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D 885
OULU 2006
UNIVERSITY OF OULU P.O. Box 7500 FI-90014 UNIVERSITY OF OULU FINLAND
U N I V E R S I TAT I S
S E R I E S
SCIENTIAE RERUM NATURALIUM
Professor Mikko Siponen
HUMANIORA
Professor Harri Mantila
TECHNICA
Professor Juha Kostamovaara
MEDICA
Professor Olli Vuolteenaho
ACTA
U N I V E R S I T AT I S O U L U E N S I S
Raija Lähdesmäki
E D I T O R S
Raija Lähdesmäki
A
B
C
D
E
F
G
O U L U E N S I S
ACTA
A C TA
D 885
SEX CHROMOSOMES
IN HUMAN TOOTH ROOT
GROWTH
RADIOGRAPHIC STUDIES ON 47,XYY MALES,
46,XY FEMALES, 47,XXY MALES AND
45,X/46,XX FEMALES
SCIENTIAE RERUM SOCIALIUM
Senior Assistant Timo Latomaa
SCRIPTA ACADEMICA
Communications Officer Elna Stjerna
OECONOMICA
Senior Lecturer Seppo Eriksson
EDITOR IN CHIEF
Professor Olli Vuolteenaho
EDITORIAL SECRETARY
Publication Editor Kirsti Nurkkala
ISBN 951-42-8169-1 (Paperback)
ISBN 951-42-8170-5 (PDF)
ISSN 0355-3221 (Print)
ISSN 1796-2234 (Online)
FACULTY OF MEDICINE,
INSTITUTE OF DENTISTRY,
DEPARTMENT OF ORAL DEVELOPMENT AND ORTHODONTICS,
UNIVERSITY OF OULU
D
MEDICA
ACTA UNIVERSITATIS OULUENSIS
D Medica 885
RAIJA LÄHDESMÄKI
SEX CHROMOSOMES IN HUMAN
TOOTH ROOT GROWTH
Radiographic studies on 47,XYY males, 46,XY females,
47,XXY 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,
on September 16th, 2006, at 12 noon
O U L U N Y L I O P I S TO, O U L U 2 0 0 6
Copyright © 2006
Acta Univ. Oul. D 885, 2006
Supervised by
Professor Lassi Alvesalo
Reviewed by
Professor Timo Peltomäki
Professor Janna Waltimo-Sirén
ISBN 951-42-8169-1 (Paperback)
ISBN 951-42-8170-5 (PDF)
http://herkules.oulu.fi/isbn9514281705/
ISSN 0355-3221 (Printed )
ISSN 1796-2234 (Online)
http://herkules.oulu.fi/issn03553221/
Cover design
Raimo Ahonen
OULU UNIVERSITY PRESS
OULU 2006
Lähdesmäki, Raija, Sex chromosomes in human tooth root growth. Radiographic
studies on 47,XYY males, 46,XY females, 47,XXY males and 45,X/46,XX females
Faculty of Medicine, University of Oulu, P.O.Box 5000, FI-90014 University of Oulu, Finland,
Institute of Dentistry, Department of Oral Development and Orthodontics, University of Oulu,
P.O.Box 5281, FI-90014 University of Oulu, Finland
Acta Univ. Oul. D 885, 2006
Oulu, Finland
Abstract
Studies on families and individuals with sex chromosome abnormalities and 46,XY females, together
with molecular research, have provided proof that both X and Y chromosome genes are expressed in
human tooth crown growth. The Y chromosome promotes the formation of both permanent tooth
crown enamel and dentin, whereas the effect of the X chromosome is seen mainly in enamel
formation. In particular, the effect of the Y chromosome on dentin formation explains the expression
of sexual dimorphism in crown size. When crown growth is complete, root dentin is formed and
requires proliferation of epithelial cells in Hertwig's epithelial root sheath to initiate the
differentiation of root odontoblasts. These epithelial cells determine the size, shape and number of the
roots. There is a clear sex difference in tooth crown sizes, men have larger teeth than women. The aim
of this research was to study completed permanent tooth root lengths in individuals with sex
chromosome abnormalities and 46,XY females, an approach which might also provide some clues for
a further insight into the development of sexual dimorphism in human growth. The underlying
hypothesis was that the effect of the X and Y chromosomes on crown growth is also expressed in root
growth.
The subjects were participants of L. Alvesalo's research project, Kvantti, and comprised 45,X/
46,XX females, 47,XYY and 47,XXY males and female sex reversals with insensitivity to androgens
(46,XY females). The root lengths were measured from dental panoramic radiographs with a sliding
digital calliper. All available teeth (except third molars) with complete root formation on both sides
of the jaws were measured.
The results showed longer final permanent tooth root lengths in 47,XYY and 47,XXY males,
while the roots in 45,X/46,XX females were shorter compared with the values of normal men and
women, respectively. The root lengths of 46,XY females were longer compared to normal women and
placed on a level with normal men. The root morphology did not reveal any major deviations from
normal variation. In terms of population dental developmental standards it is conceivable that
changes in these study groups in final size of their permanent tooth roots become evident during a
period beginning eight years after birth and continuing up to the age of 14 years, at least.
It became clear that the effect of the Y chromosome on tooth root growth is greater than that of
the X chromosome, and this may cause the observed sexual dimorphism, males having longer roots
than females. It is suggested that root growth may be affected by the same genes on the X and Y
chromosomes which promote crown growth.
Keywords: aneuploidy, chromosomes human X, chromosomes human Y, growth and
development, humans, sex characteristics, tooth root
Just keep on trusting that
everything is much more wonderful
than we can understand, it is the truth.
Vincent van Gogh
To my children Perttu, Mauri, Esko, and Seppo
Acknowledgements
This study was carried out at the Department of Oral Development and Orthodontics,
Institute of Dentistry, University of Oulu, first during postgraduate studies and later as a
part-time job in addition to work as a clinical orthodontist in the Kuopio and Iisalmi
district health care centres. The theoretical studies and writing of the summary to the
thesis were carried out in the last year as a part of full-time work at Oulu University.
This study is a part of a larger research series belonging to Lassi Alvesalo’s research
project, Kvantti, on individuals with sex chromosome abnormalities. The clinical
examinations of the patients and relatives, and the documentation were performed by
Professor Lassi Alvesalo and his research team, mainly at the Institute of Dentistry,
University of Turku, during the 1970s and 1980s. I am most grateful to Professor Lassi
Alvesalo, D.Odont., head of the Orthodontic Department, for the opportunity to take part
in his research project. My first interest was to find out factors affecting growth in
humans, and as an interesting response to this I was asked to study human tooth root
growth, which was suggested by Professor Lassi Alvesalo. I want to thank him for the
immensely valuable work he has done in conducting me into the world of science in an
extremely forbearing and sensible manner.
Special thanks go to Professor Erkki Tammisalo, D.Odont. for his great contribution to
the accomplishment of radiographic examinations. This work was based entirely on that
radiographic method as carried out by him at the Institute of Dentistry, University of
Turku.
The statistical calculations were performed by Ahti Niinimaa, Ph.D., who also kindly
advised me on related problems whenever needed. Malcolm Hicks, M.A. (Cantab.)
revised the English language of the reports during all stages of this thesis. He has been of
great help in finding good and simple phrases to express the complex notions we have
sometimes been dealing with.
Sincere thanks to the official reviewers of the thesis, Professor Janna Waltimo-Sirén,
D.Odont. Institute of Dentistry, University of Helsinki, and Professor Timo Peltomäki
D.Odont., Clinic for Orthodontics and Pediatric Dentistry, Center for Dental and Oral
Medicine and Cranio-Maxillofacial Surgery, University of Zürich, Switzerland, for the
thorough and constructive comments on the main details and concepts in this thesis. They
both get my special thanks for the opportunity to have profound discussions in this
subject and tools to clarify the message. I also want to thank in advance my opponent
Professor Grant Townsend, D.Odont., Associate Dean (Academic), Dental School,
University of Adelaide, Australia.
I received irreplaceable help from Ms Sirpa Väätäjä on many occasions during these
years, while statistician Päivi Laukkanen, M.Sc. helped me to create the computer
databases and secretary Ms Eija Tuomi helped me in transferring some of the data to the
computer program.
The staff at the Institute of Dentistry has provided good discussions and support
during these years, which has greatly encouraged me to continue with the work. The head
of the orthodontic department today, Professor Pertti Pirttiniemi, D.Odont., has adopted a
very stimulating attitude towards my studies and the personnel of the department have
given me most valuable help and support, which has made this all possible. Also I want to
thank the Deans of the Institute of Dentistry Professors Aune Raustia, D.Odont. Kyösti
Oikarinen, D.Odont. and Hannu Hausen, D.Odont. for providing the facilities to carry out
the research.
The Kvantti research project was supported during the earlier years by the Emil
Aaltonen Foundation, the University of Turku Foundation and the Academy of Finland.
In addition, this study has been supported by the University of Oulu, the Finnish Dental
Society, Apollonia and the Orthodontic Section of the Finnish Dental Society, Apollonia.
My parents have been most helpful and supportive to me in my career in so many
ways during all these years. They have always had faith in my visions, and I am most
grateful for that.
Last but not least, I wish to thank my boys, Perttu, Mauri, Esko and Seppo, for their
patience and great understanding during these years when I have been working on this
thesis away from home. I hope they feel that it was worthwhile, because it has been so
rewarding for me.
Abbreviations
45,X
45,X/46,XX
46,X,i(Xq)
46,XX
46,XY
46,XY female
47,XXY
47,XYY
AMELX
AMELY
HERS
Xp, Yp
Xq, Yq
females with one X chromosome (Turner women)
a mosaic female in whom a second cell line has the chromosome
constitution 45,X (Turner women)
an isochromosome female in which a second cell line is monocentric
(two long arms in the X chromosome) (Turner women)
normal female sex chromosome constitution (a normal woman)
normal male sex chromosome constitution (a normal man)
a female with a male sex chromosome complement
(a female sex reversal)
individuals with an extra X or Y chromosome (Klinefelter men)
males with an extra Y chromosome
X-linked amelogenin gene
Y-linked amelogenin gene
Hertwig’s epithelial root sheath
short arm of the X or Y chromosome
long arm of the X or Y chromosome
List of original articles
I
Lähdesmäki R, Alvesalo L (2004) Root lengths in 47,XYY males’ permanent teeth. J
Dent Res 83: 771-775.
II
Lähdesmäki R, Alvesalo L (2005) Root growth in the teeth of 46,XY females. Arch
Oral Biol 50: 947-952.
III Lähdesmäki R, Alvesalo L (2006) Root growth in the permanent teeth of
45,X/46,XX females. Eur J Orthod 28: 339-344.
IV Lähdesmäki R, Alvesalo L. Root growth in the teeth of Klinefelter (47,XXY) men
(manuscript).
