F, Curioni C. Apert’s syndrome: cephalometric evaluation and considerations on pathogenesis. J Craniofac Surg. 1996;7:23–31. R14 Kreiborg S, Cohen MM Jr. The oral manifestations of Apert syndrome. J Craniofac Genet Dev Biol. 1992;12:41– R15 48. R16 Luna-Paredes C, Anton-Pacheco JL, Garcia Hernandez G, Martinez Gimeno A, Romance Garcia AI, Garcia R17 Recuero II. Screening for symptoms of obstructive sleep apnea in children with severe craniofacial anomalies: assessment in a multidisciplinary unit. Int J Pediatr Otorhinolaryngol. 2012;11: pii: S0165- R18 5876(12)00479-X. R19 Langford RJ, Sgouros S, Natarajan K, Nishikawa H, Dover MS, Hockley AD. Maxillary volume growth in R20 craniosynostosis. Plast Reconstr Surg. 2003;111:1598–1604. R21 Krarup S, Darvann TA, Larsen P, Marsh JL, Kreiborg S. Three-dimensional analysis of mandibular growth and tooth eruption. J Anat. 2005;207:669–682. R22 Oberoi S, Hoffman WY, Vargervik K. Craniofacial team management in Apert syndrome. Am J Orthod R23 Dentofacial Orthop. 2012;141(Suppl):S82–S87. R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

118 | Chapter 6 Chapter 7

Craniofacial Stability in Patients With Crouzon or Apert

Syndrome After Le Fort III Distraction Osteogenesis

Jacobus H. Reitsma Edwin M. Ongkosuwito Peter H. Buschang Léon N.A. van Adrichem Birte Prahl-Andersen

Cleft Palate Craniofacial Journal 2013; 50: 561-569 R1 Abstract R2

R3 Objective: Le Fort III osteotomy with distraction osteogenesis (DO) is used to improve the retruded R4 midface in patients with Crouzon or Apert syndrome. This study aimed to evaluate sagittal and R5 vertical preoperative and postoperative cephalometric changes of DO of the midface in patients R6 with Crouzon or Apert syndrome. R7 R8 R9 Design: Population-based case-control study. R10 R11 Patients and Methods: Records of patients with the syndrome of Crouzon (n = 6) or Apert (n = R12 7) were compared, before and after Le Fort III DO, with a nonsyndromic untreated control group R13 (n = 486). R14 R15 Main Outcome Measures: Sagittal and vertical cephalometric maxillary landmarks and R16 measurements were used to predict and measure midface advancement and rotation after Le R17 Fort III DO. Cephalograms were taken before surgery (T0), 4 months after surgery at removal of R18 the distraction device (T1), and 1 year after removal of the distraction device (T2). R19 R20 Analysis: Z scores were performed to compare cephalometric measures of syndromic patients R21 with control subjects. R22 R23 R24 Results: Cephalograms of 13 patients with Crouzon syndrome (n = 6) or Apert (n = 7) (age range R25 8.2 to 19.8 years) were evaluated. Treatment changes (T1-T2) showed statistically significant R26 maxillary advancement, with no significant differences between the patients with the Crouzon R27 or Apert syndrome. R28 R29 Conclusions: DO of the midface in patients with Crouzon or Apert syndrome seems to be R30 stable in the sagittal direction after follow-up. Although Crouzon and Apert differ after DO, R31 anteroposterior craniofacial dimensions were significantly improved and were closer to patterns R32 of normal subjects. R33 R34 R35 R36 R37 R38 R39

120 | Chapter 7 7.1 Introduction R1 R2

Patients with Crouzon or Apert syndrome have similar, but not identical, craniofacial morphologies R3 R4 (Kreiborg and Aduss, 1986; Kreiborg and Cohen, 1998). Various surgical treatment methods have R5 been developed for the advancement of the midface for these patients (Marchac and Arnaud, R6 1999; Panchal and Uttchin, 2003; Figueroa and Polley, 2007; Pelo et al., 2007; Allam et al., 2011). R7 Conventional treatment of such anomalies includes Le Fort III osteotomies, which have been R8 associated with heavy blood loss, relatively long operation time, and a risk for infection (Sloan R9 et al., 1997; Cheung et al., 2006; Shetye et al., 2010; Allam et al., 2011). The postoperative R10 patients’ discomfort after such osteotomies can be great. Lethality of patients after conventional R11 Le Fort III osteotomy has also been reported (Sloan et al., 1997). Moreover, relapse after Le Fort III R12 osteotomy may occur, but it is unpredictable (Panchal and Uttchin, 2003; Meazzini et al., 2005; R13 Iannetti et al., 2006). The nonvascularized grafts that are often used to bridge the operated gap R14 are a risk for morbidity and infection; vascular grafts are technically difficult (Iannetti et al., 2006). R15 Currently, Le Fort III distraction osteogenesis (DO) is the most used treatment modality in R16 these patients (Swennen et al., 2001; Figueroa and Polley, 2007; Shetye et al., 2010; Allam et al., R17 2011). Benefits of DO compared to conventional surgery include no morbidity of donor areas, R18 R19 the absence of postsurgical bone gaps and no need for bone grafts, less intraoperative bleeding, R20 the possibility of increased volume of the soft tissues, and the possibility to achieve bigger and R21 better corrections (Swennen et al., 2001; Meazzini et al., 2005; Iannetti et al., 2006; Figueroa R22 and Polley, 2007). Under optimal conditions DO leads to the generation of bone and stretching 7 R23 of surrounding soft tissues (De Bastiani et al., 1987). Therefore, Le Fort III DO is currently the R24 treatment of choice for the severe underdeveloped midface of patients with Crouzon or Apert R25 syndrome. However, long-term evaluation for this procedure is needed (Figueroa et al., 2004; R26 Fearon, 2005; Meazzini et al., 2005; Iannetti et al., 2006; Figueroa and Polley, 2007; Shetye et R27 al., 2007; Hopper et al., 2010; Shetye et al., 2010; Allam et al., 2011). R28 The timing of surgical correction of the midface advancement in growing patients is R29 controversial. Surgical intervention of the midface before puberty shows deterioration of the R30 final result due to the continued growth of the lower jaw (Reid, 2007). Surgical overcorrection is R31 proposed in order to avoid extra surgery later in life (Swennen et al., 2001). The prediction of the R32 final outcome in younger children is difficult because the prediction of an individual’s mandibular R33 R34 growth pattern is difficult. The pubertal growth spurt, which occurs around 14 years of age for R35 boys and is larger, longer, and later than for girls, further complicates predictions (Tanner et al., R36 1983). Due to the lack of studies, controversy also exists about further maxillary growth following R37 early midfacial surgery (Fearon, 2005; Meazzini et al., 2005). Nevertheless, accurate estimates R38 R39

Craniofacial Stability in Patients With Crouzon or Apert Syndrome After Le Fort III Distraction Osteogenesis | 121 R1 of the timing and amount of midface displacement that are necessary for growing children are R2 essential for efficient and effective treatment outcomes (Prahl-Andersen, 2005). R3 The primary aim of this study was to evaluate the sagittal and vertical changes of the midface R4 after Le Fort III external DO in patients with Crouzon or Apert syndrome compared to normal R5 growing children. The secondary aim was to determine whether DO results in normalization of R6 the midface and evaluate these findings after a 1-year follow-up. R7 R8 R9 R10 7.2 Materials and Methods R11 R12 7.2.1 Study Design and Sample R13 From 1985, standardized patient records of craniofacial patients were kept at the Department R14 of Orthodontics of the Erasmus Medical Centre Rotterdam, The Netherlands. From this group, R15 a total of 62 patients with Crouzon or Apert syndrome, patient records were retrospectively R16 reviewed for the period of 1985 to 2010. The clinical diagnoses of the patients with Crouzon or R17 Apert syndrome were genetically confirmed. R18 All 13 consecutive patients treated with Le Fort III external DO were studied. The Le Fort III DO R19 procedure was used since 2003. Older patients who underwent a second midface advancement R20 by a Le Fort III DO after a previously first surgical midface advancement, were excluded. Other R21 methods of treatment to improve the retruded midface (e.g., monoblock advancement, Le Fort III R22 with internal distraction devices, Le Fort III midface advancement) were excluded. R23 R24 The data of the patients were compared with a large mixed-longitudinal dataset from the R25 Nijmegen Growth Study (Prahl-Andersen et al., 1979). This mixed-longitudinal growth study R26 comprised 486 nonsyndromic children. All cohorts were followed for a period of 5 years, from R27 4 to 14 years of age. At the start of the study, the children were 4, 7, or 9 years of age. A final R28 measurement was taken at 22 years of age for a few cohorts. R29 The hospital records of the patients, the craniofacial team assessments, and cephalometric R30 analyses were retrospectively reviewed after exemption approval from the Institutional Review R31 Board at Sophia Children’s Hospital, Erasmus Medical Centre (MEC-2010-304). R32

R33 7.2.2 Surgical Procedure R34 All patients underwent a Le Fort III distraction osteotomy. After the osteotomy and mobilization R35 of the midface, a RED (rigid external distraction) device was placed (Fig. 7.1). The RED device R36 was used in all patients using a custom maxillary palatal heavy wire frame bonded to the upper R37 molars. In nine cases, the RED device was additionally secured to the maxilla with subcutaneous R38 R39

122 | Chapter 7 suspension wires as the point of traction of the distraction force. Active midfacial advancement R1 was started after a latency period of 5 days, at a rate of 1 mm per day, until the desired R2 orbitozygomatic position was obtained. The RED device was removed under local anesthesia, R3 R4 after a 3-month retention period. After this period, a protraction facemask was used for 3 to 6 R5 months at nighttime for retention. R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 7 R23 R24 R25 R26 R27 R28 Figure 7.1 Fixation of the halo-frame of the RED II system parallel to the Frankfurter horizontal plane. This R29 patient with the syndrome of Apert underwent a Le Fort III osteotomy. R30 7.2.3 Data Collection R31 Lateral cephalograms were used to assess the changes in position of the midface at the end of R32 the consolidation period immediately after device removal. Only cephalograms of good quality, R33 R34 taken before distraction (T0), at the end of the consolidation period immediately after device R35 removal (T1), and 1 year after removal of the distraction device (T2) were used. The pretreatment R36 cephalograms were taken within 1 month prior to surgery. One patient was excluded from the R37 study because of previous midface advancement with Le Fort III DO, resulting in 13 patients for R38 R39

Craniofacial Stability in Patients With Crouzon or Apert Syndrome After Le Fort III Distraction Osteogenesis | 123 R1 further analysis. Comparison of the three groups was based on six craniofacial measurements R2 (Table 7.1) representing the sagittal and vertical jaw relationships. Viewbox software (version R3 3.1.1.12; dHal Orthodontic Software, Athens, Greece) was used to calculate the measurements. R4 R5 7.2.4 Outcome Variables R6 Seven cephalometric landmarks situated in the midsagittal plane were identified and digitized R7 (Fig. 7.2). To identify the same nasion at T0, T1, and T2, the landmark ‘N’ was located at the R8 R9 nasofrontal suture, above the surgical cut of the Le Fort III osteotomy. This alternative landmark R10 point N recorded on the presurgical lateral cephalogram was relocated as a reconstructed N point R11 on the subsequent lateral cephalograms by superimposition on sella and cranial base structures. R12 The primary horizontal and vertical measurements of anterior maxillary position were the SNA R13 and SN/PP angles, respectively (Table 7.1). R14 Four secondary craniofacial measurements (SNB angle, ANB angle, NSMe angle, and LFH R15 ratio) were used to describe relative craniofacial changes following Le Fort III DO. R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 Figure 7.2 Lateral Skull with landmark points. ANS: anterior nasal spine. The anterior tip of the sharp bony R34 process of the maxilla at the lower margin of the anterior nasal opening. Me: Menton. The lowest point on the symphyseal shadow of the mandible seen on a lateral cephalogram. N: Nasion. The most anterior point on R35 the frontonasal suture in the midsagittal plane. PNS: Posterior nasal spine. The posterior spine of the palatine R36 bone constituting the hard palate. Point A: subspinale. The most posterior midline point in the concavity between the ANS and the prosthion (the most inferior point on the alveolar bone overlying the maxillary R37 incisors). Point B: supramentale. The most posterior midline point in the concavity of the mandible between R38 the most superior point on the alveolar bone overlying the mandibular incisors (infradentale) and Pogonion R39 (the most anterior point on the chin). S: Sella. The geometric center of the pituitary fossa.

