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EFFECTS OF HUMAN X AND Y CHROMOSOMES ON ORAL AND CRANIOFACIAL MORPHOLOGY Studies of 46,XY females, 47,XYY males and 45,X/ 46,XX females MATHIAS GRÖN Institute of Dentistry OULU 1999 MATHIAS GRÖN EFFECTS OF HUMAN X AND Y CHROMOSOMES ON ORAL AND CRANIOFACIAL MORPHOLOGY Studies of 46,XY females, 47,XYY males and 45,X/46,XX females Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in Auditorium 1 of the Institute of Dentistry (Aapistie 3), on October 2nd, 1999, at 12 noon. OULUN YLIOPISTO, OULU 1999 Copyright 1999 Oulu University Library, 1999 Manuscript received 02 Sebtember 1999 Accepted 14 Sebtember 1999 Communicated by Docent Reijo Ranta Professor Juha Varrela ISBN (URL: ALSO AVAILABLE IN PRINTED FORMAT ISBN ISSN (URL: OULU UNIVERSITY LIBRARY OULU 1999 To Sari, Mikael and Anders Grön, Mathias, Effects of human Xand Ychromosomes on oral and craniofacial morphology.studiesof46,xy females,47,xyy malesand 45,X/46,XX females. Institute of Dentistry, Department of Oral Development and Orthodontics, University of Oulu, P.O.Box5000,FIN-90401Oulu, Finland 1999 Oulu, Finland (Manuscript received ) Abstract Theinfluenceof thexandychromosomesonthesizeandshapeofthedentalarches andocclusion as well as on craniofacial cephalometric dimensions, angles and dimensional ratios is studied. The material consists of Finnishpatients withsex chromosomeaneuploidies andnormalpopulation controls from the Kvantti Study series, which was collected in the 1970 s and 1980 s at the Institute of Dentistry,University of Turku. The patients arefive individuals with complete testicular feminization (CTF), eight 47,XYY males, and fourteen 45,X/46,XX females. The controls are population female and male controls, as well as five first degree relatives of the individuals with CTF,three of the 47,XYY males and nine of the 45,X/46,XX females studied. Dental arch dimensions and occlusion as well as craniofacial cephalometric dimensions, angles and dimensional ratios are measured fromdental study casts andstandardizedlateral cephalograms. The results show that the presence of the Ychromosome in 46,XY females and the supernumerary Ychromosomal gene(s) in 47,XYY males result in the enlargement of the dental arches and craniofacial dimensions without substantial effects on dimensional ratios and plane angles, but with special influence on the growth of the mandibular corpus. The reduction of Xchromosomal genetic material in 45,X/46,XX females results in the reduction of craniofacial dimensions, affecting dimensionalratios andespeciallyplaneangles of thecranial base. Keywords: chromosome aneuploidy,dental arches,craniofacial complex, Xinactivation Acknowledgements This work was carried out at the Department of Dentistry, University of Oulu. The clinical examination of the patients and relatives, as well as documentation was performed by Professor Lassi Alvesalo and his research team, mainly at the Institute of Dentistry, University of Turku. I wish to express my sincere gratitude to the head of the Department of Oral Development and Orthodontics, Professor Lassi Alvesalo, D.Odont., who - myself being an undergraduate student - encouraged me to go further into the field of craniofacial biology and genetics. I am especially grateful for his initiation of the research, and his encouragement, support and ability to create an atmosphere of enthusiasm for scientific work that made work under his leadership fluent and interesting. I am most grateful to Associate Professor Juha Tienari, Ph.D. of the Department of Applied Mathematics and Statistics of the University of Oulu, for his constructive criticism and to Jouko Remes, M.Sc. and Päivi Laukkanen, M.Sc., for their help in the statistical analysis of the data. I would like to express my gratitude to the official examiners of the thesis, Professor Juha Varrela, D.Odont. and Docent Reijo Ranta, D.Odont. and to the opponent, Professor John T. Mayhall, Ph D., for valuable suggestions and constructive criticism. I am also indebted to Kati Pietilä, Lic.Odont., for her analyses of the cephalograms and her intelligent comments. My sincere thanks go also to my colleagues and friends in Oulu. I am especially grateful to Tuomo Heikkinen, D.Odont., whose valuable comments on my work, kind support and interest in music made my time in Oulu a memorable experience. The warmest thanks go also to my friend Martti Svanberg, D.Odont., whose knowledge extended beyond dentistry and whose unselfishness was astonishing. Finally, I would like to thank Sari and our two sons for their support and understanding. This work was supported by the Academy of Finland and the University of Turku Foundation. Oulu, October 1999. List of original papers I II III IV Grön M & Alvesalo L (1997) Dental occlusion and arch size and shape in karyotype 46,XY females. Eur J Orthod 19, Pietilä K, Grön M & Alvesalo L (1997) The craniofacial complex in karyotype 46,XY females. Eur J Orthod 19, Grön M, Pietilä