In the text the articles above are referred to by their Roman numerals.
Contents
Abstract
Acknowledgements
Abbreviations
List of original articles
Contents
1 Introduction ................................................................................................................... 15
2 Review of the literature ................................................................................................. 17
2.1 Dental development................................................................................................17
2.1.1 Teeth ................................................................................................................17
2.1.2 Development of the dentition ..........................................................................19
2.1.3 Tooth crown development ...............................................................................20
2.1.4 Tooth root development...................................................................................22
2.1.5 Sexual dimorphism in tooth development .......................................................24
2.1.6 Aberrations in tooth root development ............................................................26
2.2 Human sex chromosomes .......................................................................................28
2.2.1 The genome .....................................................................................................28
2.2.2 Number of human chromosomes.....................................................................28
2.2.3 Dimorphic X and Y chromosomes...................................................................29
2.3 Individuals with abnormal sex chromosome complement and the female
sex reversal ............................................................................................................31
2.3.1 45,X/46,XX females or females with shortage of sex chromosome
material............................................................................................................31
2.3.2 47,XXY and 47,XYY male-trisomies..............................................................32
2.3.2.1 Body growth and craniofacial characteristics in 47,XXY males ..............33
2.3.2.2 Body growth and craniofacial characteristics in 47,XYY males ..............34
2.3.3 Female sex reversals (46,XY females) ............................................................34
2.4 Tooth growth and an abnormal sex chromosome complement...............................35
3 Aim of this research....................................................................................................... 38
4 Subjects and Methods.................................................................................................... 39
4.1 Population...............................................................................................................39
4.2 Methods ..................................................................................................................41
4.2.1 Dental panoramic tomogram ...........................................................................41
4.2.2 Root length measurement ................................................................................42
4.2.3 Reliability of the measurements ......................................................................44
4.2.4 Statistical analyses...........................................................................................45
5 Results ........................................................................................................................... 46
5.1 Root lengths in the permanent teeth of 47,XYY males (I) .....................................46
5.2 Root lengths in the permanent teeth of 46,XY females (II) ....................................47
5.3 Root lengths in the permanent teeth of 45,X/46,XX females (III)..........................47
5.4 Root lengths in the permanent teeth of 47,XXY males (IV)...................................47
6 Discussion ..................................................................................................................... 50
7 Conclusions ................................................................................................................... 55
References
Original articles
1 Introduction
Teeth are vertebrate organs. Their development in humans starts in the sixth week of
embryonal life, with epithelial ingrowths into the ectomesenchyme at sites
corresponding to the future deciduous teeth. The developing tooth undergoes complex
morphogenesis regulated by interactions between the epithelial and mesenchymal
tissue layers. Signaling molecules appear to regulate the early steps of tooth
morphogenesis, and transcription factors associated with these pathways have been
shown to be necessary for tooth development (Thesleff 1995; Thesleff & Sharpe 1997;
Dong et al. 2005). Tooth formation is a repetitive process, resulting in two dentitions,
deciduous and permanent. Human teeth reach their full size shortly after eruption into
the occlusion. Studies on families by Alvesalo (1971) and on individuals with sex
chromosome abnormalities by Alvesalo and co-workers in the Kvantti research project
(e.g. Alvesalo 1997), together with molecular research (Lau et al. 1989), have
provided proof that both X and Y chromosome genes are expressed in tooth crown
growth. The Y chromosome promotes growth of the permanent tooth crown enamel
and dentin, whereas the effect of the X chromosome seems to be restricted mainly to
enamel formation (Alvesalo 1997). Enamel formation is decisively influenced by the
cell secretory function of ameloblasts that differentiate from the enamel epithelial cells
after dentin formation has started in the dental mesenchyme. The differentiation of
dentin forming cells, odontoblasts, is preceded by cell proliferations or mitotic activity
in the enamel epithelium. It has been suggested that the effect of the Y chromosome,
particularly by increasing cell proliferation, explains the expression of sexual
dimorphism in crown size and shape, maturation and the number of teeth, i.e.
supernumerary permanent teeth are approximately twice as common in normal males
as in normal females and permanent ordinary teeth are more frequently missing in
females than in males. Moreover, assuming genetic pleiotropy, the expression of the
torus mandibularis, statural growth and the sex ratio (the ratio of the number of males
to that of females) at birth and in the earlier stages of development are explained by
this effect of the Y chromosome (Alvesalo 1985; Alvesalo 1997). Unlike bone, teeth
grow without constant resorption and remodelling, to form persisting mineralized
dental tissues, enamel, dentin and cementum, providing a valuable record of prenatal
16
and postnatal growth. The continuous dentin deposition in the pulpal direction does
not affect external size or shape of the teeth.
When tooth crown formation is completed, the differentiation of root odontoblasts
is induced by a double layer of epithelial cells in Hertwig’s epithelial root sheath. The
dividing epithelial cells in the root sheath determine the size, shape and number of the
roots. Formation of the primary dentin continues until the external root form is
completed. It has been shown that the cells of the inner layer of Hertwig’s epithelial
root sheath secrete small amounts of amelogenin during early differentiation of the
root odontoblasts, at a time when the adjacent dental papilla cells are still
undifferentiated, suggesting a role for amelogenin in the induction of root odontoblast
differentiation. There are morphological differences between the fully differentiated
odontoblasts in the crown and root, the coronal odontoblasts being columnar and the
root odontoblasts cuboidal, and there may also be qualitative and quantitative
differences in the inductive mechanisms operating in the crown compared with the
root. There is a clear sex difference in tooth root lengths, males having larger teeth
than females, and the roots are definitely shorter in 45,X females, or females with a
shortage of sex chromosome material compared to normal women.
The aim of this research was to study tooth growth in individuals with sex
chromosome abnormalities and 46,XY females with insensitivity to androgens by
determining completed permanent tooth root lengths, and gain additional information
about the dental development in these individuals, an approach which may also
provide some clues for a further insight into the development of sexual dimorphism in
human growth. The underlying hypothesis was that the effect of the X and Y
chromosomes on crown growth is also expressed in root growth.
2 Review of the literature
2.1 Dental development
2.1.1 Teeth
A tooth is composed of three types of calcified tissue: enamel, dentin and cementum.
Dentin forms the bulk of the tooth, the anatomical crown is covered by enamel and the
root by cementum. The junction between the enamel and cementum is the cervical
margin of the tooth. In addition, a tooth contains a pulp tissue, the sensory and nutritive
organ, and is supported by a periodontal ligament. (Fig. 1) Dentin and cementum
formation are able to continue throughout life, in the pulpal surface in the case of the
dentin and on the external surface in the case of the cementum. The continuous dentin
deposition in the pulpal direction does not affect external size or shape of the tooth.
Dental enamel is the hardest and most densely calcified tissue in the body, being
originally of ectodermal origin, and does not show continuous formation. Enamel
consists of approximately 96 percent inorganic material, made up mainly of
hydroxyapatite crystals enveloped in traces of organic material. Dentin is approximately
70 percent mineralized with hydroxyapatite crystals (Ten Cate 1994), while the rest of it,
the organic component, consists 86 percent of fibrous protein collagen type I. Unlike
bone, the teeth grow without constant resorption and remodelling, to form permanent
dentin and enamel structures, providing a valuable record of prenatal and postnatal
growth.
After the teeth have erupted into the occlusion they are worn down, and thus continue
to erupt slowly to maintain contact with the opposing teeth (Osborn 1981). Tooth wear is,
however, relatively slight in modern man. Although under genetic control, the teeth are
directly influenced by the environment (e.g. Selmer-Olsen 1949). They have significantly
reduced in size during human evolution, the molars first, followed by the front teeth, as
larger teeth were no longer necessary for survival. The range of variation in tooth crown
size is slightly larger in the maxilla than in the mandible (Reddy 1992).
18
Fig. 1. Tooth structures
The developing tooth undergoes complex morphogenesis regulated by interactions
between the epithelial and mesenchymal tissue layers (Thesleff & Hurmerinta 1981; Ten
Cate 1994; Thesleff & Sharpe 1997; Radlanski 2005; Laurikkala et al. 2006;
http://www.bite.it.helsinki.fi). Signaling molecules appear to regulate the early steps of
tooth morphogenesis, and transcription factors associated with these pathways have been
shown to be necessary for tooth development (Thesleff & Sharpe 1997). New evidence
has shown changes in the signaling pathways former supposed to be unchanged between
the animal species in the form that new signaling parts connect earlier ones (Varjosalo et
al. 2006). Msx-1 homeobox gene expression may be the key signaling mediator during
tooth morphogenesis (Thesleff 1995; Han et al. 2003). Dlx homeobox gene has also been
shown to be critical for tooth development (Dong et al. 2005). A major question in
modern biology is how gene mutations and other structural alterations affect development
and are translated into evolutionary changes in morphology (Line 2003). The expression
of the Myc genes has been shown in mouse to control multiple independent tissue
specific enhancer modules, which have implications for organ specific growth control
and they have an expression for instance in the tooth bud (Hallikas et al. 2006).
19
2.1.2 Development of the dentition
Migratory neural crest cells, once they have transformed into ectomesenchyme, provide
much of the connective tissue associated with the face and the facial bones, and also the
tissues of the teeth (except for the enamel) and their supporting structures (Ten Cate
1994). During the first four weeks of embryonal life the frontonasal process and the
branchial arches are formed starting to form the processes of the facial structures. By four
weeks some of the epithelium is already forming teeth, but not until a week later in the
premaxillary area. The positions of the neural crest cells in the maxillary and mandibular
processes are associated with their original positions in the mid-brain region and with the
time when the cells leave the crest. Specific combinations of homeobox containing genes
expressed in the neural crest cells may regulate the types of teeth and their patterning
(Thesleff & Sharpe 1997). It is known that the migratory pattern of neural crest cells is
not intrinsic but is determined by directory factors in the host tissues. Studies on mice
have shown that the specialized dental epithelium directs tooth development prior to the
bud stage (Mina & Kollar 1987; Lumsden 1988).
Proliferative activity within the ectoderm derived dental lamina leads to epithelial
ingrowths at sites which correspond to the future deciduous teeth, and to an even more
active mitotic activity in the underlying ectomesenchyme (Fig. 2a). The tooth buds in
human embryos appear in serial order from anterior to posterior part of the forming
dental arch, and show considerable variation in their growth rates, on which the order of
tooth eruption depends. The germs for each tooth type have the same genetic constitution
and potential, but their morphological appearance is dependent on their position in the
dentition (Reddy 1992). The ectomesenchyme, once determined, not only induces further
development of the tooth but also determines its identity. The alveolar plates form a
trough of bone around the developing tooth germs, which eventually become enclosed in
bony crypts. Postnatally the teeth have a central role in regulating the extent and direction
of growth of the alveolar processes of the jaws (Ten Cate 1994). In the last resort, tooth
growth is a prerequisite for the development of normal occlusion. The deciduous
dentition is initiated by two months of embryonic development (Nery et al. 1970), and
the permanent teeth by the twentieth week in utero (Ten Cate 1994).