124 | Chapter 7 Table 7.1 Description of primary predictor variables R1 ANS-Me Represents the lower anterior face height (LFH). R2 N-Me Represents the total anterior facial height. R3 LFH Ratio The ratio of the lower anterior facial height and the R4 total anterior facial height. R5 NSMe angle Measures the angle from nasion to sella to menton. R6 SN/PP angle Measures the inclination of palatal plane to the anterior cranial base. R7 ANB angle The relative position of points A and B to each other. R8 SNA angle The anterior-posterior position of point A to the anterior cranial base. R9 SNB angle The anterior-posterior position of point B to the anterior cranial base. R10 R11 R12 7.2.5 Predictor Variables R13 Quantitative data of patients with the Crouzon syndrome (n = 6) and Apert (n = 7) were compared R14 with an age, sex, and ethnic grouped matched nonsyndromic standards, derived from the mixed- R15 longitudinal dataset from the Nijmegen Growth Study (Prahl-Andersen et al., 1979). R16 R17

7.2.6 Data Analysis R18 R19 Due to the heterogeneity of the sample, the cephalometric measurements of the patients with R20 Crouzon or Apert syndrome were transformed into z scores using the following formula: z score R21 = (X –M) /SD, where X is the subject’s cephalometric measurement taken at a given age, M is the R22 mean value of the control data at the same age and sex, and SD is the standard deviation of the 7 R23 control data at the same age and sex. R24 R25 7.2.7 Assessment of Interexaminer and Intraexaminer Variation R26 To calculate the systematic and random errors, a subsample of 20 randomly selected radiographs R27 was retraced and redigitized by two examiners with a 3-month interval. The statistical analyses R28 of the data were carried out with SPSS (version 15.0, SPSS, Chicago, IL). Intraobserver duplicate R29 measurement errors were calculated according to Dahlberg formula (Dahlberg, 1940), and R30 reliability coefficients between the first and second digitizing were calculated as Pearson R31 correlation coefficients. An interclass correlation coefficient value greater than 0.75 represents R32 a high level of reliability. Values between 0.40 and 0.75 indicate a fair to moderate level of R33 R34 reliability, and a value less than 0.40 represents a poor level of reliability (Shrout and Fleiss, 1979). R35 R36 R37 R38 R39

Craniofacial Stability in Patients With Crouzon or Apert Syndrome After Le Fort III Distraction Osteogenesis | 125 R1 7.3 Results R2

R3 A total of six patients with the Crouzon syndrome (three girls and three boys; mean age at R4 the time of surgery 13.2 years) and seven patients with Apert syndrome (six girls and one boy; R5 mean age at the time of surgery 15.4 years) satisfied the inclusion criteria (Table 7.2). The mean R6 distraction time was 26 (± 12) days (range 11 to 54 days). The distractor was in place for a mean R7 of 114 (± 17) days, including the latency and distraction period. R8 R9 R10 Table 7.2 Intraobserver and interobserver agreement for digitization of the cephalometric landmarks. R11 Intraobserver reliability n Interobserver reliability n = 20 = 20 R12 Correlation coefficient Correlation coefficient R13 SNA angle (degrees) 0.921 0.972 R14 SNB angle (degrees) 0.970 0.706 R15 ANB angle (degrees) 0.847 0.872 LFH ratio 0.984 0.742 R16 NSMe angle (degrees) 0.977 0.962 R17 SN/PP (degrees) 0.969 0.652 R18 R19 The analysis of the cephalometric data prior to treatment (T0) showed that the syndromic R20 patients and the control subjects differed significantly (Tables 7.3 through 7.8). The SNA, ANB, R21 and SN/PP angles were significantly smaller in the syndromic patients, and the LFH ratio was R22 significantly larger than control values. The SNB angle, the sagittal position of the mandible, for R23 R24 the Crouzon patient was significantly larger than the angle for the control subjects; there was R25 no significant difference in the SNB angle between the Apert patients and control subjects. The R26 pretreatment NSMe angles of the patients with Crouzon or Apert syndrome were not significantly R27 different from the control subjects (Table 7.7). R28 The immediate postsurgical midfacial advancement, measured by the SNA angle, showed R29 values that closely approach the values of the control subjects (T1, Table 7.3). Treatment changes R30 (T0-T1) were statistically significant for all of the sagittal measurements, with no significant R31 differences between the patients with Crouzon or Apert syndrome (Table 7.3). The SNA and ANB R32 angle increased significantly and the SNB angle decreased significantly during treatment. None R33 of the immediate postdistraction (T1) sagittal measurements were significantly different from the R34 control averages. R35 R36 R37 R38 R39

126 | Chapter 7 ** ** ** R1 R2 R3 0.34 <0.01 0.38 <0.01 0.36 <0.01 R4 ** ** ** R5 T1-T0 T2-T1 T2-T0 0.43 0.070.35 0.10 0.360.47 0.23 0.18 0.15

T1-T0 T2-T1 T2-T0 R6 * * * R7 Prob Prob Prob Prob Prob <0.01 <0.01 <0.01 0.29 <0.01 0.22 <0.01 0.48 <0.01 Prob. Prob. Prob. Prob. R8 R9 R10 R11 value (SD) 8.49 (2.76) 8.32 (3.25) 8.41 (3.20) 80.62 (3.67) 80.40 (3.83) 80.50 (3.76) value (SD) R12

* * R13 * R14 T2 T2 -14.80 (9.11) -2.57 (1.26) -11.07 (10.56) (8.86) (8.22) (8.58) R15 * * * R16 Prob (SD) Value NGO Control <0.01 <0.01 <0.01 0.17 78.64 0.32 83.31 0.38 80.73 Prob. Prob. (SD) Value NGO Control R17 R18 R19 R20 value (SD) 8.50 (2.77) 8.31 (3.23) 8.41 (3.21) 80.61 (3.67) 80.40 (3.83) 80.49 (3.74) value (SD) R21

* R22 * * R23 T1 T1 -10.89 (7.51) -1.38 (5.69) -8.12 (9.09) 77.16 (6.91) 82.16 (8.09) 79.37 (7.57) 7 R24 * * * * * * R25 Prob (SD) Value NGO Control Prob. Prob. (SD) Value NGO Control <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 R26 R27 R28 R29 value (SD) value (SD) 8.50 (2.77) 8.31 (3.24) 8.41 (3.21) 80.56 (3.69) 80.39 (3.81) 80.48 (3.74) R30 *

* * * R31 * * R32 Value (SD)Value NGO Control Value (SD)Value NGO Control (8.46) (7.78) (10.87) (5.48) (2.61) (5.03) R33 R34 R35 Crouzon -0.15 Total -7.86 Crouzon 70.14 Total 67.17 R36 Changes in sagittal measures of SNA angle. Mean values, NGO control values and standard deviations (SD) probability scores for Changes in vertical measures of SN/PP. Mean values, NGO control values and standard deviations (SD) probability scores for sagittal pretreatment Changes in vertical measures of SN/PP. R37 R38 SN/PP Apert -11.39 Variance Syndrome T0 Variance Syndrome T0 SNA Apert 64.69 Table 7.3 Table pretreatment (T0), immediate post-distraction (T1), and one year after removal of the distraction device (T2) patients with syndrome Apert Crouzon. * = significant (p<.05) difference from control mean. ** change over time. 7.4 Table (T0), immediate post-distraction (T1), and one year after removal of the distraction device (T2) patients with syndrome Apert Crouzon. * = significant (p<.05) difference from control mean. ** change over time. R39

Craniofacial Stability in Patients With Crouzon or Apert Syndrome After Le Fort III Distraction Osteogenesis | 127 R1 The vertical measurements did not change significantly with the treatment (Tables 6 through R2 8). At the end of treatment (T1), LFH was significantly larger and the SN/PP was significantly R3 smaller than the control values. Only NSMe showed a difference between the syndromes after R4 treatment; patients with Crouzon syndrome did not differ significantly from controls, whereas the R5 patients with Apert syndrome showed statistically significant larger values. R6 After the follow-up period (T2), the sagittal measurements of the syndromic patients and R7 control subjects were not significantly different (Table 7.3). The midface showed a counterclockwise R8 R9 rotation of the palatal plane (SN/PP angle) relative to the cranial base during follow-up, which was R10 even more evident than during activation (T0-T1). In terms of the vertical measurements, the SN/ R11 PP and NSMe angles decreased significantly between T1 and T2 (Tables 7.4 and 7.7). Both angles R12 became smaller in patients with Apert syndrome, but not in patients with Crouzon syndrome. R13 At the end of the follow-up (T2), the SN/PP angle and LFH ratio for syndromic patients were R14 significantly smaller and larger, respectively, than the control values. R15 The overall treatment effect (T0-T2) showed statistically significant increases of the SNA and R16 ANB angles. The SNA increased 13.178 for patients with Crouzon syndrome and 13.958 for R17 patients with Apert syndrome; the corresponding ANB angles improved 14.25° and 14.48°. The R18 changes that occurred for the other measurements were not significantly different from control R19 values at T2 (Tables 7.4, 7.5, 7.7, and 7.8). R20 R21 7.3.1 Assessment of Interexaminer and Intraexaminer Variation R22 The intraclass correlation coefficient values varied from 0.847 to 0.984 for cephalometric R23 R24 measures, which indicates high reliability. The interclass correlation coefficient values showed R25 sufficient reliability values for SNB angle, LFH ratio, and SN/PP, while the other measures showed R26 high reliability. R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

128 | Chapter 7 ** ** ** R1 R2 R3

0.40 <0.01 0.38 <0.01 0.49 <0.01 R4

** ** ** R5

T1-T0 T2-T1 T2-T0 R6 T1-T0 T2-T1 T2-T0 R7 Prob Prob Prob Prob 0.48 0.310.28 0.44 0.18 0.37 0.41 0.29 0.25 0.36 0.37 0.36 R8 Prob Prob Prob Prob 0.15 <0.01 0.47 <0.01 0.30 <0.01 R9 R10 R11 R12 value (SD) 77.72 (3.53) 77.34 (3.35) 77.56 (3.45) value (SD) 3.55 (2.53) 3.84 (2.48) 3.67 (2.51) R13 R14 R15 T2 (4.12) (4.62) (4.26) T2 (8.21) (3.78) (6.51) R16 R17 Prob (SD) Value NGO Control 0.10 0.92 0.36 4.04 0.30 2.36 Prob (SD) Value NGO Control 0.42 77.51 0.48 79.28 0.46 78.39 R18 R19 R20 value (SD) 3.70 (2.49) 3.94 (2.36) 3.81 (2.43) R21 77.44 (3.43) value (SD) 77.14 (3.36) 77.30 (3.40) R22 7 R23 T1 0.53 (6.27) 4.81 (5.10) 2.54 (5.97) R24 (3.97) T1 (3.76) (3.72) * * * R25 <0.01 <0.01 Prob (SD) Value <0.01 NGO Control R26 0.39 76.72 Prob (SD) Value NGO Control 0.17 77.27 0.28 76.97 R27 R28 R29 3.96 (2.35) 3.84 (2.42) 3.73 (2.48) value (SD) 77.39 (3.44) value (SD) 77.08 (3.37) 77.24 (3.40) R30 R31 R32 (3.04) (4.08) (4.94) Value (SD)Value NGO Control (4.79) Value (SD)Value NGO Control (2.71) (4.15) R33 R34 R35 Crouzon -10.21 Total -11.98 Crouzon 80.28 Total 79.23 R36 Changes in sagittal measures of SNB angle. Mean values, NGO control values and standard deviations (SD) probability scores for Changes in sagittal measures of ANB angle. Mean values, NGO control values and standard deviations (SD) probability scores for R37 R38 ANB Apert -13.56 Variance Syndrome T0 Variance Syndrome T0 SNB Apert 78.35 Table 7.5 Table pretreatment (T0), immediate post-distraction (T1), and one year after removal of the distraction device (T2) patients with syndrome Apert Crouzon. * = significant (p<.05) difference from control mean. ** change over time. pretreatment (T0), immediate post-distraction (T1), and one year after removal of the distraction device (T2) patients with syndrome Apert Crouzon. * = significant (p<.05) difference from control mean. ** change over time. Table 7.6 Table R39

Craniofacial Stability in Patients With Crouzon or Apert Syndrome After Le Fort III Distraction Osteogenesis | 129 R1 R2 Z-score Z-score SD R3 R4

R5 Z-score (SD)

R6 T1-T0 T2-T1 T2-T0 R7 T1-T0 T2-T1 T2-T0 0.16 0.270.49 0.34 0.420.30 0.43 0.41 0.38 Z-score Z-score (SD) Prob Prob Prob Prob 0.44 0.36 0.28 0.41 0.25 0.25 0.15 0.35 R8 0.41 0.31 0.21 0.38 R9 * * * <0.01 <0.01 <0.01 R10 Z-score (SD) R11 value (SD) 69.79 (3.79) 70.06 (3.50) R12 69.90 (3.65) R13 56.85 (2.47) 57.03 (2.41) 56.94 (2.44) R14 NGO Control value (SD) T2 (3.80) (4.40) R15 (4.09) R16 T2 73.96 (4.42) 64.02 (2.09) 69.31 (6.12) Value Value (SD) Prob (SD) Value NGO Control 0.23 70.35 0.34 67.76 0.28 69.09 R17 * * * R18 <0.01 <0.01 <0.01 Z-score Z-score (SD) R19 R20 value (SD) 69.99 (3.72) 70.15 (3.52) 70.06 (3.63) R21 56.83 (2.45) 57.12 (2.47) 56.96 (2.46) R22 NGO Control value (SD) R23 T1 (3.43) (3.81) R24 (3.50) T1 72.34 (2.86) 64.80 (2.63) 68.89 (4.72) R25 Value (SD) Prob (SD) Value NGO Control 0.36 72.74 0.39 71.56 0.47 72.18 R26 * * * <0.01 <0.01 R27 Z-score (SD) <0.01 R28 value (SD) 70.03 (3.72) 70.18 (3.53) R29 70.10 (3.63) R30 57.15 (2.45) 56.98 (2.45) R31 NGO Control value (SD) 56.83 (2.45) Value (SD)Value NGO Control (4.73) (3.89) R32 70.35 (4.29) R33 (5.76) (6.60) Value Value (SD) (1.93) R34 R35 Crouzon 69.19 Total

R36 Crouzon 64.69 Total 70.14 Changes in vertical measures of LFH ratio. Mean values, NGO control values and z-scores standard deviations (SD) for sagittal pretreatment (T0), Changes in vertical measures NSMe angle. Mean values, NGO control values and standard deviations (SD) and probability scores for sagittal pretreatment for sagittal scores and probability (SD) deviations standard and values control NGO Mean values, angle. NSMe measures vertical in Changes R37 R38 Variance Syndrome T0 Variance Syndrome T0 LFH Apert 74.78 NSMe Apert 71.41 Table 7.7 Table (T0), immediate post-distraction (T1), and one year after removal of the distraction device (T2) patients with syndrome Apert Crouzon. * = significant (p<.05) difference from control mean. ** = significant change over time. immediate post-distraction (T1), and one year after removal of the distraction device (T2) patients with syndrome Apert Crouzon. * = significant (p<.05) difference from control mean. ** = significant change over time. R39 7.8 Table