K & Alvesalo L (1997) The craniofacial complex in 47,XYY males. ArchsOralBiol42, Grön M, Pietilä K & Alvesalo L (1999) The craniofacial complex in 45,X/46,XX females. Archs Oral Biol, in press. In the text, the above articles are referred to by their Roman numerals. Contents Abstract Acknowledgements List of original papers 1. Introduction Reviewoftheliterature Generalgrowthanddevelopment Sexchromosomalcontrol Hormonal factors in sex chromosome aneuploidies Growthanddevelopmentofthecraniofacialstructures Headdimensions Cranialbaseanddentofacialcomplex Dentalarchesandocclusion Toothcrowngrowth Thepresentstudygroups Completetesticularfeminization(46,XYfemales) ,XYYmales ,X/46,XXfemales Purposeofthestudy Subjects Methods Analysesofdentalarchandocclusalvariables Analysesofcraniofacialvariables Statisticalmethods Reliability of the measurements Results Completetesticularfeminization(46,XYfemales)(I,II) ,XYYmales(III) ,X/46,XXfemales(IV) Comparisonwithfirstdegreerelatives(I-IV) Discussion XandYchromosomeeffects Summary Conclusions References... 40 1. Introduction The rapid progress in the development of methods in molecular genetics has made localization and identification of genes possible, however, identifying the phenotype and relating it to the genotype have not lost their importance. Craniofacial structures as well as dental arch dimensions and occlusion are studied longitudinally and cross-sectionally within several disciplines, such as anthropology, developmental biology, orthodontics and reconstructive surgery. The knowledge of factors regulating occlusal and craniofacial variation has, in addition to its importance in basic research, also clinical relevance in growth prediction when planning orthodontic treatment. The human X and Y chromosomes are involved in the regulation of growth and development of dental and skeletal structures. Sex chromosomal influence on tooth size, statural growth and maturation has been widely documented. The relatively common occurrence of individuals with sex chromosome anomalies, aberrations of nature, has given us the opportunity to study the effects of sex chromosomes on human growth and development. In the present study, dental arch as well as craniofacial size and shape of 46,XY females, craniofacial size and shape of 47,XYY males and 45,X/46,XX mosaics are investigated in order to clarify the influence of the X and Y chromosomes in the regulation of quantitative growth and morphology of the craniofacial complex. In general, the subjects with sex chromosomal aneuploidies have first been detected by aberrations in their somatic phenotype or behaviour, and then their genotype has been confirmed by cytogenetical testing. 2. Review of the literature 2.1. General growth and development Sex chromosomal control The role of the sex chromosomes in human growth and development has been widely documented. It is evident that sex chromosomes influence the growth of skeletal structures, taking into consideration the results of studies on subjects with sex chromosomal aneuploidies with focus on statural growth. Monosomy of the X chromosome is a decisive factor in the causation of short stature and congenital malformations in Turner s syndrome, while mosaics with one normal XX cell line and one XO line are less affected (Ferguson-Smith 1965, Varrela et al. 1984). The presence of an extra X or Y chromosome usually leads to moderate tall stature (Stewart et al. 1982, 1991, Robinson et al. 1991). A doubling of the sexual dimorphism of height in man by the additional Y chromosome in 47,XYY males was proposed by Ratcliffe et al. (1992), being consistent with the findings of 47,XYY males showing larger, but proportional bodily dimensions than normal males (Varrela & Alvesalo,1985). In 47,XXY males height was increased, mainly due to increased leg length compared to normal males (Varrela 1984). Adult stature in 46,XY females was found to be close to, but slightly below the mean male standards (Varrela 1984, Smith et al. 1985). The adult height in patients with sex chromosome aberrations was primarily defined by the dosage effect of pseudoautosomal genes on the X chromosome and Y-specific growth genes, together with a growth disadvantage caused by alteration of the quantity of the region escaping inactivation on the X chromosome (Ogata and Matsuo 1993). Furthermore, an interval of DNA within the pseudoautosomal region in the short arm of both the X and Y chromosomes has been postulated to control fundamental aspects of statural growth and development (Rao et al. 1997). Tanner et al. (1959) concluded that genes on the Y chromosome are responsible for the sex dimorphism in developmental rate in man, causing retardation of skeletal maturation in males. Normal peak height velocity for females was found in 46,XY females with androgen insensitivity (Zachmann et al. 1986), but they reach final height earlier than normal males (Smith et al. 1985). This may explain their final height lying between the 