Heterodonty, divergent development of the teeth in the dentition, has evolved in many
vertebrates, particularly mammals (Butler 1995). The number of teeth has diminished
from mesial to distal in the premolars and in the reverse order in the molars. Most
mammals have two dentitions (deciduous and permanent). The point where the dental
lamina joins the dental organ in a deciduous tooth germ gives rise to the development of
the tooth germs for the permanent incisors, canines and premolars (Fig. 2d). The molars
of the permanent dentition have no predecessors. When the jaws have grown big enough,
the dental lamina burrows posteriorly and gives off epithelial ongrowths with the
associated ectomesenchymal response, to form the germs of the first, second and third
molars. There are higher correlations in dental maturity within the two tooth groups, that
is incisors and first molars versus canines, premolars and second molars (Demirjian &
Levesque 1980), and the same grouping can be seen in the timing of tooth emergence.
Abnormalities of development may result for instance in missing teeth or the
formation of extra teeth, features which seem to be correlated between the deciduous and
20
permanent dentitions in the same individual (Grahnen & Granath 1961). Most studies
indicate that missing and supernumerary teeth show dominant autosomal transmission
(Grahnen 1956; Alvesalo & Portin 1969), whereas others have proposed a complex of
genetic factors (Brook 1984). In any case, supernumerary permanent teeth are found
approximately twice as often in normal men as in normal women, and ordinary teeth are
missing more frequently in women compared to normal men, suggesting sex
chromosome effect in the determination of tooth number (Alvesalo 1985; Alvesalo 1997).
2.1.3 Tooth crown development
Tooth crown development proceeds in bud, cap, bell and crown stages, followed by root
development (Fig. 2). The epithelial ingrowth during the bud stage is called the dental
organ, the one that forms the enamel of the tooth (Fig. 2b). The ball of condensed
ectomesenchymal cells, called the dental papilla, located just beneath the dental organ,
forms the dentin and pulp of the tooth, and the condensed ectomesenchyme limiting the
dental papilla and encapsulating the dental organ, the dental follicle, gives rise to the
cementum and supporting tissues of the tooth. In this stage of tooth development, the cap
stage, the dental tissues can be identified as discrete entities, comprising a tooth germ
(Fig. 2c). (Ten Cate 1994)
Fig. 2. The different stages of tooth crown development starting from the thickened oral
epithelium with active mitotic activity in the underlying ectomesenchyme (a), the tooth
development proceeds to the bud stage, the dental organ (b), after that comes the cup stage
and the developing tooth can be called a tooth germ (c). In the bell stage the outer and inner
enamel epithelium are formed and connected in the cervical loop, also, the permanent tooth
bud can be seen arising from the dental lamina (d). The formation of the hard tissues, dentin
followed by enamel, starts the crown stage (e). The last ameloblasts are lost when the tooth
erupts into the oral cavity, the root formation continues until tooth reaches the occlusion (f).
21
Through histodifferentiation and morphodifferentiation in the bell stage, similar epithelial
cells in the dental organ are transformed into morphologically and functionally distinct
components (Fig. 2d). The centre of the dental organ is termed the stellate reticulum. The
cells at the periphery of the dental organ form the outer dental epithelium, the cells
adjacent to the dental papilla form the inner dental epithelium, and the junctional zone is
known as the cervical loop. The folding of the inner enamel epithelium results from its
intrinsic growth caused by differential rates of mitotic cell division, which first occurs
throughout the epithelium and precedes dentin formation. A structure known as the basal
lamina supports the inner dental epithelium and separates it from the mesenchyme.
This is largely the product of epithelial cells, and contributes to epithelialmesenchymal communication by controlling the passage of molecules between the two
tissues. For example, the bone morphogenetic protein synthesized by the inner dental
epithelial cells may be secreted into the dental papilla and induce its mesenchymal cells
to differentiate into odontoblasts. (Ten Cate 1994)
Differentiation of the odontoblasts starts beneath the enamel knot in the mesial part of
the tooth germ, representing the site of the future cusp development, and progresses
distally (Kraus & Jordan 1965; Jernvall et al. 1994). It has been shown that expression of
the Msx-2 transcription factor gene (MacKenzie et al. 1992) and cytokine fibroblast
growth factor 4 (Niswander & Martin 1992) is confined to the enamel knot, which
indicates a role for these in determining the pattern of the tooth formation (MacKenzie et
al. 1992).
Dentinogenesis, which always precedes enamel formation, marks the onset of the
crown stage (Fig. 2e). The odontoblasts begin to elaborate the organic matrix of dentin,
and move towards the centre of the dental papilla, establishing the tubular character of
the dentin. Dentin mainly consists of type I collagen (86 percent) but it also contains the
precursor protein DSPP (DSPP gene mapped to 4q21) for two unique proteins, dentin
phosphoprotein and dentin sialoprotein (Butler 1998). Dentin phosphoprotein plays an
initiative and regulatory role in the formation of apatite crystals (Butler et al. 2003). As
crown development continues, there is a progressive maturation of the cells of the inner
dental epithelium down the cusp slopes. It has been suggested that small proteins
resulting from deletion of a major part of the amelogenin, the main protein in enamel
matrix, may play a signal transduction role that inhibits ameloblast maturation until a
layer of mineralized dentin has been formed (Veis 2003). The cells of the inner enamel
epithelium differentiate further to preameloblasts, assuming a secretory function and
producing an organic matrix against the newly formed dentinal surface. During
amelogenesis the enamel-forming cells, or ameloblasts, move away from the dentin,
leaving behind an increasing thickness of enamel. Ameloblasts undergo gradually
apoptosis following the secretory stage or during maturation (Smith & Warshawsky
1977), the remaining cells are lost as the tooth erupts into the oral cavity (Fig. 2f). The
extracellular organic matrix of the enamel is composed mainly of abundant amelogenins
(over 90 percent), which are generally hydrophobic in nature, and of acidic proteins
originally termed enamelins. Amelogenin is involved in the control of mineral crystal
size, morphology and orientation (Gibson et al. 2001).
22
2.1.4 Tooth root development
The epithelial and mesenchymal interactions regulate the morphogenesis of normal root
development. When crown growth is completed a double layer of cells known as
Hertwig’s epithelial root sheath is formed by cells of the outer and inner dental
epithelium (Fig. 3). The formation of the root dentin requires proliferation of epithelial
cells in Hertwig’s epithelial root sheath to initiate the differentiation of root odontoblasts
and determine the size, shape and number of the roots (Ten Cate 1996). It is even likely
that there is a linkage between crown shape and root number. As the inner epithelial cells
of the root sheath enclose more and more of the expanding dental papilla, they initiate
differentiation of the odontoblasts from the mesenchymal cells at the periphery of the
dental papilla. Formation of the primary physiological dentin continues until the external
root form is completed (Ten Cate 1994). In this way a single-rooted tooth is formed,
while in the formation of multi-rooted teeth the primary apical foramen is converted into
two or more secondary apical foramina and the tongues of the epithelium grow towards
each other.
Fig. 3. The formation of the hard tissues during tooth root development.
The cells of the inner layer of the epithelial diaphragm of the apical end of Hertwig’s
epithelial root sheath secrete small amounts of amelogenin during the early differentiation
of human root odontoblasts, at a time when the adjacent dental papilla cells are still
23
undifferentiated, suggesting a role in the induction of root odontoblast differentiation
(Hammarström 1997). The peripheral dentin in the crown contains highly branched
dentinal tubules, whereas that in the root is atubular, and only after a certain amount of
root dentin is present do the tubules form, somewhat chaotically, what is known as the
granular layer of Tomes (Weber 1983). There are morphological differences between the
fully differentiated odontoblasts in the crown and root, as the coronal odontoblasts are
columnar and the root odontoblasts cuboidal (Avery 1986). There may be both qualitative
and quantitative differences in the inductive mechanisms operating in crown and root
dentin formation (Thomas 1995). The first–formed radicular mantle dentin is not
deposited directly against the basal lamina of the root sheath, while a hyaline layer,
formed from an admixture of the connective tissue extracellular matrix and an epithelial
secretory product, separates them. The hyaline layer is involved in establishing an initial
attachment of the cellular extrinsic fibre cementum to the tooth surface, and must
therefore be regarded as a tooth support tissue (Ten Cate 1996). There is increasing
evidence that the cells of Hertwig’s epithelial root sheath are involved in the development
of both acellular and cellular cementum (Hammarström et al. 1996). The cells of
Hertwig’s epithelial root sheath fragment when root dentinogenesis starts, and are known
as the epithelial cell rests of Malassez. It has been suggested that these may be necessary
for the secretion of non-collagenous proteins – osteopontin and bone sialoprotein – for
the formation of cementum (Janones et al. 2005). (Fig. 3)
Taurodontism is a morphological tooth variation in a multi-rooted tooth in which the
pulp chamber is long and bifurcates into short root canals near the apical third of the root.
It is also a familial trait frequently associated with a variety of systemic disturbances
(Jaspers & Witkop 1980). Normal populations have been shown to exhibit taurodontism
at frequencies of 0.5-5 percent (Jaspers & Witkop 1980; Shifman & Chanannel 1978).
The affected teeth are molars, sporadically lower premolars (Madeira et al. 1986) and
occasionally lower canines or upper premolars, in patients with an otherwise normal
dentition. Taurodontism has been classically divided by degree into hypo-, meso-, and
hypertaurodontism (Shaw 1928) and a pyramidal (cuneiform) tooth displaying a singlerooted wedge shape (Bell et al. 1989). Taurodontism is found in a higher frequency in
populations of early man living under relatively primitive conditions. The prevalence of
taurodontism increases with additional X chromosomes (Stewart 1974; Jaspers & Witkop
1980; Varrela & Alvesalo 1989), and tooth agenesis, and a certain type of amelogenesis
imperfecta are features associated with it. Almost third of all patients with oligodontia
have been reported to exhibit taurodontism and reduced tooth lengths (Schalk-van der
Weide & Steen 1993), and these features may all be interrelated, resulting from decreased
mitotic activity in the cells of the developing tooth germs (Bell et al. 1989).