130 | Chapter 7 7.4 Discussion R1 R2

This study evaluated sagittal and vertical changes of the midface after Le Fort III external DO R3 R4 in patients with Crouzon or Apert syndrome. Maxillary advancement in patients with these R5 syndromes showed statistically significant improvement at removal of the RED device and after R6 1-year follow-up. The sagittal craniofacial measurements for both syndromes showed values R7 closer to normal after treatment. Maxillary sagittal advancement using Le Fort III DO has been R8 shown to be a successful treatment for the severely retruded midface (Figueroa et al., 2004; R9 Fearon, 2005; Prahl-Andersen, 2005; Iannetti et al., 2006; Figueroa and Polley, 2007; Shetye et R10 al., 2007; Hopper et al., 2010; Shetye et al., 2010; Allam et al., 2011). R11 No change was seen during the follow-up period. Relapse has been previously reported shortly R12 after distractor removal (Cheung et al., 2006). The amount of early relapse can be important for R13 the prediction of the amount of necessary overcorrection. In this study, a cephalogram was not R14 taken before the removal of the distraction device in order to prevent unnecessary radiation. R15 Although 1 year post surgery is a short retention period, others (Shetye et al., 2007; Hopper et R16 al., 2010; Shetye et al., 2010) have also found that sagittal movement of the midface by Le Fort R17 III DO is stable 1 year later. Statements regarding long-term stability should not be relied upon R18 R19 in studies with a short follow-up because most patients are still in active orthodontic treatment, R20 which may influence surgical treatment results positively. Although most studies have to deal with R21 a small number of patients with Crouzon or Apert syndrome, long-term stability after Le Fort III R22 DO consistently shows successful stable advancement (Swennen et al., 2001; Figueroa et al., 7 R23 2004; Figueroa and Polley, 2007; Pelo et al., 2007; Hopper et al., 2010). R24 Presurgical sagittal measurements showed midfacial retrusion in the syndromic patients, with R25 greater retrusion among Apert than Crouzon patients. This difference could be due to the fact R26 that more craniofacial sutures are prematurely fused at birth in Apert than Crouzon syndrome R27 patients. Patients with Crouzon syndrome sometimes show some open craniofacial sutures R28 at birth (Renier et al., 2000). The synostosis of the sutures in the Crouzon patients is often R29 progressive during postnatal growth (Renier et al., 2000; Connolly et al., 2004) and causing the R30 variation of sagittal facial growth in syndromic patients. R31 The midface showed a counterclockwise rotation of the palatal plane in the syndromic R32 patients. This suggests that, during forward traction of the midface, the posterior part of the R33 R34 maxilla extruded more than the anterior part. This may cause an undesirable posterior rotation of R35 the mandible, lengthening of the total anterior face height, and often an increase of the anterior R36 open bite, although not statistically significant (Fig. 7.3b). However, the fact that the SNB and SN/ R37 PP angles of the syndromic patients decreased and the LFH ratio did not change suggests that the R38 R39

Craniofacial Stability in Patients With Crouzon or Apert Syndrome After Le Fort III Distraction Osteogenesis | 131 R1 midface came forward, and vertical control was maintained (Fig. 7.3a). After the follow-up period R2 the patients with Apert syndrome showed the largest increase in the SN/PP angle (Table 7.4). R3 A continuation of vertical maxillary growth after surgery has been reported for the syndromic R4 patients (Bachmayer et al., 1986; Meazzini et al., 2005; Shetye et al., 2007; Shetye et al., 2010). R5 This also makes it important to avoid extrusion of the maxilla and to maintain the vertical height R6 of the midface during the Le Fort III DO. R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29

R30 Figure 7.3a Drawing showing surgical midfacial Figure 7.3b Theoretical situation of the patient R31 movement in a patient (15.2 years) with the where extrusion of the midface is causing R32 syndrome of Apert, with superimposition posterior rotation and lengthening of the face. R33 tracing on the anterior cranial base. The black line represents the patient before the Le Fort III R34 osteotomy, and the red line represents the patient R35 1 year and 4 months after surgery. R36 R37 R38 R39

132 | Chapter 7 Various degrees of counterclockwise palatal plane rotation have been previously reported with R1 DO (Shetye et al., 2007; Hopper et al., 2010; Shetye et al., 2010; Allam et al., 2011). Variation in R2 palatal plane rotation during DO is probably attributable to the direction of force by the external R3 R4 device relative to the center of resistance of the Le Fort III segment (Hopper et al., 2010). R5 The cranial base, Ba-S-N, for patients with Crouzon and Apert syndromes has been reported R6 to be 12% to 15% shorter than in nonsyndromic patients, with a shape comparable to the normal R7 population (Kreiborg and Cohen, 1998; Allam et al., 2011). The distance SN was significantly R8 smaller for patients with Crouzon and Apert syndromes compared to controls (Reitsma et al., R9 2012). A short anterior cranial base means a more forward placed mandibular condyle and a R10 positional Angle Class III. In addition, a more distally placed point N also increases the likelihood R11 of an Angle Class III. Other geometric effects of the used cephalometric points, like the vertical R12 lengths of N to A and N to B, may also distort an underlying skeletal discrepancy (Jacobson, 1975; R13 Kreiborg and Cohen, 1998; Posnick and Ruiz, 2000). These geometric effects should be kept in R14 mind when making comparisons between syndromic patients and the controls. R15 Although the facial morphology of patients with Crouzon and Apert syndromes is different R16 from a normal population, it has been shown that extreme variations in facial morphology R17 do not affect the accuracy of cephalometric evaluation (Wah et al., 1995). Six cephalometric R18 R19 measurements were used to describe the sagittal facial morphology of patients with Crouzon or R20 Apert syndrome. In a meta-analysis on landmark identification and reproducibility in nonsyndromic R21 patients, it was concluded that 0.6 mm of the total error in the x- or y-coordinate was acceptable R22 (Trpkova et al., 1997). The cephalometric landmarks chosen in this study had even lower total 7 R23 error for reproducibility in the x- or y-coordinate. R24 The sagittal growth rate of the mandible in syndromic patients is fairly normal, resulting in R25 a prognathic appearance due to a retrusion of the midface and the short anterior cranial base R26 (Costaras-Volarich and Pruzansky, 1984; Bachmayer et al., 1986; Kreiborg and Aduss, 1986). R27 Previous research (Costaras-Volarich and Pruzansky, 1984; Bachmayer et al., 1986; Kreiborg and R28 Aduss, 1986; Kreiborg and Cohen, 1998) showed a reduced mandibular body and anterior cranial R29 base lengths for patients with Crouzon or Apert syndrome. These aspects influence the SNB angle R30 and, in combination with the individual growth potential of the lower jaw, makes it difficult to R31 estimate the success of midfacial advancement in surgical cases. When the midface is extruded, R32 the mandible might be expected to show a posterior rotation (Tables 7.5 and 7.7; Fig. 7.4). R33 R34 R35 R36 R37 R38 R39

Craniofacial Stability in Patients With Crouzon or Apert Syndrome After Le Fort III Distraction Osteogenesis | 133 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 Figure 7.4 a: Standardized profile photographs of a patient with Apert syndrome: before distraction (T0). b: R14 Standardized profile photographs of a patient with Apert syndrome: 1 year after removal of the distraction device (T1). Standardized profile photographs of a patient with Apert syndrome: 1 year after removal of the R15 distraction device (T2). R16 R17 7.4.1 Treatment Timing R18 Treatment in patients younger than 13 years of age was performed for functional, psychological, R19 and social considerations. Young adult patients older than 13 years of age were treated at an R20 older age because DO was not available at that time. It has been recommended to surgically R21 overcorrect the midface in patients younger than 15 years of age, whereby the necessity for R22 secondary Le Fort III procedures could be reduced (Meazzini et al., 2005; Shetye et al., 2010). R23 R24 However, the final positioning of the maxilla at this age does not guarantee that the maxillary- R25 mandibular relationship will be normal later in life because the amount and timing of mandibular R26 growth is difficult to estimate in syndromic patients (Reitsma et al., 2012). Overcorrection during R27 childhood to adult norms may give a distorted facial appearance. Extreme overcorrection can R28 be difficult for both the children and their parents. The facial appearance changes during the R29 distraction process from abnormal to normal to abnormal once again. From the psychological R30 perspective, it is recommended not to distract to the final normal adult midface position (Shetye R31 et al., 2007). The aim of the surgeon for Le Fort III DO is an adequate positioning of the inferior R32 parts of the orbits and zygomata. When correction is aimed at the relationship between the R33 upper and lower dental arches, often inadequate positioning of the orbits will occur. Therefore, R34 the current protocol aims to correct both inferior orbits, zygomata, and, if possible, the occlusion R35 during Le Fort III DO, monoblock DO, or facial bipartition DO. For the orthodontist this may R36 not always create an ideal occlusion. Although efforts have been made to reach this goal, the R37 treatment result may unfortunately need secondary corrections later in life. R38 R39

134 | Chapter 7 After surgical correction of the midface, the orbits and zygoma should be in a normal position. R1 For control subjects the overall cranio-orbito-zygomatic skeleton is greater than 85% of its adult R2 size at the age of 5 years. This explains the frequent finding of recurrent exophthalmos in patients R3 R4 with Apert or Crouzon syndromes after a total midface osteotomy with advancement has been R5 performed during early childhood (Waitzman et al., 1992). The orbital region showed the R6 greatest dysmorphology in the entire craniofacial complex for patients with Crouzon syndrome. R7 The intercanthal, binocular, and eye fissure lengths all tended to be greater than average (Kolar R8 et al., 1988). For control subjects, additional growth increments after maturation of the orbit R9 continue until adolescence, but only a fraction of a millimeter (Waitzman et al., 1992). The skeletal R10 maturation of the orbit is an important factor for the timing of midface advancement in patients R11 with a retruded midface. However, the growth pattern of the orbital region for patients with R12 craniosynostosis remains unknown. Therefore, the decision for surgical midfacial advancement R13 should not rely solely on growth data of nonsyndromic subjects. R14 The indication and timing of surgical treatment of patients with craniosynostosis still remains R15 controversial. A general trend is seen to perform midfacial advancement in early childhood R16 (Marchac and Arnaud, 1999; Renier et al., 2000; Swennen et al., 2001; Panchal and Uttchin, R17 2003). Research shows that the incidence of complications using halo-frames is higher in children R18 R19 compared to adults (Baum et al., 1989). By contrast, limited information about incidence rates R20 of complications in craniofacial patients is available. This is remarkable since this patient category R21 might be even more prone to developing complications (Nout et al., 2006). A functional indication R22 for midfacial advancement is ocular proptosis, while palliation of obstructive sleep apnea is a 7 R23 controversial indication because long-term results are not present (Iannetti et al., 2006). R24 Finally, a literature review of DO of the craniofacial skeleton showed a lack of long-term data, R25 especially regarding skeletal relapse (Swennen et al., 2001). Relapse factors and prediction of the R26 result of DO surgery remain unknown. Long-term data are needed to quantify soft tissue changes R27 and facial growth and development after maxillary DO. Such data are essential to perfect the R28 timing of midfacial DO for patients with Crouzon or Apert syndrome. R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

Craniofacial Stability in Patients With Crouzon or Apert Syndrome After Le Fort III Distraction Osteogenesis | 135 R1 7.5 Conclusions R2

R3 1. Le Fort III external DO improved the position of the midface in patients with Crouzon or R4 Apert syndrome are significantly improved in the sagittal direction 1 year and 4 months R5 postoperatively. R6 2. Vertical dimensions of the midface were difficult to correct during treatment in patients R7 with Crouzon or Apert syndrome, and these should be taken into consideration during R8 R9 DO treatment. R10 3. From a growth perspective, surgical intervention and Le Fort III DO can be considered R11 from 10 to 12 years of age. Taking the individual growth maturation and pubertal R12 growth spurt into consideration, postponement of treatment for a few years may be R13 advisable. R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

136 | Chapter 7 7.6 References R1 R2 Allam KA, Wan DC, Khwanngern K, Kawamoto HK, Tanna N, Perry A, Bradley JP. Treatment of Apert R3 syndrome: a long-term follow-up study. Plast Reconstr Surg. 2011;127:1601–1611. R4 Bachmayer DI, Ross RB, Munro IR. Maxillary growth following LeFort III advancement surgery in Crouzon, Apert, and Pfeiffer syndromes. Am J Orthod Dentofacial Orthop. 1986;90:420–430. R5 Baum JA, Hanley EN Jr, Pullekines J. Comparison of halo complications in adults and children. Spine. R6 1989;14:251–252. R7 Cheung LK, Chua HD, Hägg MB. Cleft maxillary distraction versus orthognathic surgery: clinical morbidities R8 and surgical relapse. Plast Reconstr Surg. 2006;118:996–1008. R9 Connolly JP, Gruss J, Seto ML, et al. Progressive postnatal craniosynostosis and increased intracranial pressure. Plast Reconstr Surg. 2004;113:1313–1323. R10 Costaras-Volarich M, Pruzansky S. Is the mandible intrinsically different in Apert and Crouzon syndromes? Am R11 J Orthod. 1984;85:475–487. R12 Dahlberg G. Statistical Methods for Medical and Biological Students. New York: Interscience Publications; 1940:184. R13 De Bastiani G, Aldegheri R, Renzi-Brivio L, Trivella G. Limb lengthening by callus distraction (callotasis). J R14 Pediatr Orthop. 1987;7:129–134. R15 Fearon JA. Halo distraction of the Le Fort III in syndromic craniosynostosis: a long-term assessment. Plast R16 Reconstr Surg. 2005;115:1524–1536. R17 Figueroa AA, Polley JW. Management of the severe cleft and syndromic midface hypoplasia. Orthod Craniofac Res. 2007;10:167–179. R18 Figueroa AA, Polley JW, Friede H, Ko EW. Long-term skeletal stability after maxillary advancement with R19 distraction osteogenesis using a rigid external distraction device in cleft maxillary deformities. Plast R20 Reconstr Surg. 2004;114:1382–1392. R21 Hopper RA, Sandercoe G, Woo A, Watts R, Kelley P, Ettinger RE, Saltzman B. Computed tomographic analysis of temporal maxillary stability and pterygomaxillary generate formation following pediatric Le Fort III R22 distraction advancement. Plast Reconstr Surg. 2010;126:1665–1674. 7 R23 Iannetti G, Fadda T, Agrillo A, Poladas G, Iannetti G, Filiaci F. LeFort III advancement with and without R24 osteogenesis distraction. J Craniofac Surg. 2006;17:536–543. R25 Jacobson A. The ‘‘Wits’’ appraisal of jaw disharmony. Am J Orthod. 1975;67:125–138. R26 Kolar JC, Munro IR, Farkas LG. Patterns of dysmorphology in Crouzon syndrome: an anthropometric study. Cleft Palate J. 1988;25:235–244. R27 Kreiborg S, Aduss H. Pre- and postsurgical facial growth in patients with Crouzon’s and Apert’s syndromes. R28 Cleft Palate J. 1986;23(suppl):78–90. R29 Kreiborg S, Cohen MM Jr. Is craniofacial morphology in Apert and Crouzon syndromes the same? Acta R30 Odontol Scand. 1998;56:339–341. Marchac D, Arnaud E. Midface surgery from Tessier to distraction. Childs Nerv Syst. 1999;15:681–694. R31 Meazzini MC, Mazzoleni F, Caronni E, Bozzetti A. Le Fort III advancement osteotomy in the growing child R32 affected by Crouzon’s and Apert’s syndromes: presurgical and postsurgical growth. J Craniofac Surg. R33 2005;16:369–377. R34 Nout E, Wolvius EB, van Adrichem LN, Ongkosuwito EM, van der Wal KG. Complications in maxillary distraction using the RED II device: a retrospective analysis of 21 patients. Int J Oral Maxillofac Surg. R35 2006;35:897–902. R36 Panchal J, Uttchin V. Management of craniosynostosis. Plast Reconstr Surg. 2003;111:2032–2048. R37 R38 R39