15 averages for normal females and males. A delay in onset of puberty and in reaching peak height velocity of statural growth in 47,XYY boys and 47,XXX girls has also been reported (Ratcliffe et al. 1991, 1992) Hormonal factors in sex chromosome aneuploidies The effects of oestrogens on statural growth have been studied by Zachmann et al. (1986) and discussed by Ritze n (1992), who concludes that androgens are not needed for normal female peak height velocity in 46,XY females with androgen insensitivity, and also that oestrogens can produce a pubertal growth spurt in the absence of androgenic influence. In Turner patients with one X chromosome missing, the effects of oestrogen therapy alone or in combination with growth hormone may support growth initially, but final stature is unchanged by oestrogen therapy (Kastrup et al. 1988). 47,XXX females and 47,XYY males seem to show relatively normal endocrine status, while in 47,XXY males testosterone levels tend to drop off at late adolescent and early adulthood (Robinson et al. 1991, Ratcliffe et al. 1991) Growth and development of the craniofacial structures Head dimensions Studies on subjects with sex chromosome aneuploidy have shown that the head circumference is lower in 47,XXX females and 47,XXY males and normal in 47,XYY males (Stewart et al. 1982, Stewart et al. 1991, Ratcliffe et al. 1994). These findings are consistent with those of Varrela (1984) on 47,XXY males, having smaller head dimensions and smaller calvaria (Ingerslev & Kreiborg 1978) than male controls. Varrela and Alvesalo (1985), on the other hand, found that 47,XYY males had overall larger but proportionally similar head dimensions compared to male controls Cranial base and dentofacial complex Angular measurements and length ratios of the cranial base and the dentofacial structures measured from lateral head cephalograms are used as diagnostic tools for growth prediction in the planning of orthodontic treatment. The assumption that all angular measurements would be independent of age and sexual dimorphism, have been considered untenable by Walker and Kowalski (1972) after a longitudinal study on 1,100 children. Results from a longitudinal cephalometric study on Norwegian children between ages 6-18 years showed that males consistently showed larger values for most measurements and the increase of maxillary and mandibular prognathism was larger in males than in females (El-Batouti et al. 1994). 16 Most of the facial dimensions seem to follow the heigth-growth curve, with a circumpuberal spurt occurring later in the face than for height (Krogman 1968). According to Björk (1966), sutural growth in the maxilla has its puberal maximum at 14 years in males and its cessation at 17 years, about two years earlier than condylar growth and growth in height. The increment in width is greater in the posterior than in the anterior segments of the maxilla (Björk & Skieller 1974). An additional Y chromosome is found to increase linear dimensions of the cranial complex, and extra sex chromosomes seem to be associated with a more acute cranial base angle (Rzymski & Kosowicz 1975, 1976, Ingerslev & Kreiborg 1978, Peltomäki, Alvesalo & Isotupa 1989, Babic' et al. 1991, Brown, Alvesalo & Townsend 1993). A more extended head posture due to a backward inclined cervical spine, a steeper nasal floor with regard to both the mandibular and ramal planes, and a more flattened cranial base and gonial angle seem to be related with cold air breathing (Huggare 1986). The sagittal dimension of the nasopharynx has been found to be larger, the angle between the sphenoidal and clival planes smaller, and the angles between the nasal and ramal planes as well as the nasal and mandibular planes greater in children from northern Finland compared to those from southern Finland (Huggare 1987). Along with their more acute cranial base angle, 47,XXY males show increased maxillary and mandibular prognathism, with an increased intermaxillar angle, an increased gonial angle and a shortened mandibular ramus compared to normal males (Ingerslev & Kreiborg 1978). The angle between the anterior and posterior cranial base was proposed to influence the degree of mandibular protrusion by Williams and Ceen (1982). This is in disagreement with Varjanne and Koski (1982), who found no significant differences in the cranial base, but rather in the angulation and dimensions of the mandibular ramus, between representatives of different Angle classes. Due to the loss of one X chromosome, the mandible shows posterior growth rotation and reduced posterior face height in 45,X females compared to normal females (Babic' et al. 1997) Dental arches and occlusion The term occlusal variation is, according to Townsend et al. (1998), a more appropriate term than different types of malocclusion, when approaching occlusion as a biological phenomenon. In a review-article of the literature Rudge (1981) concluded that occlusion and arch shape are, at present, believed to be