Little is known about the genetic influences of signaling pathways during the
morphogenesis of normal root development. One of the four genes encoding nuclear
factor I (NFI) transcription-replication proteins is Nfic. It is expressed in many organs,
including the developing tooth. The most prominent phenotypic feature of the mutation of
the Nfic gene in mouse is the failure of the differentiation of odontoblasts and/or dentin
formation in the lingual dentinal aspect of the incisor root as well as at the base of the
molar leading to arrested molar root growth (Steele-Perkins et al. 2003). MT1-MMP is a
membrane type matrix metalloproteinase and essential for remodeling of soft and hard
24
tissue interfaces. Tooth eruption and root elongation are severely inhibited in mice with
deficient MT1-matrix metalloproteinase enzyme (Beertsen et al. 2002).
Soon after root formation is initiated, the tooth begins to erupt, until it assumes its
position in the occlusion (Fig. 2f). After that, posteruptive tooth movement
accommodates jaw growth and interproximal tooth wear, and compensates occlusal wear
of the teeth in relation to the occlusion (Ten Cate 1994). There are differences in root
stage and the timing of eruption. Teeth usually emerge when the root has reached threequarters of its length, except for the upper central incisors and first molars, which emerge
with their roots half-formed, and the canines, whose root length is almost complete
(Haavikko 1970). The permanent tooth roots apart from those of the third molars
complete their growth during a time period beginning at the age of eight years and
continuing up to fourteen years, at least (Table 1).
Table 1. Permanent tooth formation stages in years by Haavikko (1970).
Tooth stage
Boys
Maxilla
Central incisor
Crc
3.3
Ac
9.8
Lateral incisor
Crc
4.6
Ac
10.8
Canine
Crc
4.6
Ac
13.6
First premolar
Crc
6.8
Ac
13.3
Second premolar
Crc
7.1
Ac
14.0
First molar
Crc
3.6
Ac
9.8
Second molar
Crc
7.3
Ac
16.2
Crc = tooth crown growth is completed.
Ac = tooth root growth is completed and apex closed.
Girls
Mandible
Maxilla
Mandible
8.0
3.3
9.3
8.0
3.3
9.6
4.4
9.6
9.0
4.3
13.2
4.5
12.7
4.1
11.5
5.9
12.8
6.3
12.6
5.4
12.1
7.0
13.8
6.6
13.4
6.4
12.8
3.5
9.8
3.5
9.2
3.5
9.2
7.4
15.7
6.9
15.1
7.0
14.7
2.1.5 Sexual dimorphism in tooth development
Sexual dimorphism in final form can already be observed some months after birth in
deciduous tooth crown sizes (Kari et al. 1980; Harila et al. 2003). In permanent tooth
crowns the size difference for the most of the teeth ranges between two to four percent,
25
men having larger teeth than women (Selmer-Olsen 1949; Garn et al. 1964; Alvesalo
1971). The proportion differs between the tooth groups, however, being even nine percent
in the mandibular canines. By comparison, sexual dimorphism in stature is about three
percent in late childhood, rising to approximately nine percent at the end of the pubertal
growth spurt (Garn et al. 1966). The size difference between normal men and women in
the tooth crowns is solely due to a thicker dentin measured on a radiograph as a distance
between mesial and distal dentino-enamel junctions (Alvesalo & Tammisalo 1981; Stroud
et al. 1994; Harris & Hicks 1998). Normal men have longer tooth roots than women
(Selmer-Olsen 1949), the average difference being six percent in the mandibular canines,
premolars and molars (Garn et al. 1978). There also seems to be a clear sex difference in
extreme root lengths, with extremely short roots to be found most often in girls and
extremely long roots in boys (Jakobsson & Lind 1973).
The sex differences in the mesio-distal diameters of the tooth crowns in deciduous and
permanent molars increase from earlier developing teeth to later developing teeth, except
that the third molars show the least dimorphism (Kondo & Townsend 2004). Mayhall and
Alvesalo (1995) found sexual dimorphism between the earlier developing cusps of the
tooth, but not between the last cusps. On the other hand, the opposite has been suspected,
in that the first developing cusp, the paracone, may express the least dimorphism (Kondo
et al. 2005). The expression of the cusp of Carabelli in the permanent first upper molars
shows a large variation, but the dichotomy of having a cusp or not may have a genetic
basis (Alvesalo et al. 1975b). Alvesalo et al. (1975b) found no sexual dimorphism in the
occurrence or in the degree of expression of Carabelli trait in permanent upper first
molars. However, a tendency for greater expressivity of the trait in normal men compared
to women has been found.
It has been concluded from the results for sibling and cousin pairs that genes affecting
tooth size are apparently situated both on the X and Y chromosome, with different
influences on phenotypic quantity so that the observed sexual dimorphism in average
tooth crown size is the influence of the Y chromosome genes (Alvesalo 1971). According
to studies on individuals with sex chromosome abnormalities by Alvesalo (1997) and coworkers in the Kvantti research project the Y chromosome promotes growth of the
permanent tooth crown, both enamel and dentin, whereas the effect of the X chromosome
seems to be restricted mainly to enamel formation. In terms of population developmental
standards (Haavikko 1970), the size difference in permanent tooth crowns between
normal men and women indicates obvious increases in final growth between the time
period of two months after birth up to the age of eight years, apparently expressing a
continuous gene effect (Alvesalo 1997).
It has been proposed that the genes on the Y chromosome are responsible for the
sexual dimorphism in the rate of bone development (Tanner et al. 1959). Girls are
generally more advanced in their somatic growth and development than boys up to the
pre-adolescent years (Tanner 1978; Garn & Rohmann 1962). The sex differences in tooth
development and size manifest themselves before the adolescent growth spurt, indicating
that the mechanisms involved are independent of somatic and/or sexual maturity
(Demirjian et al. 1985; Kari 1993). There is no sex difference in dental mineralization
during the first stages of crown formation in the majority of teeth, but girls are more
advanced at the completion of crown development than boys. The difference between the
sexes for all teeth in root development is 0.54 years, the largest difference, 0.90 years,
26
being seen in the canines (Demirjian & Levesque 1980), being similar to the delay in
skeletal maturation in boys (Tanner 1978). Also Kari (1993) has found a clear sex
difference in the mineralization stages of the tooth crowns, girls showing a more
advanced crown development than boys.
The lower face height, which is connected to the chewing apparatus, shows a greater
difference between the sexes than do the other craniofacial dimensions. There seems to be
some connection between root length and facial height, focused on the upper first incisors
and canines (Selmer-Olsen 1949). The sex differences in the time required for root
formation are much less for the second molar than for other teeth (Thompson et al. 1975).
The differences in the duration of tooth mineralization between specific teeth are due to
delay rather than an increase in the velocity of growth and rates of eruption show only a
modest variation. So, the larger teeth in males compared to females erupt later due to the
longer mineralization period (Leigh et al. 2005). As an example, the completion of the
crowns of human permanent incisors takes three to five years, but the clearly larger
permanent incisors in the great apes takes over five years. These facts tie together tooth
size and the time required for tooth crown formation (Dean & Beynon 1991).
2.1.6 Aberrations in tooth root development
Abnormal tooth root length and/or morphology have been associated with a number of
genetic defects. Hypodontia has been linked to decreased tooth size in the developing
teeth of the same dentition (Brook 1984), and dental development has been found to be
delayed relative to controls (Uslenghi et al. 2006). Enamel hypoplasia and taurodontism
have also been reported to be associated with hypodontia (Lai & Seow 1989).
Cleidocranial dysplasia is an autosomal dominant generalized skeletal dysplasia
caused by mutation in the Runx 2 transcription factor gene (Lee et al. 1997; Kim et al.
2006). It is characterized by moderate short stature, delayed skeletal and dental
development, numerous supernumerary teeth and non-eruption of permanent teeth, and
occasionally excess root development in the first molars (Seow & Hertzberg 1995).
In Down syndrome (trisomy 21) tooth crown and root size is reduced in most cases,
with fluctuating asymmetry, and the mesio-distal crown dimensions of the lower incisors
are relatively greater than the labio-lingual dimensions, which is the reverse of the normal
situation (Townsend & Brown 1983). Frequencies of hypodontia and taurodontism are
increased; taurodontic molars have been found in about half of the Down syndrome
individuals examined (Rajić & Rajić Meštrović 1998).
A short root anomaly is expressed in the upper incisors and upper and lower
premolars, and inherited in an autosomal dominant manner with incomplete penetrance,
but its genetic background is unknown (Apajalahti 1999). A general reduction in
permanent tooth root lengths and crown size is seen in individuals with a lack of sex
chromosome material. That is evident in Turner females, as compared with normal
women (Filipsson et al.1965; Alvesalo & Tammisalo 1981; Midtbø & Halse 1994b).
Gene defects that cause abnormalities in tooth structure may also affect the root
morphology, involving pulp morphology in the case of enamel defects and root size and
pulp morphology in the case of dentin defects. Amelogenesis imperfecta (AI) is an
inherited disorder affecting the tooth enamel, usually in both dentitions. Fourteen
different subtypes, based upon mode of inheritance and clinical manifestations, have been
27
reported (Witkop 1967; Witkop & Sauk 1976). Thus far, mutations causing different
types of AI have been identified in genes coding for certain enamel extracellular matrix
proteins (amelogenin and enamelin) and proteolytic enzymes required for enamel
maturation (MMP-20 and kallikrein-4; reviewed by Stephanopoulos et al. 2005). The AI
hypoplastic-hypomaturation form is inherited in an autosomal dominant manner (ADAI),
and associated with reduced tooth crown size and enamel thickness, and with enlarged
pulp chambers and taurodontism in the molars of some affected individuals. It is allelic
with trichodento-osseus syndrome which is caused by mutations in the DLX-3
transcription factor gene (Dong et al., 2005). Taurodontism, pulpal calcifications, coronal
defects and unerupted teeth have also presented in some individuals with X-linked AI
(Lykogeorgos et al. 2003), resulting from mutated amelogenin gene. In a hypoplastic
form of the dominantly inherited form of X-linked AI (XDAI) the entire enamel in men is
thin, shiny and yellow-brown, while in women it can be of almost normal thickness with
defective vertical ridging and a wide range of individual variation in its manifestation
(Greene et al. 2002).
The diseases mainly affecting dentin formation, dentinogenesis imperfecta (DI) and
dentin dysplasia (DD) are inherited in an autosomal dominant manner (Witkop 1957). DI
types II and III and DD type II are allelic disorders, in which the formation of dentin is
affected by mutations in the dentin sialophosphoprotein gene (DSPP, 4q21.3). These three
non-syndromic heritable dentin defects can nowadays also be considered to be
manifestations of a single disease with milder and more severe forms (Beattie et al.
2006). DI-II, known as a hereditary opalescent dentin condition appears in both
dentitions. Markedly short roots and obliterated pulp chambers and root canals are
typical. The penetrance is almost complete and expressivity consistent within each family
(Shields et al. 1973). Dentin dysplasia (DD) affects both dentitions as well. In DD-II, or
coronal DD (Shields et al. 1973), the deciduous teeth are grey or brown in colour and
translucent, with their pulp chambers obliterated. The permanent teeth have normal
crown and root morphology and colour, but exhibit large coronal pulp chambers with
numerous pulpal calcifications (Melnick et al. 1982; Brenneise et al. 1999).