Craniofacial Stability in Patients With Crouzon or Apert Syndrome After Le Fort III Distraction Osteogenesis | 137 Pelo S, Gasparini G, Di Petrillo A, Tamburrini G, Di Rocco C. Distraction osteogenesis in the surgical treatment R1 of craniostenosis: a comparison of internal and external craniofacial distractor devices. Childs Nerv R2 Syst. 2007:23:1447–1453. R3 Posnick JC, Ruiz RL. The craniofacial synostosis syndromes: current surgical thinking and future directions. Cleft Palate Craniofac J. 2000;37:434. R4 Prahl-Andersen B. Controversies in the management of craniofacial malformations. Semin Orthod. R5 2005;11:67–75. R6 Prahl-Andersen B, Kowalski CJ, Heyendaal PHJM. A Mixed-Longitudinal Interdisciplinary Study of Growth and R7 Development. New York: Academic Press; 1979. R8 Reid RR. Facial skeletal growth and timing of surgical intervention. Clin Plast Surg. 2007;34:357–367. R9 Reitsma JH, Ongkosuwito EM, Buschang PH, Prahl-Andersen B. Facial growth in patients with Apert and Crouzon syndromes compared to normal children. Cleft Palate Craniofac J. 2012;49:185–193. R10 Renier D, Lajeunie E, Arnaud E, Marchac D. Management of craniosynostoses. Childs Nerv Syst. 2000;16:645– R11 658. R12 Shetye PR, Boutros S, Grayson BH, McCarthy JG. Midterm followup of midface distraction for syndromic R13 craniosynostosis: a clinical and cephalometric study. Plast Reconstr Surg. 2007;120:1621–1632. Shetye PR, Davidson EH, Sorkin M, Grayson BH, McCarthy JG. Evaluation of three surgical techniques for R14 advancement of the midface in growing children with syndromic craniosynostosis. Plast Reconstr Surg. R15 2010;126:982–994. R16 Shrout PE, Fleiss JL. Intraclass correlations: uses in assessing rater reliability. Psychol Bull. 1979;86:420–428. R17 Sloan GM, Wells KC, Raffel C, McComb JG. Surgical treatment of craniosynostosis: outcome analysis of 250 consecutive patients. Pediatrics. 1997;100:E2. R18 Swennen G, Schliephake H, Dempf R, Schierle H, Malevez C. Craniofacial distraction osteogenesis: a review R19 of the literature: Part I: clinical studies. Int J Oral Maxillofac Surg. 2001;30:89–103. R20 Tanner JM, Whitehouse RH, Cameron N, Marshall WA, Healy MJR, Goldstein H. Assessment of Skeletal R21 Maturity and Prediction of Adult Height (TW2 method). London: Academic Press; 1983. R22 Trpkova B, Major P, Prasad N, Nebbe B. Cephalometric landmarks identification and reproducibility: a meta analysis. Am J Orthod Dentofacial Orthop. 1997;112:165–170. R23 Wah PL, Cooke MS, H ägg U. Comparative cephalometric errors for orthodontic and surgical patients. Int J R24 Adult Orthodon Orthognath Surg. 1995;10:119–126. R25 Waitzman AA, Posnick JC, Armstrong DC, Pron GE. Craniofacial skeletal measurements based on computed R26 tomography: Part II. Normal values and growth trends. Cleft Palate Craniofac J. 1992;29:118–128. R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

138 | Chapter 7 Chapter 8

General Discussion R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

140 | Chapter 8 8.1 Introduction R1 R2

Standardized longitudinal data of patients with Crouzon or Apert syndrome are very important R3 R4 for quantifying and describing their abnormal craniofacial growth and development and the R5 morphological variation. In general, many craniofacial anomalies are characterized by complex R6 deviations in the shape and configuration of facial hard and soft tissue structures. Longitudinal R7 reference data are urgently needed for treatment planning in terms of timing, type of surgery, R8 amount of surgical overcorrection, orthodontic guidance and evaluation of treatment results. New R9 methods of data collection have made longitudinal evaluation, defining, locating and comparing R10 of anatomical structures and landmarks complex. For example, definitions of landmarks used in R11 3D are largely adapted from their 2D definitions and have been shown to be less precise (Hassan R12 et al., 2011). Discrepancies may result from differences in how the landmarks are viewed in R13 2D images (in a single tomographic plane) and 3D images (in multiple planes). That is why a R14 comparison between 2D and 3D images should be undertaken with great caution. There is no R15 evidence that 3D-CT analysis of the normal skull is more reliable than conventional cephalometric R16 methods (Hassan et al., 2011). However, conventional cephalometrics are inadequate for assessing R17 patients with severe asymmetric craniofacial syndromes; therefore, 3D-CT cephalometrics are R18 R19 indicated in these patients (Fourie et al., 2012). R20 For several disciplines dealing with craniofacial anomalies knowledge of longitudinal R21 craniofacial development and dental development is important for the choice and timing of R22 treatment. In the following, the general and specific research aims described in Chapter 1 are R23 addressed in relation to findings in this thesis. In addition, the clinical relevance of the findings R24 and future perspectives regarding the study of craniofacial growth and development in patients R25 with Crouzon or Apert syndrome will be explored. R26 8 R27 8.2.1 Facial development in Crouzon or Apert syndrome R28 Patients with Crouzon or Apert syndrome showed unique longitudinal craniofacial growth R29 patterns (Chapters 2 and 3). The patients showed increased mandibular asymmetry, increased R30 lower facial height ratios, decreased transversal dimensions, increased inclination of the palatal R31 plane, a more retruded midface, and a more protruded mandible compared with control subjects. R32 The craniofacial measurements showed that patients with Apert syndrome had a more severe R33 R34 abnormal craniofacial growth pattern, morphology and mandibular asymmetry compared to R35 patients with Crouzon syndrome (Chapters 2 and 3). Differences in craniofacial growth between R36 the syndromes may imply the necessity of different treatments, different treatment timing, and R37 type of any kind of intervention in both syndromes (Reardon et al., 1994). R38 R39

General Discussion | 141 R1 From early childhood maxillary dimensions are very small with minimal changes over time in R2 both syndromes (Chapters 2 and 3). Marked craniofacial deformities are present at birth in Apert R3 syndrome, while in Crouzon syndrome craniofacial deformities are often milder (Kreiborg and R4 Cohen, 1998). The results of this study support previous reports (Costaras-Volarich and Pruzansky, R5 1984; Cohen and Kreiborg, 1996; Kreiborg and Cohen, 1998) indicating significant differences in R6 sagittal and vertical craniofacial patterns in children with Crouzon or Apert syndrome compared R7 to controls. A more abnormal craniofacial morphology in patients with Apert syndrome than R8 R9 in those with Crouzon syndrome has been found (Cohen and Kreiborg, 1992; Cohen, 1993; R10 Kreiborg and Cohen, 1998; Cohen and McLean, 2000; Sgouros, 2005). Patients with Crouzon R11 and Apert syndromes exhibit severe constriction of midfacial development. With the continuous R12 growth of the mandible the midfacial malformation increases. Premature fusion of calvarial R13 sutures in patients with Crouzon and Apert syndromes influence growth and development of R14 the maxilla and indirectly the mandible, with severe consequences for the developing maxillary- R15 mandibular complex (Costaras-Volarich and Pruzansky, 1984; Cohen and Kreiborg, 1996; R16 Kreiborg and Cohen, 1998). The ceased sutural growth potential may also explain the changes in R17 dental arch measurements seen in these patients. R18 Asymmetry is common in Apert and Crouzon syndromes (Cohen, 1986) whereas mild R19 asymmetries are found in normal children (Palmer and Strobeck, 1986). Abnormal craniofacial R20 development is often characterized by strong asymmetries. In the case of craniosynostosis R21 developmental differences between the two opposing sides of the skull and growth compensation R22 in all other calvarial sutures and synchondroses create asymmetry (Cohen, 1986). The increased R23 R24 degree of asymmetry of the face in syndromes with craniosynostosis (Kreiborg and Cohen, 2010) R25 is related to differences in the bilateral onset of sutural area closure (Kreiborg et al., 1993). R26 In addition, asymmetry in the midface has impact on the mandible, because the mandible R27 is influenced during growth of the base of the skull at the side of temporomandibular joint. R28 The mandible normally adapts to the maxilla, but also the other way around, the maxilla may R29 adapt to the mandible (Laspos et al., 1997). In the literature a wide range of differences of R30 mandibular ramal heights and mandibular morphology in Crouzon and Apert syndromes was R31 found (Costaras-Volarich and Pruzansky, 1984; Bu et al., 1989). Therefore, it is reasonable to R32 expect maxillomandibular skeletal asymmetry to be inherent to syndromes with craniosynostosis R33 (Pelo et al., 2011). For instance, asymmetry of the mandible was primarily located in the region R34 of the ramus and condyle in a dry skull in Crouzon syndrome (Kreiborg and Björk, 1981). But the R35 normal variation in directional asymmetry of the lower jaw was more evident in controls than in R36 patients with craniosynostosis (Chapter 3). The average value of directional asymmetry showed a R37 possible misleading value, close to zero (Chapter 3, Fig. 3.1b), being the direction of asymmetry R38 R39

142 | Chapter 8 is either left or right. The incidence of directional asymmetry tended to be higher in patients with R1 Apert syndrome than in patients with Crouzon syndrome. The mandibular asymmetry may also R2 be influenced by occlusal interference such as malpositioned teeth, dental crossbites caused by a R3 R4 constricted maxillary arch in growing syndromic children (Chapter 5) (Pelo et al., 2011). Abnormal R5 initial tooth contact causes subsequent mandibular displacement in maximum intercuspation and R6 possible growth adaptations. R7 Asymmetry can also be measured as fluctuating asymmetry. Fluctuating asymmetry is a R8 measurement of minor developmental deviations and developmental instability over time (Chapter R9 3, Fig. 3.1b) (Van Valen, 1962; Adams and Niswander, 1967; DeLeon and Richtsmeier, 2009). It R10 is reasonable to expect developmental instability in patients with syndromic craniosynostosis. R11 Increased fluctuating asymmetry is an expression of environmental and genetic disturbances of R12 an otherwise symmetrical phenotype and may imply pathology (Van Valen, 1962; Palmer and R13 Strobeck, 1986; Parsons, 1992; Furlow et al., 1997). In contrast to directional asymmetry, the R14 increased degree of fluctuating asymmetry (Chapter 3) demonstrates a higher developmental R15 instability in patients with Crouzon or Apert syndrome compared to normal children. Fluctuating R16 asymmetry is an important indicator for a population’s state of adaptation and coadaptation to R17 environmental and genetic influences (Palmer and Strobeck, 1986). This is logically less in patients R18 R19 with craniosynostosis (DeLeon and Richtsmeier, 2009). R20 R21 8.2.2 Differences in dental findings in Crouzon or Apert syndrome R22 The indication of delayed dental development before seven years of age in both syndromes R23 was pronounced (Chapter 4, fig. 4.2). Dental development in syndromic patients was delayed R24 compared to control subjects, and small differences between patients with Crouzon and Apert R25 syndrome were found (Chapter 4). Hypodontia seems related to delayed dental development R26 (Cohen and McLean, 2000; Ruiz-Mealin et al., 2012). Increased prevalence of tooth agenesis and 8 R27 delayed dental development were found in both syndromes (Chapter 5). In healthy children the R28 most prevalent type of tooth agenesis is third molars followed by mandibular second premolars or R29 maxillary lateral incisors. Although the prevalence of tooth agenesis was much higher in syndromic R30 patients, the same pattern of agenesis of third molars followed by second mandibular premolars R31 and maxillary lateral incisors was found both in syndromic children as in healthy children. The R32 mutated FGFR2 gene may be involved in the pathogenesis of dental agenesis. Expression of the R33 R34 signaling molecules that bind to FGFRs, the FGFs, have been observed during all stages of dental R35 morphogenesis (Thesleff, 1998). Failure in the function of FGFs in the dental epithelium and/or in R36 the underlying mesenchyme during tooth development may result in dental agenesis (De Coster R37 et al., 2009). Consequently, certain patterns of agenesis can be linked to specific gene mutations, R38 R39

General Discussion | 143 R1 also in nonsyndromic children. The recently introduced Tooth Agenesis Code (TAC) was used to R2 describe the number and location of missing teeth (Van Wijk and Tan, 2006). More symmetrical R3 patterns of tooth agenesis were found in Crouzon and Apert syndrome than in healthy children R4 (Chapter 4). Analyzing large numbers of subjects with the same gene mutations may show similar R5 TAC codes that are typical for specific gene mutations (Coussens et al., 2007; Coussens et al., R6 2008). This also may reveal the relation between increased fluctuating asymmetry and increased R7 patterns of symmetrical tooth agenesis seen in for example cleft lip and palate (Laspos et al., R8 R9 1997; DeLeon and Richtsmeier, 2009; Bartzela et al., 2010). Specific TAC codes may be used as R10 biomarkers linked to specific gene mutations. R11 Dental arch morphology was very abnormal in patients with Crouzon or Apert syndrome. R12 Children with Apert syndrome had smaller arch dimensions than children with Crouzon syndrome R13 (Chapter 6). The dental arch dimensions showed hardly any change from primary dentition to R14 mixed permanent dentition in both syndromes (Chapter 6). Dental arch dimensions of normal R15 children remained relatively stable during primary dentition (Moorrees et al., 1969; Prahl et al., R16 1979). The normal children showed continuous growth and development, particularly during the R17 transitional period from primary to mixed dentition to accommodate the permanent teeth. The R18 premature arrest of maxillary sutural growth in patients with craniosynostosis clarifies the small R19 maxillary intermolar and intercanine dimensions (Chapter 6). The maxillary intermolar width in R20 patients with Apert syndrome showed an increase over time but were much smaller compared R21 to control subjects. This increase in intermaxillary arch width may be related to ectopic eruption R22 of maxillary first molars as the second maxillary premolars often show palatal eruption in a R23 R24 transversally reduced maxilla. Clinically, reduced dental arch dimensions of the upper and lower R25 jaw result in severe crowding in the mixed and permanent dentition (Kreiborg and Cohen, 1992). R26 The limited sutural growth potential seen in these patients explain the very small longitudinal R27 changes in upper dental arch measurements for both syndromes (Chapters 2, 3 and 6). R28 Well-aligned teeth and coordinated dental arches are needed as a prerequisite basis for midface R29 surgical reconstructive procedures in patients with syndromic craniosynostosis. Extractions of R30 some deciduous and selected permanent teeth are often needed and should be determined by R31 the pediatric dentist and the orthodontist together (Vargervik et al., 2012). R32 R33 R34 R35 R36 R37 R38 R39