determined by an interplay between genetic factors and environmental factors. Proffit (1986a) stated that dental and facial characteristics are inherited on a polygenic basis and affected by environmental influences. Generally, occlusal traits seem to show low degrees of heritability. Early twin studies indicated that occlusal traits would be under strong genetical control, while recent reports emphasize the importance of environmental factors. Results from a study of mono- and dizygotic twins of both sexes suggested strong heritability for palatal width, heigth and length (Riquelme & Green 1970). Corruccini (1980) found in a study of mono- and dizy- 17 gotic twins that arch breadth and especially arch length are heritable traits but could not detect heritability for overjet. Molar sagittal relationship seems to have a fairly low degree of heritability (Townsend et al. 1988, 1998). Dental arch size seems to have a fairly low degree of heritability in Aborigines, stressing that variation in arch size is mainly due to environmental factors. Dental arch shape, on the other hand, seems to be under relatively strong genetical control (Townsend et al. 1998). Results from dental arch and occlusion studies on humans with sex chromosome aneuploidies show a disturbance of growth pattern in most of the syndromes. 45,X females show an increased prevalence of occlusal anomalies compared to normal females. The most common are large maxillary overjet, distal molar occlusion, cross bite, a broader and shorter mandibular arch in relation to a narrower maxillary arch, a tendency to open bite and a decreased frequency and expression of torus mandibularis (Laine et al. 1985, 1986, Laine & Alvesalo 1986, Alvesalo 1996). Parallel findings with those of 45,X females have been found in a study on 45,X/46,XX and 46,Xi(Xq) females, who presented a higher tendency to lateral cross bite, distal molar occlusion and increased maxillary overjet compared with normal females (Harju et al. 1989). 47,XXY males present more mesial molar occlusion, a shallower palate and a narrower but lengthened dental arch of the maxilla and the mandible than normal males (Alvesalo and Laine 1992, Laine & Alvesalo 1993a). 47,XYY males tended to exhibit mesial molar occlusion, mandibular overjet and incisal open bite more often than male population controls (Laine, Alvesalo & Lammi 1992) and a wider palate as well as longer maxillary and mandibular alveolar arches (Laine & Alvesalo 1993b) Tooth crown growth Findings from twin and full-sibs studies and from studies on full-cousin level indicate that genes influence tooth crown growth (Lundström 1948, Alvesalo 1971, Alvesalo & Tigerstedt 1974). Data from tooth-crown studies on sex chromosome aneuploidies show that the Y chromosome influences the growth of both dentine and enamel, probably because of the proliferative activity of odontoblasts and the secretory activity of ameloblasts (Alvesalo & Tammisalo 1981, Alvesalo, Tammisalo & Hakola 1985, Alvesalo, 1985, 1997, Alvesalo, Tammisalo & Therman 1987, Alvesalo, Tammisalo & Townsend 1991). Among the factors that have tentatively been assigned to the long arm of the Y chromosome is tooth size (Alvesalo & de la Chapelle, 1981). The nature of the influence of the Y chromosome on tooth growth has been suggested to be of genetic regulation (Alvesalo 1985). Permanent teeth of 46,XY females were found larger in labio-lingual dimension than the teeth of normal female controls as well as those of their first degree female relatives, and seemed to be closer in size to those of normal men (Alvesalo & Varrela 1980). The enamel of the maxillary central permanent incisors had similar mesio-distal thickness in 18 the 46,XY females as in the population control males and females, while the dentine was about the same thickness in the 46,XY females and control males and thicker than in control females (Alvesalo 1985). Permanent and deciduous teeth of 47,XYY males were found to be larger in both the mesio-distal and labio-lingual dimensions and permanent teeth exhibited less variation than those of normal male population controls and those of first degree male relatives (Alvesalo, Osborne & Kari 1975, Alvesalo & Kari 1977 Townsend & Alvesalo 1985). Effects of the human X chromosome on tooth growth have been reported by various investigators, indicating influences of the X chromosome on the secretory activities of ameloblasts in enamel formation (Alvesalo 1971, Alvesalo & Tammisalo 1981, Alvesalo, Tammisalo & Therman 1987, Alvesalo 1997). It seems that structural genes on the X chromosome have an influence on tooth growth (Alvesalo 1997). In earlier studies of the oral cavities of 45,X/46,XX females, permanent teeth were found to have smaller mesio-distal, but near to normal labio-lingual dimensions compared to those of normal female population controls and those of first degree female relatives (Varrela, Townsend & Alvesalo 1988). Co
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