Of genetically unknown origin is still, however, DD-I (“rootless teeth”), in which the
tooth crowns are of normal shape, occasionally slightly amber in colour, but the roots are
short and conical with an apical constriction and the dentin is dysplastic and has a high
radiodensity (Melnick et al. 1982). Pulpal obliteration in the permanent teeth may result
in a “half-moon”-shaped pulp chamber and completely obliterated root canals in both
dentitions, while dental eruption is delayed (Kosinski et al. 1999; Kalk et al. 1998).
Since type I collagen is the major extracellular component of dentin matrix, it is
conceivable that mutations in the two genes that encode type I collagen alpha chains
(COL1A1 and COL1A2) also affect dentin. These patients generally exhibit a connective
tissue disorder osteogenesis imperfecta, characterized by bone fragility and deformity,
blue sclerae, and hearing impairment (Sillence et al. 1979). The affected teeth markedly
resemble those seen in DI patients with bulbous crowns, short and blunted roots,
constricted coronal-radicular junctions and obliterated pulp chambers and root canals.
The pulp chambers may also be abnormally wide prior to the onset of obliteration
(Lukinmaa et al. 1987). The deciduous dentition is more affected than the permanent
teeth. Teeth are brown-bluish in colour, translucent and prone to breakage. The variability
in collagen composition is large, but the first dentin to form is normal (Shields et al.
1973; Waltimo et al.1994).
28
Hypophosphataemic vitamin D-resistant rickets is inherited in an X-linked dominant
manner, and men are more severely affected. Patients are short in stature, and tooth
eruption is delayed, pulp chambers are large and the dentin is abnormal and presents
marked fissures and cracks (Melnick et al. 1982).
Hypophosphatasia is a rare inherited metabolic disease of decreased tissue nonspecific alkaline phosphatase and defective bone mineralization. A mutation in the gene
ALPL (1p36.1-34) is believed to be the cause of this desease. It has clinically five
categories. The perinatal and infantile forms are inherited by an autosomal recessive
mode, and the childhood, adult, and odontohypophosphatasia forms are inherited in an
autosomal recessive and dominant mode. The odontohypophosphatasia form affects
mostly uniradicular teeth in both dentitions with abnormal dentin. In these patients teeth
are lost due to decrease in cementum formation, pulp chambers are large, and the
calcification of the root apices is delayed. Patients with childhood and adult forms exhibit
premature loss of deciduous teeth due to lack of cementum formation. (Melnick et.al.
1982; Anadiotis 2003)
2.2 Human sex chromosomes
2.2.1 The genome
Present view of the magnitude of the human genome is between 20 000 and 25 000
genes. Only one to two percent of the genetic material, known as exons, code for or
adjust proteins, while the introns, constituting 24 percent of the total genome, include
many repeat sequences of the genes, the intergene space being 75 percent. Genetic
variation is large, because one gene may produce several gene products, and individual
variation is even larger, because exons are randomly read. The main gene structures and
functions of 60 000 proteins are known so far. (Frilander 2003)
2.2.2 Number of human chromosomes
Chromosome mutations also include changes in the number of normal chromosomes, as
opposed to the number of sets of chromosomes, leading to unequal numbers of different
chromosomes in one individual, and this is called aneuploidy. The human somatic cell
contains 46 chromosomes: two sex chromosomes and 22 paired autosomes, with one
chromosome derived from the mother and one from the father. The X chromosome is
comparable in size to autosomes, while the Y chromosome is much shorter. All viable
individuals possess at least one X chromosome. Normal women have a 46,XX
chromosome constitution and men a 46,XY constitution. The number of autosomes is
quite constant, as triploidy and tetraploidy are seldom found and haploidy only in the
extremely rare 21 monosomy. Individuals with that kind of chromosome complement are
seldom viable because of a serious illness. Aneuploidies for autosomal chromosome 13,
18 and 21 trisomies are found, however. It should be noted that sex chromosomes show a
29
much wider range of aneuploidy and the phenotype of these individuals is not so
destructive as those for autosomes, mosaicism also is much more common and often
involves structurally abnormal X and Y chromosomes. If the trisomic and monosomic
cells arising in somatic tissues through the misdivision of the chromosomes or
chromosome loss are viable, the result is mosaicism, which means the presence of
differing cell lines in relation to genotype in one individual. If the mosaicism occurs very
early in development, the entire individual may be mosaic. Patients with more than three
sex chromosomes suffer from mental retardation and display various other somatic
anomalies. The abnormalities vary considerably from case to case. (Therman & Susman
1993)
Aneuploidy results from non-disjunction in either the meiotic division of the parents
or the early cleavage divisions of the affected individuals. Aneuploidy for more than one
chromosome is the result of non-disjunction in both meiotic divisions, non-disjunction in
the meiosis of both parents, multiple non-disjunction in the same mitosis or meiosis, or
abnormalities in more than one mitosis. The incidence of 47,XXX and 47,XXY children
increases with maternal age, as does that of autosomal trisomies, indicating nondisjunction in maternal meiosis (Barr et al. 1969; Therman 1986). The incidence of 45,X
children seems to be independent of maternal age, however, and studies on the Xg blood
group gene have shown that 78 percent of the gamete without another sex chromosome
comes from the father (Therman & Susman 1993). Nielsen and Wohlert (1991) found in
liveborn children in Århus, Denmark total incidence of sex chromosome abnormalities to
be one in 448 children.
2.2.3 Dimorphic X and Y chromosomes
Human sex chromosomes are thought to be descended from a homologous pair of
autosomes (Ohno 1967). There is evidence for gene loss from the Y chromosome during
mammalian evolution, and mutations and inversions have further reduced the level of
homology. The length of the Y chromosome is highly inheritable, the variation affecting
mostly the long arm (McKenzie et al. 1972). A regulatory role of the Y chromosome in
human growth has been pointed out, especially in the differential ontogenesis of the sexes
(Ounsted & Taylor 1972). The morphology of the X chromosome, on the other hand, has
changed remarkably little and is still the same between monkeys and man. The gene
content in the X chromosome has remained the same throughout mammalian
development (Ohno 1967). The X chromosome contains 3 000 genes and the Y
chromosome close to hundred.
The double dosage of X chromosomes in women compared with men is compensated
for by random inactivation of one X chromosome in each somatic cell at an early stage of
embryonic development (Lyon 1962), and the same chromosome remains inactive in all
descendants of any given cell. Particularly in humans, several genes are known to escape
X inactivation and are expressed in both the active and inactive X chromosomes. These
represent about ten percent of the X-linked transcripts (Carrel et al. 1999). For instance
the Xg blood group genes, the loci for the blood-group antigens (Ducos et al. 1971), and
the X-linked amelogenin gene (AMELX) are located in the short arm of X (Xp)
30
chromosome in its always active region (Therman & Susman 1993). X chromosomes in
women can change genetic material in recombination during meiosis in the same way as
autosomes, whereas recombination of the X and Y chromosomes in men is limited to the
pseudoautosomal regions found in the telomeric parts (Schaffner 2004). A dozen
pseudoautosomal genes have been identified, most of them on the short arm (Cooper
1999). The male-specific region of the Y chromosome (MSY) is between the
pseudoautosomal regions, and comprises 95 percent of the chromosome length. MSY
consists of a mosaic of heterochromatic sequences and three classes of euchromatic
sequences. Skaletsky et al. (2003) report 78 protein-coding genes in MSY that
collectively encode 27 distinct proteins locating in euchromatic sequences. The
occurrence of MSY gene pairs subject to frequent conversion might provide a mechanism
for conserving gene functions in the course of evolutionary time in the absence of
crossing over in the Y chromosome.
X- and Y-linked gene pairs encode very similar but not identical protein isoforms. The
coding regions of the X and Y chromosome amelogenin genes, for instance, are
approximately 87 percent homologous (Chen et al. 1998) and both of them are
transcriptionally active (Lau et al. 1989; Nakahori et al. 1991; Salido et al. 1992; Gibson
1999). Molecular studies have indicated that loci for human amelogenin, the main protein
component of the enamel organic matrix, are to be found on the distal short arm of the X
chromosome (Xp22.1-p22.3) and possibly on the proximal long arm of the Y
chromosome (Yq11), although the short arm of the Y chromosome has also been
suggested (Lau et al. 1989; Nakahori et al. 1991; Salido et al. 1992). Amelogenin genes
are expressed only in the developing teeth. The level of Y chromosome locus expression
is ten percent of that of the X chromosome (Salido et al. 1992). Some Y chromosomelinked genes have assumed a testis-specific expression pattern, whereas their X
chromosome-linked homologues are ubiquitously expressed (Foster & Graves 1994).
A gene known as the short-stature homeobox (SHOX) is situated in the freely
recombining region of the human sex chromosomes (Kauppi et al. 2004) and proposed to
be the cause of the short stature observed in Turner Syndrome individuals (Lahn et al.
2001). Ellison et al. (1997) reported an osteogenic gene named PHOG, which has been
shown to be identical to SHOX, and has been mapped to Xp22 and Yp11.3, which encode
proteins with different patterns of expression (Rao et al. 1997), and also are suggested
loci for amelogenin.
31
2.3 Individuals with abnormal sex chromosome complement
and the female sex reversal
2.3.1 45,X/46,XX females or females with shortage of sex
chromosome material
An American, Henry Turner, was the first to describe in 1938 a syndrome in women with
decreased height and lack of development of the secondary sex characteristics. Not until
twenty years later in 1959 it was discovered that women with Turner syndrome lack an X
chromosome or part of it, and with it the genes for the development of the ovaries, sex
hormone production, physical sex development and height (Nielsen et al. 1991). The
incidence of Turner syndrome in Denmark is approximately one in 2000 girls (Nielsen &
Wohlert 1991), and approximately half of them are 45,X females having one X
chromosome in every cell. The mosaic chromosome constitution 45,X/46,XX consists of
both normal XX and one X sex chromosome cell lines. It is found in about 20 percent of
Turner females. (Nielsen et al. 1991) It has been estimated that 98 percent of 45,X
conceptions end in a spontaneous abortion, and many foetuses who survive also have
genital, cardiac, renal and dermal abnormalities (Park et al. 1983). The degree of Turner
characteristics in mosaic individuals has been found to reflect the degree of mosaicism
(Sarkar & Marimuthu 1983). 46,X,i(Xq) is a subgroup of Turner syndrome with a longarm isochromosome or one X chromosome with two long arms (Xq), caused by a
misdivision, and one normal X chromosome.