144 | Chapter 8 8.3 Clinical implications R1 R2

Apert and Crouzon syndromes are different disorders, and the craniofacial and dental development R3 R4 is not the same. The craniofacial morphology are distinct at all ages between both syndromes. R5 The role of the orthodontist in an interdisciplinary craniofacial team consists of the observation R6 and management of (abnormal) growth and dental development from infancy to adulthood. In R7 most team settings, the orthodontist takes care of growth data (e.g. dental and cephalometric R8 radiographs, computed tomography (CT) scans, cone-beam CT (CBCT) scans, dental casts, R9 photographs, height and weight measurements, and for some patients, handwrist radiographs) R10 and thus plays an important role in the timing and planning of jaw reconstructive and facial R11 surgical procedures. It is suggested that a detailed growth analysis, as described in the present R12 study, can provide a rational basis for treatment planning in individual patients with Crouzon or R13 Apert syndrome. In craniofacial teams standardized data collection of all patients is important R14 in order to gain accurate information about growth and development of rare syndromes. The R15 often used cephalometric norm values are difficult to use as guideline for adequate positioning R16 of the inferior parts of the orbits and zygomatic bone during surgery (Chapter 7), because the R17 anatomy of the orbit is distorted due to syndromic factors and sometimes previous surgical R18 R19 intervention. Normative cephalometric values can not be used directly as templates or surgical R20 goals for syndromic patients. R21 Management of individuals with syndromic craniosynostosis requires a team of experienced R22 specialists and extends over the entire growth period from infancy to adulthood. An interdisciplinary R23 craniofacial team can be expected to house the experience, knowledge, skills and organizational R24 logistics to provide the highest level of care. Midfacial advancements with several surgical R25 techniques are common in different published treatment protocols (Renier et al., 2000; Perlyn R26 et al., 2009; Sant’Anna et al., 2010; Shetey et al., 2010). Some protocols describe a midfacial 8 R27 advancement combined with a mandibular set-back osteotomy (Hohoff et al., 2007; Stavropoulos R28 et al., 2012). This procedure may increase a present obstructive sleep apnea in these patients R29 (Bannink et al., 2010). It should be kept in mind that the length of the mandible is significantly R30 shorter than normal (Costaras-Volarich and Pruzansky, 1984) and anteriorly positioned in the R31 face, because the cranial base is short in Crouzon and Apert patients (Chapter 2). The question of R32 timing for restoring abnormal morphology early in the patient’s life is still a problem. R33 R34 There are differing opinions on the best timing for midface surgical advancement in patients R35 with midface hypoplasia. This is in part due to variations in each patient’s medical, physical, and R36 developmental needs as well as the acknowledgment that various interdisciplinary teams will R37 have different treatment philosophies. Obstructive sleep apnea or severe exorbitism are pressing R38 R39

General Discussion | 145 R1 indications for early midface advancement. The orthodontist facilitates the dentition for tooth R2 eruption in severe crowding, prepares surgical prediction tracings and splints as needed, and R3 provides long-term follow-up with appliances and treatment (Kreiborg et al., 1999; Kreiborg and R4 Aduss, 1986). The orthodontist and surgeon would ideally plan a midface advancement only R5 once, both for practical/technical and psychological reasons, and still achieve a normal position R6 of the midface. Although desirable, this goal may not be achievable due to impaired midfacial R7 growth in syndromic patients. Since surgery does not restore the innate lack of growth potential, R8 R9 patients operated on before the completion of skeletal growth will often require repeated surgical R10 procedures. The cooperation between orthodontist and surgeon is critical not only to plan R11 midface and jaw procedures, but also to prevent dental injuries that could result in irreversible R12 tooth damage or loss, especially in infants and children in the deciduous and transitional dentition R13 stages (Santiago et al., 2005; Sant’Anna et al., 2010). R14 Implicit in the choice of treatment made by the surgeon is the understanding that the first R15 adapted procedure often provides the best opportunity for a good surgical outcome (Shetye R16 et al., 2010; McCarthy et al., 2012). To achieve a good or excellent surgical outcome is more R17 challenging if crucial tissues are surgically malpositioned or damaged. An experienced surgeon R18 and an interdisciplinary team are even more important when contemplating surgical revision after R19 a previous suboptimal outcome (McCarthy et al., 2012). R20 In the case of no acute indication for surgical intervention it is advisable before any R21 maxillary surgery is undertaken in young children with Crouzon or Apert syndrome and wait R22 with surgical intervention after the skeletal growth has stopped. Even more important, patients R23 R24 with craniosynostosis exhibit a higher chance developing psychosocial problems and irrational R25 expectations when a Le Fort III is performed between 12 and 18 years of age (NVPC, 2010). R26 Preferably a Le Fort III should not be performed during this period (NVPC, 2010). Greater R27 utilization of two- or three-dimensional imaging techniques may improve the standardization and R28 accuracy of growth analysis, and treatment planning. Considering the high rate of oral anomalies R29 in patients with Crouzon or Apert syndrome, observation and knowledge of the extent of the R30 oral abnormalities is important. This information is important for the orthodontic treatment, to R31 guide dental eruption, management of space and choice of the often needed extractions in these R32 patients. R33 Delayed dental development is a problem for the orthodontist, because surgical intervention R34 starts often in childhood between 6 and 12 years of age with an early midface advancement with R35 or without a facial bipartition. At this time retention of orthodontic braces on permanent teeth R36 can be difficult or is impossible, because the first permanent molars are often unerupted, due R37 to severely delayed dental development. Dental arch morphology in the permanent dentition is R38 R39

146 | Chapter 8 very abnormal in patients with Crouzon or Apert syndrome. Children with Apert syndrome have R1 smaller arch dimensions than children with Crouzon syndrome. Without orthodontic intervention R2 no normal arch development will occur and at this time the choice is to expand the upper jaw R3 R4 orthodontically or possibly surgically. The already clinically, reduced dental arch dimensions in R5 the primary dentition of the upper and lower jaw may therefore result in even more severe R6 crowding in the mixed and permanent dentition. At this time, between 12 and 15 years of age R7 a new decision or evalution should be made to create well aligned arches in preparation for the R8 final ideal operatively obtained occlusion (at the age of 18 years or older). Knowledge of dental R9 and craniofacial development is important for any kind of intervention. The orthodontist and R10 the surgeon should inform other team members when craniofacial interventions are planned. R11 It is important when circumstances permit to prepare dental arch dimensions before surgical R12 intervention and coordinate this treatment with other team members. The orthodontist should R13 have sufficient experience with presurgical orthodontic treatment in patients with craniofacial R14 anomalies are fundamental. Knowledge of normal and abnormal dental and craniofacial growth R15 and development. R16 Consensus on timing and type of intervention and experience in treatment of craniosynostosis R17 are important on the effects of growth and intervention. The physicians and other involved R18 R19 specialists should be able to monitor and plan surgical interventions in patients, performing the R20 planned procedures, and establish adequate follow-up for evaluating the results. Disappointing R21 or unexpected results as well as deviations from the protocols should be reported and hopefully R22 lead to re-evaluation of the guidelines over time (Marchac and Renier, 1996; NVPC, 2010; Shetye R23 et al., 2010). Evidence-based knowledge about the optimal care for children with craniosynostosis R24 is rare. Unfortunately, at the moment prospective randomized clinical trials are not feasible to R25 conduct due to small sample sizes and ethical issues. R26 8 R27 R28 8.4 Statistical data analysis R29 R30 In this thesis statistical multilevel modeling has been used. Multilevel models are statistical models R31 of parameters that vary at more than one level. The units of analysis are usually individuals (at a R32 lower level) who are nested within contextual/ aggregate units (at a higher level). These models R33 R34 can be seen as generalizations of linear models (in particular, linear regression), although they can R35 also extend to non-linear models (Goldstein, 1986). It can describe both individual and average R36 growth curves; it is flexible because it uses polynomials, which can describe growth curves of R37 almost any form. Additionally, the model can handle missing values very easily (without loss R38 R39

General Discussion | 147 R1 of complete cases). Finally, the model can be used with different sample and research designs R2 (Hoeksma and Van der Beek, 1991). While the lowest level of data in multilevel models is usually R3 an individual, repeated measurements of individuals may also be examined. As such, multilevel R4 models provide an alternative type of analysis for univariate or multivariate analysis of repeated R5 2 3 measures. The initial equation was:yij = β0ijconstant + β1tij + β2tij + β3tij R6 R7 with 2 3 R8 yij = β0ijconstant + β1tij + β2tij + β3tij R9 with β0ij = u0j + e0ij with R10

R11 The e0ij refers to the random errors of prediction for the level 1 equation. At level 1, both the where the craniofacial growth measurement y was computed by adding the intercept (β0ij) to the β0ij = u0j + e0ij R12 intercepts and slopes in the groups can be either fixed (meaning that all groups have the same β β β R13 values,products although of other in fixed the coefficientsreal world ( this1 , 2would, and 3)be multiplied a rare occurrence),by age (t) at each or occasion.non-randomly The u0j varyingand where the craniofacial growth measurement y was computed by adding the intercept (β0ij) to the R14 (meaninge0ij comprise that thethe interceptsrandom portion and/or of theslopes model are and predictable are assumed from to havean independent means equal tovariable zero, to at be level R15 2), productsor randomly of other varying fixed coefficients(meaning that(β1 , βthe2, and intercepts β3) multiplied and/or by ageslopes (t) atare each different occasion. in The the u different0j and uncorrelated, and to be normally distributed. The level 1 residual e0ij represents within-subject R16 groups),e0ij comprise and that the eachrandom have portion their of ownthe model overall and mean are assumed and variance. to have meansArguments equal to for zero, choosing to be a variation, or the ‘‘error’’ term, while the level 2 residual u0j represents, in this case, between-subject R17 rondom intercept model in this thesis: the groups are not unique entities; the groups are regarded uncorrelated, and to be normally distributed. The level 1 residual e0ij represents within-subject R18 as avariation sample (Goldstein,from a population; 1987). the number of values in the study is small relative to the values of R19 variation, or the ‘‘error’’ term, while the level 2 residual u0j represents, in this case, between-subject the variable as it appears in the population it is drawn from (Goldstein, 1986). R20 The polynomial model takes full advantage of each patient’s individual longitudinal growth variationMost measurements (Goldstein, 1987). contain some error component. This may be due to observer error R21 whendata measuring and statistically distances evaluates on radiographs.the shape of the When curve. variables Iterative generalizedin statistical least models squares contain were used relatively to R22 The polynomial model takes full advantage of each patient’s individual longitudinal growth large components of such error the resulting statistical interferences can be very misleading. To R23 estimate the model’s parameters (Goldstein, 1987). Two-level models were also used to estimate the preventdata andlarge statistically measurement evaluates errors the shape the ofmeasures the curve. ofIterative the observer, generalized first least digitizingsquares were of usedlandmarks to R24 groups’ adult stat status at 22 years of age (intercept = age - 22). R25 wereestimate practiced the model’s and reviewed parameters by (Goldstein, an expert, 1987). and Two-levelsecond reliability models were tests also were used performed. to estimate theIn the current study assessment of goodness of the model fit in the multilevel modeling procedure was R26 groups’ adult stat status at 22 years of age (intercept = age - 22). R27 performed; scatter plots were used to check for outliers; models were checked for significance

R28 and2.3 statistics Results procedures were performed under guidance of an expert. Some of the growth R29 curves showed cubic statistically significant multilevel models. Cubic models showing four waves, R30 although2.32.3.1 Results Assessment tested significant, of Interexaminer explains the and complexity Intraexaminer involved Variation in fitting the data. With an increased R31 number for modeling of the data a quadratic or linear model seems to be more realistic for ICC values for intraobserver reliability were excellent (Table 2.2). The ICC values for interobserver R32 growth2.3.1 models Assessment (Goldstein, of Interexaminer 1986). and Intraexaminer Variation R33 reliabilityIn chapter were 4 faira different to excellent longitudinal (Table 2.2): statistical Fair to good procedure reliability and was control found for group measurements were used R34 comparedICC values to thefor otherintraobserver studies. reliability Nonsyndromic were excellent logistic (Table curve-fitting 2.2). The ICCprocedures values for were interobserver used instead R35 concerning the inclination of the maxilla and point B relative to the cranial base and LFH, and all the of multilevelreliability weremodeling. fair to This excellent procedure (Table treats 2.2): Fairdata to as good independent reliability wasobservations. found for measurementsA consequence R36 other measurements showed excellent reliability. of failing to recognize hierarchical structures is that standard errors of regression coefficients will R37 concerning the inclination of the maxilla and point B relative to the cranial base and LFH, and all the be underestimated, leading to an overstatement of statistical significance. In contrast to the other R38 other measurements showed excellent reliability. R39 2.3.2 Growth Models 148 | Chapter 8 2.3.2Control Growth Subjects Models