Sex chromosomes have an effect on body growth and its timing. With a normal
chromosome constitution there is a growth spurt in puberty, and many children also have
a mild growth spurt between the ages of five and nine years. The mean height for girls is
about 165 cm in western countries and it is reached mostly by the age of 16 years. The
absence of X chromosome material affects body growth, however, so that the average
height of Turner girls (including mosaics) at birth is a few centimetres less than normal
(Park et al. 1983; Nielsen et al. 1991) and their adult stature is clearly shorter compared
to normal women, being 146.9 cm in a Finnish study (Varrela et al. 1984a). The adult
stature of 45,X/46,XX females is above the average for 45,X females (Park et al. 1983).
Turner females have changes in body proportions on the longitudinal axis to a greater
extent than in body width: first they are short-legged, while in adulthood the body
proportions are like in normal women (Park 1977; Varrela et al. 1984a). Their head
dimensions are close to those of normal women with a tendency to a narrower upper face
(Varrela et al. 1984a), while the facial dimensions are smaller (Grön et al. 1999). They
have a delay in skeletal maturity averaging 2.4 years, which is commonly attributed to the
lack of primary oestrogen, since growth hormone levels are normal (Webber et al. 1982;
Midtbø & Halse 1992). Dental maturity is accelerated, however, the mean difference
being one year (Filipsson et al. 1965; Midtbø & Halse 1992). Turner girls are often
offered growth hormone therapy from the age of six years and small doses of oxandrolon
(a synthetic growth hormone which resembles male sex hormone) when they are 10 years
of age, enabling their final height to be increased by 5-10 cm (Nielsen et al. 1991). With
32
oxandrolone or growth hormone alone the final height can be increased by 3-4 cm
(Naeraa et al. 1990). They are also given oestrogens together with progestogens to ensure
normal pubertal development, and this is continued at least until they are in their fifties.
As the phenotype of 45,X/46,XX females is in proportion to the rate of mosaicism, they
have at least partial natural hormone production (Park et al. 1983; Nielsen et al. 1991)
and the great majority of known pregnancies among Turner women involve mosaics.
The facial skeleton in normal individuals is one fourth and the neurocranium is half of
the adult size at birth. Thus it is no wonder that the lack of sex chromosome material in
Turner females leads to more pronounced growth changes in the facial region than in
other head dimensions after birth. The anterior and posterior cranial bases are shorter than
normal and flattened (Midtbø et al. 1996; Grön et al. 1999), which may originate from
the foetal period (Filipsson et al. 1965; Midtbø et al. 1996), when the primary cartilages
form the craniofacial skeleton. The face is retrognathic, i.e. maxillary growth is normal
but the mandible is short (Peltomäki et al. 1989; Hass et al. 2001), and the jaws are
posteriorly rotated (Midtbø et al. 1996). The occlusal morphology of 45,X females differs
from that of normal women in that the prevalences of distal molar occlusion, lateral
crossbite, maxillary overjet and tendency for open bite are increased (Laine et al. 1986;
Harju et al. 1989; Midtbø & Halse 1996). The dental arch in the mandible is broader and
that in the maxilla narrower than in normal women (Laine & Alvesalo 1986). A narrow
palate compared to normal women and exostosis on the palatal alveolar plates are
frequent features (Laine et. al. 1985). By comparison with the 45,X females, 45,X/46,XX
and 46,X,i(Xq) females show a milder expression of malocclusion (Harju et al. 1989).
Turner women have been found to have increased asymmetry in tooth size and/or in the
morphology of antimeric teeth (Midtbø and Halse 1994a; Pirttiniemi et al. 1998). These
findings suggest that another sex chromosome is of importance for harmonious growth
and development of the craniofacial skeleton and ultimately normal occlusal morphology
and relations (Laine et al. 1986).
2.3.2 47,XXY and 47,XYY male-trisomies
Trisomy of the sex chromosomes, the most prevalent aneuploidy in humans, occurs in
three types: XXX, XXY, and XYY. Trisomy has only a minor phenotypic effect, and most
of these individuals are never diagnosed (estimated 64 percent of 47,XXY males and 85
percent of 47,XYY males) (Ratcliffe 1999). An American, Harry Klinefelter and
associates, were the first to describe in 1942 the syndrome in men with a tendency to
breast development, decreased production of sperm cells and increased excretion of
pituitary hormones (Nielsen 1999). Individuals with Klinefelter syndrome have two X
chromosomes in addition to one Y chromosome (47,XXY), or in rare cases three or four
X chromosomes. The chromosome constitution 47,XXY is found in about 80 percent of
males with Klinefelter syndrome, six percent of whom have a chromosomal mosaic.
Klinefelter syndrome is the most common sex chromosome abnormality, with an
incidence of one in 596 newborn boys (Nielsen & Wohlert 1991), although one in 769 has
also been suggested (Ratcliffe 1999). 47,XYY males, or males with one extra Y
chromosome, represent the only aneuploidy which is not selected against before birth,
33
being found in one male birth out of 894 (Nielsen & Wohlert 1991). The chromosome
constitution 47,XYY is found in approximately 80 percent of males with an extra
Y chromosome.
Normal men and 47,XXY and 47,XYY males have no significant differences in
prenatal testosterone levels, while all these groups differ from normal women (Ratcliffe
et al. 1994a). Later the hormone levels of 47,XYY males can still be considered normal,
although they show greater variability in plasma testosterone levels (BénéZech & Noël
1985), and they usually have normal children. By contrast, the production of testosterone
in 47,XXY boys is insufficient later and requires substitution therapy from the age of
eleven until fifty years of age (Nielsen 1999). This may prevent breast development and
normalize body hair and beard growth. The testicles are of normal size at birth, but
remain around that size all through life. A few males with Klinefelter syndrome have
nevertheless produced children. Skeletal maturity in sex chromosome trisomies does not
differ significantly from that in a normal population (Webber et al. 1982).
2.3.2.1 Body growth and craniofacial characteristics in 47,XXY males
Birth weight, height and head circumference are smaller in individuals with an extra X
chromosome, such as 47,XXY boys, than in normal boys, and head circumference
remains below average values to a significant degree (47,XXY -0.7 SD) (Ratcliffe et al.
1994b). Acceleration in height growth is greater than in normal boys up to the age of
eight years, owing to accentuated leg length (Nielsen 1999). The pubertal growth spurt in
47,XXY males is similar in magnitude and timing to that in normal boys. They grow
taller than normal men, with a mean adult height of 186 cm and 180 cm accordingly, but
remain eight to ten centimetres shorter than 47,XYY males (Ratcliffe 1999). In a Finnish
study the final height of 47,XXY males was 182 cm (Varrela 1984). The somewhat
greater growth acceleration in height is due to relatively increased leg length, and the
feminine trunk proportions in 47,XXY males are caused by a decrease in shoulder width
(Varrela 1984), and the double dose of X chromosomes inhibits masculine muscular
development (Tanner et al. 1959).
The head and face dimensions of 47,XXY males are smaller than those of normal men
(Varrela 1984) as is also the cranial base angle (Ingerslev & Kreiborg 1978; Brown et al.
1993). The ramus of the mandible is shorter, but the gonial angle and corpus length are
larger than those of normal men, while if compared to normal women there are few
contrasts in facial shape apart from mandibular prognathism (Brown et al. 1993).
Bimaxillary prognathism and a tendency for a reduction in face height is seen in 47,XXY
males. In addition, they have relatively frequently occlusal anomalies, predominantly
mesial molar occlusion and anterior open bite (Alvesalo & Laine 1992), and the
maxillary and mandibular dental arches are narrow compared to normal men.
34
2.3.2.2 Body growth and craniofacial characteristics in 47,XYY males
Birth weight, height and head circumference of 47,XYY males do not differ from those of
normal boys (Ratcliffe 1985). The velocity of height growth increases significantly from
two years of age and continues to be high throughout childhood. By the age of seven
years the most prominent features are relatively long legs and a small head
circumference. The increased height growth is still evident during puberty, which occurs
an average six months later than in controls and lasts longer (Ratcliffe et al. 1990;
Ratcliffe et al. 1992). Not only height, but virtually all adult body, head and
cephalometric dimensions of 47,XYY males are larger than those in normal men with
similar body proportions (Varrela & Alvesalo 1985; Grön et al. 1997). 47,XYY males
have somewhat narrower shoulders and relatively wider hips and an otherwise
generalized size increase (Ratcliffe 1985; Varrela & Alvesalo 1985). The extra Y
chromosome in these males affects adult height by about 13 cm compared to normal men,
which is close to the difference between normal men and women (Ratcliffe et al. 1992).
47,XYY males have larger craniofacial dimensions than normal men, without any
substantial differences in the dimensional ratios or plane angles (Grön et al. 1997). They
have a longer cranial base and the cranial base angle is smaller, however. The lower
anterior face height is bigger compared to normal men, and the mandible is posteriorly
rotated. The foramen magnum is smaller in the sagittal plane than in normal men or
women, men having smaller foramen magnum than women. That could be explained by
the appositional bone growth in calvaria combined with longer growing bones in men.
47,XYY males have seldom occlusal anomalies, but they tend to have progenia with
mesial molar occlusion and negative overjet (Laine et al. 1992), which is accounted for
the larger transversal and sagittal maxillary dental arch and mandibular arch length
relative to normal men (Laine & Alvesalo 1993). The palatal height and transversal with
of the mandibular dental arch are smaller compared to normal men (Laine & Alvesalo
1993).
2.3.3 Female sex reversals (46,XY females)
The testicular feminization syndrome, or females with a male sex chromosome
complement, female sex reversals (Therman & Susman 1993) or 46,XY females, can be
divided into complete and incomplete forms (Dewhurst 1971). The complete form of
androgen insensitivity syndrome involves normal androgen synthesis, the basic endocrine
defect being end-organ insensitivity to androgens, which is a genetically determined
condition and runs in families. It is a very rare condition and is estimated to occur in one
out of 62 400 live-born males (Jagiello & Atwell 1962). These individuals are
phenotypically females, and the clinical signs include testes, female external genitalia,
puberty with breast development and a blind-ended vagina (Dewhurst 1971). They are
females in their psychosexual behaviour, and are usually detected on account of primary
amenorrhoea or an inguinal hernia, and occasionally through other affected family
members (Dewhurst 1971; Simpson 1976).
35
In the complete form of testicular feminization syndrome in 46,XY females the body
dimensions, including stature (mean 171,5 cm) and head circumference, are above the
average for normal women (Varrela et al. 1984b). The body proportions are similar with a
tendency towards a slimmer figure compared to normal women. Stature is above the
expected mid-parental height. The role of the Y chromosome genes in determining stature
and head circumference is conceivable in these individuals (Smith et al. 1985; Varrela &
Alvesalo 1985).
The growth change in the complete testicular feminization syndrome females is also
seen in the dimensions of the cranial base and maxillary complex falling between those of
normal men and women, but the length of the mandibular corpus has been measured to
exceed even the mean value for normal men and the ramus height resembles that for
normal women with an acute gonial angle (Pietilä et al. 1997). The maxillary dental arch
is larger in sagittal dimension, and the palate is higher compared to normal women, also
the mandibular dental arch is broader (Grön & Alvesalo 1997). The occlusal relationship
tend to be mesial with deep bite.
2.4 Tooth growth and an abnormal sex chromosome complement
Studies on families and individuals with abnormal sex chromosome complement and
their relatives in the Kvantti research project (Garn & Rohmann 1962; Filipsson et al.
1965; Garn et al. 1964; Alvesalo 1971; Alvesalo et al. 1975a; Alvesalo & Kari 1977;
Alvesalo & Portin 1980; Alvesalo & Varrela 1980; Kari et al. 1980; Alvesalo &
Tammisalo 1981; Townsend et al. 1984; Alvesalo 1985; Alvesalo et al. 1985; Alvesalo et
al. 1987; Mayhall et al. 1991; Mayhall & Alvesalo 1992; Alvesalo 1997; Zilberman et al.
2000), together with molecular research (Lau et al. 1989; Nakahori et al. 1991; Salido et
al. 1992), have shown that genes on the human X and Y chromosomes have an effect on
the growth of the tooth crown. The Y chromosome promotes formation of both the
coronal enamel and dentin, whereas the effect of the X chromosome on crown growth
seems to be restricted to enamel (Alvesalo & Tammisalo 1981; Alvesalo 1985; Alvesalo
et al. 1985; Alvesalo et al. 1987; Mayhall et al. 1991; Alvesalo 1997; Zilberman et al.
2000). The initiation of dentin formation is preceded by cell proliferations in the inner
enamel epithelium, and enamel formation is decisively influenced by cell secretory
function (Kraus and Jordan 1965).
Previous studies on females with a lack of sex chromosome material have shown
significantly smaller dimensions of the permanent tooth crowns in 45,X, 45,X/46,XX and
46,X,i(Xq) females than in normal women (Varrela et al. 1988; Filipsson et al. 1965;
Alvesalo & Tammisalo 1981; Townsend et al. 1984; Mayhall et al. 1991; Midtbø & Halse
1994a). The primary molars also tend to be smaller, at least in 45,X females (Kari et al.
1980). The smaller crown dimension in 45,X, 45,X/46,XX and 46,X,i(Xq) females is
mainly due to a thin enamel layer, while the mesio-distal dentin layer is close to that of
normal women in 45,X, and 45,X/46,XX females (Alvesalo & Tammisalo 1981; Mayhall
et al. 1991; Alvesalo 1985; Zilberman et al. 2000). In 46,X,i(Xq) females the mesio-distal
dentin layer is smaller compared to normal women (Mayhall et al. 1991). The change in
the labio-lingual dimension is more variable than that in the mesio-distal dimension in
36
these Turner females, and is least affected in 45,X/46,XX females (Varrela et al. 1988;
Mayhall et al. 1991; Midtbø & Halse, 1994a). The morphology of the maxillary teeth,
especially the incisors, is more variable in Turner women than in controls (Midtbø &
Halse 1994a).
Studies on tooth growth in females with the complete form of testicular feminization
syndrome (46,XY females) have shown larger crown sizes relative to normal women.
Measurements of the thickness of the tooth crown enamel in these females have
suggested values close to those in normal men and women, but dentin thickness is similar
to that of men and hence far in excess of that in women (Alvesalo 1985), suggesting a Y
chromosomal influence on tooth growth apart from androgen action. Alvesalo and de la
Chapelle (1981) found that stature and deciduous and permanent tooth crown sizes were
reduced in a boy with a deletion in the proximal portion of the long arm of the Y
chromosome, compared with another man who also displayed a deletion of the long arm
of the Y chromosome, and suggested that the location of the tooth growth-promoting
gene is Yq11, which also is the suggested locus for stature.
Studies on deciduous and permanent tooth crown dimensions in 47,XYY boys and
men (Alvesalo et al. 1975a; Alvesalo & Kari 1977) have shown bigger tooth crown sizes
compared with normal men. Larger crown size in permanent teeth is due to both thicker
mesio-distal dentin and enamel layers (Alvesalo et al. 1985). The mesio-distal dimension
of upper permanent central incisors, for example, is about five percent larger than in
normal men. The bigger crown size of permanent teeth in 47,XXY males (Alvesalo &
Portin 1980; Townsend & Alvesalo 1985) is caused by a thicker enamel layer than in
normal men or women, while the mesio-distal dentin thickness falls between those of
normal men and women (Alvesalo et al. 1991), suggesting an X chromosome gene effect
on crown size. The average difference in tooth size between normal men and women is
explainable by the postulated differential growth promoting effect of the Y chromosome
compared to the X chromosome (Alvesalo 1985). It is of interest, that the effect of the
sound X chromosome on metric enamel formation shows similar class of magnitude to
that of the Y chromosome, whereas, in crown dentin formation the influence of the Y
chromosome is clearly more than that of the X chromosome (Alvesalo 1997).
The crown morphology of 47,XYY males is changed in that the degree of shovelling
of the maxillary permanent lateral incisors is bigger and the palatal fossa is deeper than in
their relatives, while the lateral incisors of 45,X females are less shovel-shaped than in
normal women and the central incisors have a shallower fossa in addition to the tendency
towards less cusps in the molars (Kirveskari & Alvesalo 1981) and simplified tooth
crown shape (Kirveskari & Alvesalo 1981; Midtbø & Halse 1994a). Midtbø and Halse
(1994a) found an altered mamelon pattern in Turner women, especially in the incisal edge
of the maxillary lateral incisors, together with atypical mesiobuccal cusps and nippled
cusp tips of the maxillary canines and premolars, whereas the Carabelli trait in the
maxillary first molars was found far less often than in a normal Finnish population
(Alvesalo et al. 1975b; Nakayama et al. 2005). Sex chromosomes have an effect mainly
on the cusp basal area rather than cusp height. The cusp basal area is smallest in 45,X
females, with the sharpest cusps, becomes larger in normal women and men, and is even
larger in 47,XYY males, who have the bluntest cusp form (Mayhall & Alvesalo 1995).
Permanent tooth root lengths are shorter in 45,X, 45,X/46,XX and 46,X,i(Xq) females
(Filipsson et al.1965; Midtbø & Halse 1994b) relative to normal women, while the
37
premolars (Varrela 1990; Midtbø & Halse 1994b) and lower first molars (Midtbø & Halse
1994b) of 45,X females show more root components in separate forms and higher
frequency than in normal women, and also molariform mandibular premolars with mesial
and distal roots. Taurodontism appears to occur in 45,X (Varrela et al. 1990), 45,X/46,XX
females and 47,XYY males (Alvesalo & Varrela 1991) as in a normal population with a
frequency of 0.5-5 percent (Jaspers & Witkop 1980). Exceptionally, the pulp chamber of
the mandibular second premolar is often longer in 45,X females and 45,X/46,XX females
compared to normal women (Midtbø & Halse 1994b; Varrela 1992). The prevalence of
taurodontism increases with additional X chromosomes (Jaspers & Witkop 1980; Varrela
& Alvesalo 1989), and hypotaurodontic teeth appear to occur in about one third of mainly
second molars in 47,XXY males (Varrela & Alvesalo 1988).
3 Aim of this research
The general aim of the research was to study tooth root growth in individuals with an
abnormal sex chromosome complement and in 46,XY females who are insensitive to
androgens. The approach may also provide some clues for a further insight into the
development of sexual dimorphism in human growth. The underlying hypothesis was that
the effect of the X and Y chromosomes on tooth crown growth is also expressed in root
growth.
More specifically, the objectives were:
− to determine completed permanent tooth root lengths in 45,X/46,XX females, 47,XYY
and 47,XXY males, 46,XY females and normal men and women from panoramic
radiographs
− to deduce the timing of the influence of an abnormal sex chromosome complement
and of androgen insensitivity in 46,XY females on tooth root growth
− to deduce the relative magnitude of the influence of the X and Y chromosome genes
on root growth
4 Subjects and Methods
4.1 Population
The subjects were participants in professor Lassi Alvesalo’s research project, Kvantti
(Kromosomaalisen VAikutukseN Tutkimus-projekTI) on individuals with abnormal sex
chromosome constitution and 46,XY females (here called individuals) and their first
degree relatives (here called relatives). The individuals and relatives were from different
parts of Finland. Cytogenetic diagnosis of the individuals had been carried out for for
medical reasons. The Institutional Review Board of the Medical Faculty, University of
Turku, Finland, had reviewed and approved the protocol, of which the individuals and
their relatives were informed. The examinations were carried out during a time period
beginning 1974 and continuing up to 1987 with the individuals’ and relatives’ consent,
and they were not at risk in any way.
The individuals, who were 47,XYY males, 46,XY females, 47,XXY males and
45,X/46,XX females, are presented here by groups as in the original papers, referred to
by the Roman numerals (I-IV). For comparisons the relatives were chosen on a paired
basis, one relative of the same phenotypic sex for each individual and comparisons were
also extended to opposite sex in the group of 47,XXY males with extra X or Y
chromosome. In the selection of relatives the preference was put on the same generation
(sister or brother) prior to the parents and in the case of several siblings of the same
phenotypic sex the criteria was to choose the one primarily with full dentition and
minimal restorations and good quality of the radiograph. The population controls (men
and women) comprised relatives other than the group of individuals in question. (Table 2)
According to anamnestic information ten out of the fifteen 45,X/46,XX females had
received hormone therapy (mainly oestrogen), and four out of the eight 46,XY females
had received oestrogen therapy during or after puberty. 46,XY females have a pubertal
growth spurt typical of normal women both in magnitude and timing (Frank 2003).
Oestrogens are responsible for the normal development of the female secondary sex
characteristics and act on the fertilization process during the menstrual cycle.
Age
7.38
SD
10.0-36.7
Range
Age
15
23.4
8.42
7.1-41.0
9.3-41.7
10e
24.5
Range
31.2-50.6
7.55
15.1-37.4
10.60 16.9-43.5
5.64
15.53 13.5-67.5
12.64 11.9-42.7
SD
-
56
35
22
N
-
30.9
25.5
23.7
mean
Age
-
15.75
12.41
12.41
SD
Control men
-
11.6-67.5
11.6-45.6
11.6-45.6
Range
47
50
46
26
N
29.8
29.3
27.6
26.4
mean
Age
11.37
11.14
10.66
10.60
SD
Control women
9.7-59.1
9.7-44.1
9.7-55.6
9.7-55.6
Range
c = 4 mothers and 4 sisters, d= 5 sisters, e= 2 mothers and 8 sisters
N = number in study groups, Mean age in years, SD = standard deviation, Range = minimum - maximum (years), a = 4 fathers and 5 brothers, b = 16 fathers and 6 brothers,
females (III)
45,X/46,XX
9.57
24.8
(II)
25.1
5d
8
46,XY females
47,XXY males
39.7
27.9
mean
41.0
9a
N
8c
30.7 11.71 10.2-57.6
18.6
mean
Relatives
(IV)
49
15
N
Individuals
22b
(I)
47,XYY males
Study groups
Table 2. The individuals according to their cytogenetic diagnoses, their relatives and population controls. The Roman numerals indicate
the original articles.