Control Subjects 47

47 studies, the date of birth of the control group is more comparable with the syndromic groups to R1 decrease the effect of a possible secular trend. R2 R3 R4 R5 8.5 Considerations and recommendations for future research R6 R7 In the future, longitudinal 3D measurements before and after surgery may contribute to the study R8 of facial growth and development and treatment implications in Apert and Crouzon syndromes. R9 In order to prove that the quality of care is improving, comparisons of results over time, are R10 imperative. This will become more difficult in the near future because centers may change the R11 method of record taking from 2D to advanced computerized 3D equipment. All the outcome R12 variables in this study are two-dimensional. In the near future it can be expected that two- R13 dimensional pictures like photographs or cephalograms will be replaced by three-dimensional R14 images, but at the start of data collection in many studies this technology was not available. R15 Especially in patients with craniosynostosis, three-dimensional images can give new insights R16 because asymmetry of the different parts of the face can better be evaluated. However, limited R17 3D longitudinal reference data for Crouzon or Apert syndrome are available yet (Cerovac et al., R18 R19 2002). R20 At present, it still is a utopia for clinicians to be able to predict growth reliably in patients R21 with craniosynostosis, to prevent or reduce relapse in surgical and orthodontic intervention R22 and to manipulate the growth potential. Attempts should be made to integrate longitudinal R23 data for patients with craniosynostosis into the prediction of individual craniofacial growth and R24 development. The recent introduction of three-dimensional records will eventually lead to a virtual R25 head of the patient which can be used for case analysis and treatment planning. The introduction R26 of digital dental models at the end of the 20th century, 3D digital data sets, combining the bone, 8 R27 soft tissues, and the dentition, have gained increasing interest (Rangel et al., 2008). Integrating R28 different types of X-rays, 2D or 3D photographs or composite tracings, life-like 3D models provide R29 a tool for identification of areas of deformities, levels of asymmetry and relative relationships R30 between different components of the face. Combining and integrating all available data in R31 Europe with new imaging 3D techniques into a longitudinal data set should make craniofacial R32 growth prediction possible even in syndromic patients. R33 R34 The results in this thesis confirm the necessity and advantage of the use of protocolized R35 standardized (rare) data for patients with Crouzon or Apert syndrome in order to be able to predict R36 craniofacial growth and development. Most craniofacial centers now store their digital images on R37 servers or a picture archiving and communications system (PACS). The PACS is an electronic and R38 R39

General Discussion | 149 R1 ideally filmless information system for acquiring, sorting, transporting, storing, and electronically R2 displaying medical images. With proper and secure access to data protection for privacy and legal R3 issues, these digital longitudinal data can be readily accessed from inside or outside the institution R4 in real time, permitting the use of a large file of longitudinal data from which to create a database R5 of craniofacial measurements of rare syndromes like Crouzon or Apert. R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

150 | Chapter 8 8.6 References R1 R2 Aldridge K, Hill CA, Austin JR, Percival C, Martinez-Abadias N, Neuberger T, Wang Y, Jabs EW, Richtsmeier R3 JT. Brain phenotypes in two FGFR2 mouse models for Apert syndrome. Dev Dyn. 2010;239:987-997. R4 Allam KA, Wan DC, Khwanngern K, Kawamoto HK, Tanna N, Perry A, Bradley JP. Treatment of apert syndrome: R5 a long-term follow-up study. Plast Reconstr Surg. 2011;127:1601-1611. Baum JA, Hanley EN Jr, Pullekines J. Comparison of halo complications in adults and children. Spine. R6 1989;14:251-252. R7 Bannink N, Nout E, Wolvius EB, Hoeve HL, Joosten KF, Mathijssen IM. Obstructive sleep apnea in children R8 with syndromic craniosynostosis: long-term respiratory outcome of midface advancement. Int J Oral R9 Maxillofac Surg. 2010;39:115-121. Bartzela TN, Carels CEL, Bronkhorst EM, Ronning E, Rizell S, Kuijpers-Jagtman AM. Tooth agenesis patterns in R10 bilateral cleft lip and palate. Eur J Oral Sci. 2010;118:47-52. R11 Bu BH, Kaban LB, Vargervik K. Effect of Le Fort III osteotomy on mandibular growth in patients with Crouzon R12 and Apert syndromes. J Oral Maxillofac Surg. 1989;47:666-671. R13 Cerovac S, Neil-Dwyer JG, Rich P, Jones BM, Hayward RD. Are routine preoperative CT scans necessary in the management of single suture craniosynostosis? Br J Neurosurg. 2002;16:348-354. R14 Cohen MM Jr. Craniosynostosis: Diagnosis, evaluation, and management. New York: Raven Press; 1986. R15 Cohen MM Jr, Kreiborg S. New indirect method for estimating the birth prevalence of the Apert syndrome. R16 Int J Oral Maxillofac Surg. 1992;21:107-109. R17 Cohen MM Jr, MacLean RE. Craniosynostosis: diagnosis, evaluation and management. 2nd ed. New York; R18 Oxford University Press: 2000. R19 Cohen MM Jr. Sutural biology and the correlates of craniosynostosis. Am J Med Genet. 1993;47:581-616. Cohen MM Jr. Perspectives on craniofacial asymmetry. V. The craniosynostoses. Int J Oral Maxillofac. R20 1995;24:191-194. R21 Costaras-Volarich M, Pruzansky S. Is the mandible intrinsically different in Apert and Crouzon syndromes? Am R22 J Orthod. 1984;85:475-487. R23 Coussens AK, Wilkinson CR, Hughes IP, Morris CP, van Daal A, Anderson PJ, Powell BC. Unravelling the molecular control of calvarial suture fusion in children with craniosynostosis. BMC Genomics. R24 2007;8:458-1-25. R25 Coussens AK, Hughes IP, Wilkinson CR, Morris CP, Anderson PJ, Powell BC, van Daal A. Indentification of R26 genes differentially expressed by prematurely fused human sutures using a novel in vivo – in vitro approach. Differentiation. 2008;76:531-545. 8 R27 De Jong T, Maliepaard M, Bannink N, Raat H, Mathijssen IM. Health-related problems and quality of life in R28 patients with syndromic and complex craniosynostosis. Childs Nerv Syst. 2012;28:879-882. R29 DeLeon VB, Richtsmeier JT. Fluctuating asymmetry and developmental instability in sagittal craniosynostosis. R30 Cleft Palate Craniofac J. 2009;46:187-196. R31 Du X, Xie Y, Xian CJ, Chen L. Role of FGFs/FGFRs in skeletal development and bone regeneration. J Cell Physiol. 2012;227:3731-3743. R32 Farkas LG, Bryson W, Klotz J. Is photogrammetry of the face reliable? Plast Reconstr Surg. 1980;66:346-355. R33 Farkas LG. Accuracy of anthropometric measurements: past, present, and future. Cleft Palate Craniofac J. R34 1996;33:10-18. R35 Fearon JA. Halo distraction of the Le Fort III in syndromic craniosynostosis: a long-term assessment. Plast R36 Reconstr Surg. 2005;115:1524-1536. Fourie Z, Damstra J, Ren Y. Application of cone beam computed tomography in facial imaging science. R37 Shanghai Kou Qiang Yi Xue. 2012;21:220-31. R38 R39

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Genetic interactions between Pax9 and Msx1 regulate lip development and several stages of tooth morphogenesis. Dev Biol. 2010;340:438-449. Nederlandse Vereniging voor Plastische Chirurgie. Richtlijn behandeling en zorg voor craniosynostose. 2010. Nout E, Wolvius EB, van Adrichem LN, Ongkosuwito EM, van der Wal KG. Complications in maxillary distraction using the RED II device: a retrospective analysis of 21 patients. Int J Oral Maxillofac Surg. 2006;35:897-902. Ornitz DM, Marie PJ. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 2002;16:1446-1465. Palmer AR, Strobeck C. Fluctuating asymmetry: measurement, analysis, patterns. Annu Rev Ecol Syst. 1986;17:391-421. Pelo S, Marianetti TM, Cacucci L, Di Nardo F, Borrelli A, Di Rocco C, Tamburrini G, Moro A, Gasparini G, Deli R. occlusal alterations in unilateral coronal craniosynostosis. Int J Oral Maxillofac Surg. 2011;40:805-809. R1 Parsons PA. Fluctuating asymmetry: a biological monitor of environmental and genomic stress. Heredity. R2 1992;68:361-364. R3 Percival CJ, Wang Y, Zhou X, Jabs EW, Richtsmeier JT. The effect of a Beare-Stevenson syndrome Fgfr2 R4 Y394C mutation on early craniofacial bone volume and relative bone mineral density in mice. J Anat. 2012;221:434-442. R5 Perlyn CA, Nichols C, Woo A, Becker D, Kane AA. Le premier siècle: one hundred years of progress in the R6 treatment of Apert syndrome. J Craniofac Surg. 2009;20:801-806. R7 Posnick JC, Farkas LG. The application of anthropometric surface measurements in craniomaxillofacial surgery. R8 In: Farkas LG, ed. Anthropometry of the Head and Face. New York: Raven Press; 1994:125-138. R9 Prahl-Andersen B, Kowalski CJ, Heyendaal PHJM. A Mixed-Longitudinal Interdisciplinary Study of Growth and Development. New York: Academic Press, 1979. R10 Rangel FA, Maal TJJ, Berge SJ, Van Vlijmen OJ, Plooij JM, Schutyser F, Kuijpers-Jagtman AM. Integration R11 of digital dental casts in 3-dimensional facial photographs. Am J Orthod Dentofacial Orthop. R12 2008;134:820-826. R13 Renier D, Lajeunie E, Arnaud E, Marchac D. Management of craniosynostoses. Childs Nerv Syst. 2000;16:645- 658. R14 Ruiz-Mealin EV, Parekh S, Jones SP, Moles DR, Gill DS. Radiographic study of delayed tooth development in R15 patients with dental agenesis. Am J Orthod Dentofacial Orthop. 2012;141:307-314. R16 Sant’Anna EF, de Cury-Saramago A, Figueroa AA, Polley JW. Evaluation of maxillary permanent molars in R17 patients with syndromic craniosynostosis after monobloc osteotomy and midface advancement with rigid external distraction (RED). Cleft Plate Craniofac J. 2010;47:109-115. R18 Santiago PE, Grayson BH, Degen M, Brecht LE, Singh GD, McCarthy JG. The effect of an early Le Fort III R19 surgery on permanent molar eruption. Plast Reconstr Surg. 2005;115:423-427. R20 Shaw WC, Dahl E, Asher-McDade C, Brattström V, Mars M, McWilliam J, Molsted K, Plint DA, Prahl-Andersen R21 B, Roberts CT, Semb G, The RPS. A six center international study of treatment outcome in patients with clefts of lip and palate: Part 5. General discussion and conclusions. Cleft Palate Craniofac J. R22 1992;29:413-418. R23 Shaw WC, Semb G, Nelson P, Brattström V, Molsted K, Prahl-Andersen B. The Eurocleft project 1996-2000. R24 Amsterdam: IOS Press; 2000. Shetye PR, Davidson EH, Sorkin M, Grayson BH, McCarthy JG. Evaluation of three surgical techniques for R25 advancement of the midface in growing children with syndromic craniosynostosis. Plast Reconstr Surg. R26 2010;126:982-994. 8 R27 Stavropoulos D, Tarnow P, Mohlin B, Kahnberg KE, Hagberg C. Comparing patients with Apert and Crouzon R28 syndromes – clinical features and cranio-maxillofacial surgical reconstruction. Swed Dent J. 2012;36:25- 34. R29 Thesleff, I. The genetic basis of normal and abnormal craniofacial development. Acta Odontol Scand. R30 1998;56:321-325. R31 Van Valen L. A study of fluctuating asymmetry. Evolution. 1962;16:125-142. R32 Van Wijk AJ, Tan SP. A numeric code for identifying patterns of human tooth agenesis: a new approach. Eur J Oral Sci. 2006;114:97-101. R33 Vargervik K, Rubin MS, Grayson BH, Figueroa AA, Kreiborg S, Shirley JC, Simmons KE, Warren SM. Parameters R34 of care for craniosynostosis: Dental and orthodontic perspectives. Am J Orthod Dentofacial Orthop. R35 2012;141:S68-73. R36 Vastardis H. The genetics of human tooth agenesis: new discoveries for understanding dental anomalies. Am J Orthod Dentofacial Orthop. 2000;117:650-656. R37 R38 R39

General Discussion | 153 Yu K, Xu J, Liu Z, Sosic D, Shao J, Olson EN, Towler DA, Ornitz DM. Conditional inactivation of FGF receptor R1 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth. R2 Development. 2003;130:3063-3074. R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

154 | Chapter 8 Chapter 9

Summary R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

156 | Chapter 9 In Chapter 1, the influence of craniosynostosis on the facial morphology of patients with Apert R1 or Crouzon syndrome and the developmental changes over time are described and discussed in R2 general. The syndromes of Crouzon or Apert are complex congenital anomalies. Both anomalies R3 R4 are associated with numerous problems. The consequent treatments introduced to solve the R5 problems unfortunately may create additional handicaps. Research has elucidated many aspects R6 of these problems, psychosocial well-being of the affected individuals and recently the genetic R7 factors suspected of causing craniosynostosis have been reported. Research of the craniofacial R8 growth and development including morphology of untreated syndromic patients is limited R9 because of the low prevalence, early surgical midfacial intervention and a short follow-up. The R10 focus of this study was dentofacial growth and development. Midfacial treatment modalities and R11 protocols differ in timing found in the literature. This problem is related to insufficient evidence R12 based knowledge of craniofacial growth in both syndromes. Surprisingly, detailed information R13 about longitudinal craniofacial growth and development of syndromic patients is remarkably R14 scarce. It was the aim of this study to evaluate and describe the craniofacial and oral development R15 in growing patients with craniosynostosis. The patients were all treated in the craniofacial team R16 at Erasmus Children’s University Hospital in Rotterdam, The Netherlands. The Craniofacial R17 Team coordinates and provides multidisciplinary specialty care for children with congenital R18 R19 defects of the head and neck. A multidisciplinary craniofacial team may be expected to house R20 the experience, knowledge, skills and organizational logistics to provide the highest level of care. R21 In Chapter 2 the craniofacial growth pattern in patients with Crouzon or Apert syndrome was R22 analyzed in detail and compared with a sample of unaffected normal subjects. Multilevel modeling R23 was used to analyze growth changes and compare the three groups. Significant differences in the R24 sagittal and vertical dimensions within the syndromic groups showed an increased lower facial R25 height, increased inclination of the palatal plane, retrusion of the maxilla, and proposition of the R26 mandible compared with the controls. Overall, the patients with Apert syndrome had a more R27 severe abnormal craniofacial morphology than did the patients with Crouzon syndrome. R28 In Chapter 3 directional and fluctuating asymmetry in Crouzon or Apert syndrome compared R29 with unaffected controls was described. Both measurements showed that the Apert syndrome 9 R30 had more directional and fluctuating asymmetry over time followed by the Crouzon syndrome R31 and controls. R32 In Chapter 4 the prevalence patterns of tooth agenesis were described in patients with R33 R34 Crouzon or Apert syndrome compared with nonsyndromic controls. Dental agenesis is the most R35 common anomaly of the dentition and can be a component of a congenital syndrome. Tooth R36 agenesis of third molars and lower second premolars is more prevalent in the syndrome of R37 Crouzon and Apert than in control subjects. Mandibular symmetric patterns of tooth agenesis R38 are also more prevalent in syndromic patients. R39

Summary | 157 R1 In Chapter 5 dental maturation in children with Crouzon or Apert syndrome were compared R2 with nonsyndromic controls. Logistic development curves for dental age over time were R3 constructed. Significant gender differences in dental maturation scores were found for girls with R4 Crouzon or Apert syndrome. Patients with Apert syndrome demonstrated a significantly delayed R5 dental maturation, while patients with Crouzon syndrome showed non-significant delay. The R6 delay of tooth formation in patients with Crouzon or Apert syndrome suggests a relationship R7 between craniosynostosis and dental maturation. R8 R9 In Chapter 6 changes in dental arch morphology were compared in patients with Crouzon R10 or Apert syndrome and controls. Multilevel statistical techniques were used to evaluate dental R11 arch changes over time for the three groups. Dental arch dimensions were statistically significant R12 smaller in patients with Crouzon or Apert syndrome than in controls. Maxillary intermolar arch R13 width in patients with Apert syndrome increased, while all other arch width measurements R14 showed no change. Patients with Crouzon syndrome showed increase in maxillary intercanine R15 width, while intermolar width showed no increase over time. Maxillary arch depth showed no R16 change over time and was statistically significant smaller in syndromic patients than in controls. R17 The mandibular and maxillary arch lengths decreased only slightly over time. From this study it R18 can be concluded that dental arch dimensions in syndromic patients are consistently smaller than R19 in control subjects between 4 and 14 years of age. Also dental arch dimensions of patients with R20 Crouzon or Apert syndrome showed diminished increase from 4 to 14 years of age. R21 In Chapter 7 the effect was evaluated of Le Fort III osteotomy with distraction osteogenesis R22 (DO) on the retruded midface in patients with Crouzon or Apert syndrome. One year after R23 R24 removal of the distraction device no statistically significant difference of the surgical maxillary R25 advancement was found for both syndromes. From this study it could be concluded that DO R26 of the midface in patients with Crouzon or Apert syndrome seems to be stable in the sagittal R27 direction after one year follow-up. Although Crouzon or Apert syndromes differ in craniofacial R28 characteristics, anteroposterior craniofacial dimensions were significantly improved and were R29 closer to normal after treatment. R30 In Chapter 8 the general aims of this thesis are discussed in relation to the main results. It R31 can be concluded that: R32 1. Children with Crouzon and Apert syndromes showed retarded craniofacial growth, R33 decreased craniofacial dimensions and facial asymmetry. R34 2. It appeared that most craniofacial dimensions from early childhood are abnormal small R35 and hardly change over time. R36 3. The lack of craniofacial growth potential explains the differences in dental arch R37 dimensions seen in these patients. R38 R39

158 | Chapter 9 4. Delayed dental development and increased agenesis of teeth are part of both syndromes R1 and may be related to the genetic background. R2 Although the syndrome of Crouzon and Apert show similarities in their craniofacial growth R3 R4 and development they are two distinct syndromes with more severe growth and development R5 deficiencies in the Apert syndrome. Regarding the implementation of the findings of the present R6 study, it should be mentioned that individual and overall growth should be monitored in advance R7 to the decision regarding timing of any kind of treatment and discussed with the patient and the R8 parents. Surgical midfacial advancement performed at early childhood may often need secondary R9 midfacial surgery later in life because the mandible grows continually until adulthood. R10 Management of cleft lip and palate and craniofacial deformities has recently been focused R11 on interdisciplinary approach with several recommendations in the literature. Cleft lip and palate R12 and craniofacial teams have evolved across the globe over the last 40 years in order to provide R13 coordination between different professionals involved in the care of patients with clefts and R14 craniofacial deformities. Hopefully, an interdisciplinary care system with each member of the team R15 involved in a coordinated treatment approach should give the best possible treatment outcome. R16 The mission for the future will be the national implementation of the recommendations from R17 this study and to urge craniofacial centers to (re)evaluate their treatment protocols. The use of R18 R19 protocolized standardized data for patients with Crouzon or Apert syndrome gathered at these R20 national centers should be pooled in order to confirm the necessity and advantage of the used R21 treatments and to predict craniofacial growth and development. International intercenter studies R22 are necessary! R23 R24 R25 R26 R27 R28 R29 9 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

Summary | 159

Chapter 10

Samenvatting R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

162 | Chapter 10 In hoofdstuk 1 wordt de invloed besproken van craniosynostose op de aangezichtsmorfologie R1 bij patiënten met het syndroom van Crouzon en Apert, waarbij ook de veranderingen tijdens de R2 groei en ontwikkeling worden beschreven. Het syndroom van Crouzon en Apert zijn ernstige R3 R4 aangeboren afwijkingen. Beide afwijkingen hebben meerdere functionele problemen. Bij de R5 behandeling van deze functionele problemen kunnen ook bijkomende ongemakken ontstaan. R6 Wetenschappelijk onderzoek verklaart aspecten van deze problemen, zoals psychosociale R7 aspecten van patiënten en vrij recent de genetische factoren die craniosynostose veroorzaken. R8 Wetenschappelijk onderzoek naar aangezichtsgroei en ontwikkeling bij chirurgisch onbehandelde R9 patiënten is zeer schaars door de lage prevalentie, de vaak vroege chirurgische interventie in het R10 middengezicht en de korte vervolgperiode. Het doel van dit onderzoek was de dentale en de R11 aangezichtsgroei en ontwikkeling te beschrijven. Er zijn veel verschillende behandelingsprotocollen R12 voor het aangezicht beschreven. Dit probleem is gerelateerd aan onvoldoende wetenschappelijke R13 onderbouwing van de craniofaciale groei in beide syndromen. Het is echter opmerkelijk dat R14 gedetailleerde kennis omtrent longitudinale craniofaciale groei en ontwikkeling van syndromale R15 patiënten zeer schaars is. Het doel van deze studie is om de craniofaciale en orale groei te R16 evalueren en te beschrijven bij patiënten met craniosynostoses. De patiënten werden behandeld R17 in het craniofaciale team van het Erasmus Medisch Centrum te Rotterdam. Het craniofaciale team R18 R19 coördineert en voert multidisciplinaire zorg uit bij kinderen met aangeboren afwijkingen aan het R20 gezicht en de nek. Van een multidisciplinair team mag verwacht worden dat zij expertise, kennis, R21 behandelvaardigheiden en organisatie heeft om zo de kwalitatief hoogst mogelijke patiëntenzorg R22 te geven. R23 Hoofdstuk 2 beschrijft het craniofaciale groeipatroon bij patiënten met het syndroom van R24 Crouzon en Apert vergeleken met normale kinderen. Statistische multilevel modeling technieken R25 werden gebruikt om de groeiverandering te analyseren en deze te vergelijken tussen de drie R26 groepen. Significante verschillen voor sagittale en verticale dimensies werden gevonden bij de R27 syndromale groepen en deze lieten een vergrootte onderste aangezichtshoogte, een toegenomen R28 inclinatie van het palatinale vlak, een toegenomen retrusie van de maxilla en een toegenomen R29 propositie van de mandibula vergeleken met een controle groep. Patiënten met het Apert R30 syndroom hebben een meer abnormale craniofaciale morfologie dan patiënten met het Crouzon R31 syndroom. R32 In hoofdstuk 3 wordt de directionele en de fluctuerende asymmetrie bij het syndroom van R33 10 R34 Crouzon en Apert vergeleken met een niet aangedane controle groep. De metingen lieten zien R35 dat tijdens de groei het Apert syndroom meer directionele en fluctuerende asymmetrie hadden R36 gevolgd door het Crouzon syndroom en vervolgens de controle groep. R37 R38 R39

Samenvatting | 163 R1 In hoofdstuk 4 wordt het prevalentie patroon beschreven van tandagenesie bij patiënten R2 met het syndroom van Crouzon en Apert vergeleken met een niet syndromale controle groep. R3 Tandagenesie is de meest voorkomende afwijking in de dentitie die een onderdeel kan zijn R4 van een aangeboren syndroom. Tandagenesie van derde molaren en tweede premolaren in de R5 onderkaak komen meer voor bij het syndroom van Crouzon en Apert dan bij een controle groep. R6 Symmetrische patronen van tandagenesie in de onderkaak zijn meer prevalent bij syndromale R7 patiënten. R8 R9 In hoofdstuk 5 werd de tandontwikkeling bij kinderen met het syndroom van Crouzon R10 en Apert vergeleken met een niet-syndromale controle groep. Daarvoor werden logistische R11 ontwikkelingscurves geconstrueerd voor tandontwikkeling. Significante geslachtsverschillen R12 in tandontwikkeling werden gevonden bij meisjes met het syndroom van Crouzon en Apert. R13 Patiënten met het Apert syndroom lieten een significant vertraagde tandontwikkeling zien, terwijl R14 patiënten met het syndroom van Crouzon geen verschil in tandontwikkeling lieten zijn met de R15 controle groep. De vertraagde tandontwikkeling bij patiënten met het syndroom van Crouzon en R16 Apert suggereert een relatie tussen craniosynostose en tandontwikkeling. R17 In hoofdstuk 4 worden veranderingen in tandboog morfologie vergeleken tussen patiënten R18 met het syndroom van Crouzon en Apert met een controle groep. Statistische multilevel technieken R19 werden gebruikt om de veranderingen in de tijd van de tandboog tussen de drie groepen te R20 vergelijken. Tandboogdimensies waren significant kleiner bij patiënten met het syndroom van R21 Crouzon en Apert dan bij de controle groep. De tandboogbreedte in de bovenkaak bij patiënten R22 met het Apert syndroom namen toe, terwijl alle andere breedte metingen van de tandboog R23 R24 geen verandering lieten zien. Patiënten met het Crouzon syndroom lieten een toename zien van R25 de tandboogbreedte tussen de bovenhoektanden, terwijl de boogbreedte tussen de molaren R26 geen verandering liet zien. De boogdiepte in de bovenkaak liet geen verandering zien en de R27 gevonden warden waren significant kleiner bij syndromale patiënten dan bij de controle groep. R28 De booglengte in de onder- en bovenkaak nam af tijdens de groei. Uit deze studie blijkt dat de R29 tandboogdimensies bij syndromale patiënten kleiner zijn dan een controle groep in de leeftijd R30 tussen 4 en 14 jaar. Daarnaast lieten tandboogdimensies beperkte toename zien in de leeftijd R31 tussen 4 en 14 jaar. R32 In hoofdstuk 7 werd het effect van een Le Fort III osteotomie met distractie osteogenese R33 geëvalueerd op het teruggevallen middengezicht bij patiënten met het Crouzon en Apert R34 syndroom. Een jaar na verwijdering van het distractie apparaat waren geen significante R35 verschillen gevonden na chirurgische bovenkaak voorwaartse verplaatsing in beide syndromen. R36 Uit deze studie kan worden geconcludeerd dat distractie osteogenese van het middengezicht R37 bij patiënten met het Crouzon en Apert syndroom stabiel lijkt in de sagittale dimensie na een R38 R39

164 | Chapter 10 vervolgtijd van 1 jaar. Ondanks dat het Crouzon en Apert syndroom verschillen in craniofaciale R1 kenmerken, verbeterden de sagittale craniofaciale dimensies significant. De sagittale waarden na R2 de behandeling lagen dicht bij de waarden van de controle groep. R3 R4 In hoofdstuk 8 worden de uitkomsten in relatie tot het algemene doel van dit proefschrift R5 besproken. De uitkomsten van dit proefschrift bevestigen dat: R6 1. Kinderen met het Crouzon en Apert syndroom lieten een vertraagde craniofaciale groei, R7 en kleine craniofaciale dimensies en faciale asymmetrie zien. R8 2. Het blijkt dat bepaalde craniofaciale dimensies van de kindertijd zijn abnormaal klein en R9 nauwelijks verandering tijdens de groei. R10 3. Het gebrek aan craniofaciale groei potentiaal verklaart de verschillen in tandboog R11 dimensies bij syndromale patiënten. R12 4. Vertraagde tandontwikkeling en het meer voorkomen van tandagenesie zijn beide R13 onderdeel van het syndroom van Crouzon en Apert en kunnen gerelateerd zijn aan de R14 genetische achtergrond. R15 Hoewel het syndroom van Crouzon en Apert vergelijkbare craniofaciale groei en ontwikkeling R16 lieten zien, zijn beide syndromen verschillend met meer ernstige groeien ontwikkelingsdeficiëntie R17 bij het syndroom van Apert. Bij de integratie van de resultaten in dit proefschrift moet de R18 R19 individuele en de algemene syndromale groei betrokken worden voor de behandeling en de R20 bespreking van het behandelplan met de patiënt en zijn of haar ouders/verzorgers. Bij een R21 voorwaartse chirurgische verplaatsing van het middengezicht tijdens de kindertijd is vaak een R22 tweede chirurgische ingreep in het middengezicht nodig, omdat de onderkaak blijft groeien tot R23 volwassenheid van de patiënt. R24 De behandeling van schisis en craniofaciale afwijkingen heeft tegenwoordig een R25 multidisciplinaire benadering welke ook wordt ondersteund door wetenschappelijk onderzoek. R26 Schisis- en craniofaciale teams zijn de laatste 40 jaar ontstaan voor een goede samenwerking R27 tussen verschillende professionals in de patiëntenzorg van schisis en craniofaciale afwijkingen. R28 Een interdisciplinaire benadering van patiëntenzorg vraagt van elk teamlid een goede R29 samenwerking, waardoor het best mogelijke behandelresultaat mag worden verwacht. Een R30 doel voor de toekomst is de nationale realisatie van de aanbevelingen uit dit proefschrift en R31 het aanzetten van craniofaciale centra tot (her-) evaluatie van behandelprotocollen. Het gebruik R32 van geprotocolleerde gestandaardiseerde data van patiënten met het syndroom van Crouzon R33 10 R34 en Apert bijeengebracht uit de nationale centra kunnen zo onderling worden vergeleken om de R35 behandelnoodzaak van gebruikte behandeltechnieken te bevestigen en de craniofaciale groei R36 en ontwikkeling te voorspellen. Bij voorkeur zijn studies tussen internationale behandelcentra R37 noodzakelijk! R38 R39

Samenvatting | 165

Publications

Curriculum Vitae

PhD Portfolio

Acknowledgements R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

168 | Publications Publications R1 R2

1. Mandibular Asymmetry in Patients With the Syndrome of Crouzon or Apert. Elmi P, R3 R4 Reitsma JH, Buschang PH, Wolvius EB, Ongkosuwito EM. Cleft Palate Craniofac J. R5 (submitted) R6 R7 2. Dental Maturation in Children With the Syndrome of Crouzon and Apert. Reitsma JH, R8 Balk-Leurs IH, Ongkosuwito EM, Wattel E, Prahl-Andersen B. Cleft Palate Craniofac J. R9 2013; doi: 10.1597/13-071. R10 R11 3. A Longitudinal Study of Dental Arch Morphology in Children With the Syndrome of R12 Crouzon or Apert. Reitsma JH, Elmi P, Ongkosuwito EM, Buschang PH, Prahl-Andersen R13 B. Eur J Oral Sci. 2013; 121: 319-327. R14 R15 4. Patterns of Tooth Agenesis in Patients With the Syndrome of Crouzon of Apert. Reitsma R16 JH, Ongkosuwito EM, van Wijk AJ, Prahl-Andersen B. Cleft Palate Craniofac J. 2014; 51: R17 178-183. R18 R19 R20 5. Craniofacial Stabillity in Patients With Crouzon or Apert Syndrome After Le Fort III R21 Distraction Osteogenesis. Reitsma JH, Ongkosuwito EM, Buschang PH, Adrichem LN, R22 Prahl-Andersen B. Cleft Palate Craniofac J. 2013; 50: 561-569. R23 R24 6. Facial Growth in Patients with Apert and Crouzon Syndromes Compared to Normal R25 Children. Reitsma JH, Ongkosuwito EM, Buschang PH, Prahl-Andersen B. Cleft Palate R26 Craniofac J. 2012; 49: 185-193. R27 R28 7. Oligodontia: treatment plan and therapy. Reitsma JH, Meijer HJ, van Oort RP. Ned R29 Tijdschr Tandheelkd. 2005; 112: 325-329. Dutch. R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

Publications | 169 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

170 | Curriculum Vitae Curriculum Vitae R1 R2

The author is a farmers son born on June the 25th, 1981 in Dokkum, The Netherlands. He R3 R4 finished secondary school in 1999 at the ‘Dockinga College’ in Dokkum, The Netherlands. The R5 following year he started his dental education at the Rijksuniversiteit Groningen, Groningen, The R6 Netherlands, which he completed in June 2005. From August 2005 to 2006 he started working R7 as a dentist in a private practice in London, United Kingdom and also worked as researcher at the R8 Department of Orthodontics in orthodontic materials at the University Medical Centre Groningen R9 (UMCG). In 2006 he started the full-time orthodontic training program at the Department of R10 Orthodontics at the Academic Centre for Dentistry Amsterdam (ACTA), which he completed R11 in 2010. In 2010 he also received the diploma of Membership in Orthodontics from the Royal R12 College of Surgeons of Edinburgh. Until November 2013 he combined working in several R13 orthodontic practices with the research in this thesis, before starting an orthodontic practice in R14 Groningen, The Netherlands. R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

Curriculum Vitae | 171 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

172 | PhD Portfolio PhD Portfolio R1 R2

Name PhD student: J.H. Reitsma R3 R4 Erasmus MC department: Department of Orthodontics R5 PhD Period: 2008-2013 R6 Promotors: Prof. Dr. E.B. Wolvius, Prof. Dr. P.F. van der Stelt R7 Supervisors: Em. Prof. Dr. B. Prahl-Andersen, Dr. E.M. Ongkosuwito R8 R9 R10 1. PhD training R11 Year Workload R12 Research skills R13 Introduction to data analysis and regression analysis, ACTA 2006-2007 2.0 R14 R15 Introduction to multilevel modeling, Baylor, Texas, USA 2009, 2012 1.4 R16 R17

Specific courses R18 R19 Basiscursus stralingsbescherming deskundigheidsniveau 2009 1.0 R20 4A/M voor medisch specialisten (variant kaakchirurgie/ R21 orthodontie), ACTA R22 R23 Presentations R24 Facial growth in patients with Apert and Crouzon 2010 1.4 R25 syndromes compared to normal children. 7th R26 International Orthodontic Congress, Sydney R27 R28 Poster presentation R29 Craniofacial stability in Crouzon and Apert 2010 1.4 R30 patients one year post Le Fort III distraction. R31 European Orthodontic Congress, Portoroz R32 R33 R34 Oral presentation R35 A longitudinal study of dental arch morphology 2013 1.4 R36 in children with the syndrome of Crouzon or R37 Apert. European Orthodontic Society, Reykjavik R38 R39

PhD Portfolio | 173 R1 Poster presentation R2 Growth and development in patients with 2009, 2012 1.5 R3 congenital craniosynostosis. Department of R4 orthodontics, Baylor University R5 R6 (Inter)national conferences R7 Najaarsvergadering Vereniging voor Orthodontisten 2008-2010 3.0 R8 R9 R10 European Orthodontic Congress 2008-2010 4.0 R11 2013 R12 Biennial Symposium Surgical Orthodontics 2009 1.0 R13 R14 2nd International Conference on Ectodermal Dysplasia 2009 0.7 R15 R16 International Orthodontic Congress 2010 1.0 R17

R18 American Orthodontic Congress 2010, 2011 2.0 R19 R20 Seminars and workshops R21 Introduction to evidence based orthodontics, ACTA 2008 1.0 R22 R23 R24 Gezichtschirurgie: Schisis, cranio-faciale afwijkingen, 2009 0.5 R25 brandwonden en aangezichtswondgenezing, operaties bij R26 schisis patienten. Academisch Medisch Centrum Amsterdam R27 R28 3D diagnosis and virtual treatment planning of cranio-maxillo- 2010 1.0 R29 -facial deformity. Eindhoven R30 R31 Workshop: symptomen en syndromen, ACTA 2010 0.5 R32 R33 R34 R35 R36 R37 R38 R39

174 | PhD Portfolio 2. Teaching activities R1 Lecturing R2 Craniofacial growth and development. dental 2008-2010 2.0 R3 R4 students, ACTA R5 R6 Supervising postgraduate orthodontic student R7 Supervising Poejan Elmi, postgraduate orthodontic 2010-2013 3.6 R8 student ACTA. Retrospective research, statistics and R9 article writing R10 R11 3. Other activities R12 Treasurer European Postgraduate Students 2010-2011 2.0 R13 Orthodontic Society R14 R15 One ECTS stands for around 28 working hours (including preparation, self-study, examinations R16 etc.) R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

PhD Portfolio | 175 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

176 | Acknowledgements Acknowledgements R1 R2

Why is it that I spend so much time writing my thesis and less than one day writing my R3 R4 acknowledgements if the latter is so much more often read than the former? I find myself facing R5 a fast-moving deadline. This has however no effect on the gratitude I feel towards all those who R6 have helped me on my way, shared with me their knowledge, their time, their friendship and their R7 patience. So if you haven’t already done so, please go back and read chapter 8 to see all those R8 who made this thesis possible. R9 R10 First and foremost I would like to thank all the children and adults who participated in this study. R11 This thesis would not have happened without you! R12 R13 To Prof. Dr. B. Prahl-Andersen. Dear Prof. Prahl. Once quoted: ‘This woman is headstrong, R14 obstinate and dangerously self-opinionated and even her closest friends would agree she could R15 be all those things…’ Now looking back I don’t think it is wrong, but the point is this: ‘dear Prof. R16 Prahl, you have used that conviction and most of your time, energy and resolve in service of R17 orthodontic research and we are the better for it!’ With this thesis I end a very pleasant time of R18 R19 research and monthly visits to your home for the last five years. Many thanks for all the work you R20 put into it and the countless things besides the research work you taught me. R21 R22 To (Prof?) Dr. E.M. Ongkosuwito. Dear Dr. Ongkosuwito. We know: ‘the first step is the hardest’. R23 You started this project. Many thanks for being a knowledgeable trustworthy teacher, for R24 supporting my ideas, even the insane ones, and for always understanding what I meant even R25 when I was not able to clearly vocalize it. Your continuing support and your keen eye for detail R26 enabled me to achieve this goal. Thank you for believing that I could be pushed further and for R27 continuously opening my eyes when all I wanted to do was close them and settle. R28 R29 To Prof. Dr. E.B. Wolvius. Dear Prof. Wolvius and promotor, many thanks for your help and R30 improvements during the final part necessary in the completion of this research work. R31 R32

To Prof. Dr. P. Van der Stelt. Dear Prof. Van der Stelt and promotor, many thanks for being R33 R34 representative for the department of Orthodontics, ACTA, Amsterdam. R35 R36 I greatly appreciate and wish to thank the members of the reading committee: Prof. Dr. I.M.J. R37 Mathijssen, Prof. Dr. E.M.E.H. Lesaffre, Prof. Dr. G.J. Kleinrensink for taking the time and making R38 the effort reviewing this thesis. R39

Acknowledgements | 177 R1 To Prof. P.H. Buschang. Dear Prof. Buschang, many thanks for having me twice in Dallas at your R2 department. I learned many things and really enjoyed working with you. R3 R4 To Dr. Z. Fourie and Drs. A. Fongers. Dear friends, you know me already for such a long time, R5 thank you for being my paranymphs. R6 R7 I would like to thank all others who shall remain nameless here, but who are very important and R8 R9 should be mentioned somehow. Many thanks to all of you who have contributed in one way or R10 the other to the realisation of this thesis even you were not aware. You have all been invaluable. R11 R12 To drs. C.A.J.M van Aken, drs. M.W. Beerens, drs. J.W. de Boer, drs. P. Elmi, drs. J.A. Kelderman, R13 drs. A.E.G. Kerbusch, drs. A.V. Kho, drs. G.H. Maertens, drs. J.P.M. Nan, drs P.G. Nijkamp, drs. R14 A.E.M. Noverraz, drs. F.O.J. van Ruyven, drs. R.J.G. Tinselboer, Dr. O.J. van Vlijmen, drs. E.M. van R15 Westendorp and especially mister Wolter Prikken. Many thanks for all the work with the set-up R16 of my practice so I was able to finish this thesis. R17

R18 Last but not least I want to thank the most important people in my life, my family. To my parents: R19 Jan and Hinke; to my two sisters: Ina and Foekje; to my two brothers: Jelle Jan and Douwe Piet; R20 to their children and beloved ones: I am really proud to be part of this dynamic farmers family. R21 Both my mother and my father have a phenomenal ability to draw the best out of each family- R22 member. There are no words to describe my love and many thanks for all you have done for our R23 R24 family and me. R25 R26 Yesterday my mum turned 71 years of age. In general, most people don’t know my mum R27 well enough to compliment her or criticize her. My mother couldn’t care less what just about R28 anybody thinks. Because my mother knows who she is, and she knows why she is here. She R29 has no illusions about trying to be someone she is not. My mother, like my grandmother, has R30 discovered her genius – the peace from knowing that who we are, where we are, and what we R31 are doing makes sense regardless of the outcome or other people’s opinions. Thereby helping R32 many. Amazing women! R33 R34 R35 R36 R37 R38 R39

178 | Acknowledgements R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

Acknowledgements | 179 romotie is er Jacobus Harmen Reitsma [email protected] Voor het Voor bijwonen van Craniofacial and Dental Aspects of Crouzon and Apert door Jacobus Harmen Reitsma Paranimfen: Z. Fourie Dr. 3015 CE, te Rotterdam. Na afloop van de p een receptie ter plaatse waarvoor u van harte bent uitgenodigd. de openbare verdediging van [email protected] Drs. A. Fongers [email protected] Op woensdag 19 maart om 15.30 in de Prof. Andries Queridozaal (Onderwijscentrum), Eg-370, ErasmusMC, Dr Molewaterplein 50, Syndrome het proefschrift romotie is er romotie is er romotie is er Jacobus Harmen Reitsma [email protected] Craniofacial Craniofacial and Dental Aspects of Crouzon and Apert door Jacobus Harmen Reitsma Paranimfen: Z. Fourie Dr. Voor het Voor bijwonen van een receptie ter plaatse waarvoor u van harte bent uitgenodigd. [email protected] Drs. A. Fongers [email protected] Op woensdag 19 maart om 15.30 in 3015 CE, te Rotterdam. Na afloop van de p de openbare verdediging van Syndrome de Prof. Andries Queridozaal (Onderwijscentrum), Eg-370, ErasmusMC, Dr Molewaterplein 50, het proefschrift Jacobus Harmen Reitsma [email protected] Craniofacial Craniofacial and Dental Aspects of Crouzon and Apert door Jacobus Harmen Reitsma Paranimfen: Z. Fourie Dr. 3015 CE, te Rotterdam. Na afloop van de p Voor het Voor bijwonen van een receptie ter plaatse waarvoor u van harte bent uitgenodigd. [email protected] Drs. A. Fongers [email protected] Op woensdag 19 maart om 15.30 in de Prof. Andries Queridozaal (Onderwijscentrum), Eg-370, ErasmusMC, Dr Molewaterplein 50, de openbare verdediging van Syndrome het proefschrift Jacobus Harmen Reitsma [email protected] Craniofacial Craniofacial and Dental Aspects of Crouzon and Apert door Jacobus Harmen Reitsma Paranimfen: Z. Fourie Dr. 3015 CE, te Rotterdam. Na afloop van de p Voor het Voor bijwonen van een receptie ter plaatse waarvoor u van harte bent uitgenodigd. [email protected] Drs. A. Fongers [email protected] Op woensdag 19 maart om 15.30 in de Prof. Andries Queridozaal (Onderwijscentrum), Eg-370, ErasmusMC, Dr Molewaterplein 50, de openbare verdediging van Syndrome het proefschrift

Jacobus Harmen Reitsma Jacobus Harmen Reitsma Jacobus Harmen Reitsma Jacobus Harmen Reitsma Jacobus Harmen Reitsma Jacobus Harmen Reitsma Jacobus Harmen Reitsma