40
41
4.2 Methods
4.2.1 Dental panoramic tomogram
A dental panoramic tomogram can provide information on the whole dentition in one
radiograph. The parabolic basic form of the image layer in orthopantomography is
obtained by means of a rotary movement taking place on three axes in succession. The
form of the image layer can be changed to some extent, especially by means of the profile
guide of the orthopantomograph and by regulating the speed of the film (Tammisalo
1964b). It was proposed empirically by Tammisalo & Nieminen (1964) that the position
of the centre of the sharply depicted object plane is dependent on the ratio between the
velocity of the film in relation to the beam and the velocity of the beam in relation to the
object. This empirical postulate, the outcome of a mathematical analysis by Tammisalo
(1964a) of the position and form of the image layer in images exposed with one specific
device, the Orthopantomograph 2, was later confirmed in experimental tests (Sjöblom &
Welander 1978; Welander & Wickman 1978). Distortion tolerance is better when the
projection radius is large, as is the case with the lateral parts of an image (Welander &
Wickman 1978), but the errors appearing in the reproduction of the inner surface of the
image layer on a horizontal plane are greater than those of the outer surface, because the
displacement and the difference in speed between the film and projection have an effect
similar to a change in dimensions. On the vertical plane, dimensional reproduction of the
object layer is dependent on the projection alone, any enlargement of the points situated
in the basic plane being linear, and the magnification is 31.7 percent (Tammisalo 1964a).
Distortion of the image in rotational panoramic radiography with respect to the vertical
dimension has also been analysed by Tronje et al. (1981) and Stramotas et al. (2002),
who stress the importance of the proper position of the patient in the device during
exposure.
Larheim et al. (1984), investigating the reproducibility of radiographs with the
Orthopantomograph 5, found the variability of measurements assessed from repeated
radiographs to range from 0.65 to 0.85 millimetres, or 2.4 to 3.1 percent of the mean
radiographic tooth length in different patient groups. The measurement error ranged from
0.43 to 0.56 millimetres, indicating that the main source of error inherent in the method
was recognition of the reference points. Small differences were found between the tooth
groups and between the right and left sides. Thanyakarn et al. (1992) observed that
radiographic tooth length measurements are highly influenced by observer performance,
the variation being higher for measurements of the maxillary teeth (0.3-1.9 mm) than for
the mandibular teeth (0.3-0.9 mm) in the case of most observers. The highest variation
was for the palatal root of the maxillary first molar.
The panoramic dental radiographs had been taken of all the patients and their relatives
in this study by one person at the Institute of Dentistry, University of Turku, within a
period of approximately ten years starting in 1974, following a standardized procedure
and with the same machine, an Orthopantomograph 3, Palomex. The magnification
ranged between 1.28-1.31 (28-31 percent) over the whole image layer of the panoramic
radiograph.
42
4.2.2 Root length measurement
The root lengths of the teeth of the individuals and controls were measured from the
dental panoramic radiographs, and crown heights were measured at the same time for
further studies (Fig. 4). The aim was to measure all the teeth with complete root
formation on both sides of the jaws except for the third molars. A computer-aided digital
system was first undertaken to measure the root lengths on the tomographic radiographs.
A videocamera was used to copy the radiograph on a light table and the root length was
calibrated. However, that method was found to be inadequate for defining the outlines of
the teeth on these radiographs because of weak contrast in places.
In the present study the following method was used: the radiograph was placed on a
light table and observed in a dark room, and magnifying lens (2x) was used to determine
the outlines of the teeth on the radiograph. The outlines were marked with a special, sharp
pencil for use with plaster (Schwan All Stabilo 8008). Measurements were all made in the
same manner with a sliding digital calliper (Mitutoyo, digimatic 500-123U, CD-15B,
England) to an accuracy of 0.01 mm. The measured value was rounded to one decimal in
the results in the following way: if the second decimal value was from one to four the
first decimal remained unchanged and if it was five or more the first decimal was raised.
The measurements of root lengths were made on a perpendicular between two parallel
lines, a line touching the outermost part of the root and a line joining the mesial and distal
cervical margins of the enamel. The value of the measurement was taken according to the
outer edges of the traces of the pencil on the radiograph. Root length refers to the longest
root on the radiograph in the case of premolars and the longest mesial root in the case of
molars. All the drawings and measurements were made by the present author (RL).
(Fig. 5).
The cervical margin was determined in the manner as Lind (1972) has described:
“points of intersection between outer contours of root and crown connected by a straight
line” combined with scrutinizing the lighter shade of enamel compared to dentin in a
radiograph. The root lengths and crown heights were measured as the projections of the
cusp tip and root apex to the film. The projections were considered the maxillary palatal
cusp tip and mandibular distal cusp tip in molars and the longer cusp tip in premolars. All
separate roots were first measured except the palatal root of the maxillary first molar
because of its great enlargement in this kind of radiograph. In the case of two roots on the
top of the other on the radiograph the longest dimension was chosen to be measured.
Only mesial root length was measured in the case of multi-rooted teeth with mesial and
distal root. (Fig. 5b)
Teeth that were partly outside the image layer in the panoramic radiograph or showed
obvious distortion because of being on its inner or outer surface (Tammisalo 1964b), and
teeth with incomplete root formation, were excluded. The dilacerated roots were
measured as perpendicular lengths as described above. A couple of impacted canine teeth
43
Fig. 4. A dental panoramic tomogram of a Klinefelter boy (47,XXY) aged 16 years. The
outlines of the teeth were marked using a special pencil for plaster, as also was a line joining
the mesial and distal cervical margins of the enamel.
a.
Fig. 5. Root lengths were measured by reference to lines marked on the tomographic
radiographs (a) as described in the text and shown in the picture (b).
with a closed apex and good posture in the radiograph were measured (Haavikko 1970).
Permanent tooth root lengths may be affected by several external factors, which could
bias the results. Orthodontic treatment, especially with fixed appliances, may cause root
resorption, as also can traumatic occlusion, bruxism, nail-biting, trauma, apical infection
44
or root treatment, for instance. Teeth with apparent root resorption occurring for any
reason were not included.
Acellular cementum is formed on the root surface until the tooth reaches the
occlusion, at which point the proliferation of the epithelial root sheath is reduced and it
may become entrapped within the forming matrix of cellular cementum (Thomas 1995).
Cellular cementum formation continues after the root form is complete. The line between
apical cementum and dentin was evaluated while marking the outlines of the roots and
the apical cementum layer was excluded from the present root length determinations.
4.2.3 Reliability of the measurements
The reliability of the measurements was examined by performing double determinations
on a total of 45 dental radiographs from the ”Kvantti” research material, representing
adult 45,X females and their female and male relatives, with fifteen persons in each
group. The measurements were made without knowing the patient group by the present
author at an interval of two weeks, the marked line joining the mesial and distal cervical
margins of the enamel on each tooth being rubbed out after the first measurement and
determined again and re-drawn for the second measurement. The drawing of the outline
of crown and root remained untouched.
The standard deviation of the differences between the repeated measurements was
calculated and 95% of the differences were expected to lie within the limits of ± 2 SD.
Scatterplot graphics were used to determine the limits of agreement (Bland and Altman
1986).There were only two out of the total of 28 teeth in maxillary anterior region that
showed more variation than ± 2 SD, the standard deviation remaining mainly within the
limits of ± 3 SD, with only one point in the intervals ± 3 - 4 SD. According to these
calculations the root length measurements lied within the assumed limits.
The absolute error values for the root length measurements ranged from 0.35 mm to
0.75 mm, the corresponding percentages being 1.95 and 5.11. The values were considered
acceptable for further measurements.
The reproducibility of the double determinations of root length was expressed in terms
of the method error statistic (Dahlberg 1948). The difference between the first and second
measurements was also analyzed with coefficients of intra-class correlation (Table 3).
45
⎛ ( d1 − d 2 )2
SDd = ⎜ ∑
⎜
2N
⎝
⎞
⎟
⎟
⎠
SDd = standard deviation
d1 = original measurement value
d2 = repeated measurement value
N = number of patients
Table 3. Coefficients of intra-class correlation between the first and second
measurements of tooth root lengths.
Tooth
Maxilla
Mandible
Right second molar
0.948
0.912
first molar
0.889
0.933
second premolar
0.954
0.957
first premolar
0.927
0.890
canine
0.958
0.949
lateral incisor
0.928
0.945
central incisor
0.977
0.948
Left central incisor
0.975
0.942
lateral incisor
0.890
0.955
canine
0.981
0.970
first premolar
0.894
0.965
second premolar
0.950
0.973
first molar
0.932
0.938
second molar
0.966
0.884
4.2.4 Statistical analyses
The SPSS package 12.0 (Statistical Package for the Social Sciences, CA, USA) was used
for the statistical analysis. Mean values for root length were calculated and compared
between the individuals, relatives and population controls using the two-tailed T-test for
equality of means. Results were considered statistically significant when p was less than
0.05. The analysis of variance (ANOVA) was used to find out the significance of
differences between the individual and population control groups. Duncan’s multiple
comparison procedure was used to itemize the differences between the study groups as
homogenous subgroups were concerned with p equal to 0.05.
5 Results
The results are presented by study groups in the original papers and referred to here by
the Roman numerals indicating these papers (I-IV). The summary tables (Tables 4 and 5)
present the means, numbers and standard deviations for the tooth root length
measurements performed on the individuals with sex chromosome abnormalities and the
population controls (men and women). In these summary tables the population controls
comprise parents and siblings of all the individuals grouped together and are taken to
represent the normal population. In the original articles the population controls comprise
relatives of the other individuals. The individuals and their paired relatives of the same
sex were compared in each paper to approach the problem of normal variation.
The analysis of ANOVA indicated that the differences in tooth root length between the
individual and control groups were highly significant. Two-tailed t-test showed
differences between separate groups of individuals and control groups, and these
differences were further supported by the test of Duncan.
5.1 Root lengths in the permanent teeth of 47,XYY males (I)
The mean permanent tooth root lengths in 47,XYY males were larger than those for the
population control men (Tables 4 and 5). The differences were significant in eleven out of
the total of 28 comparisons, and the actual relative metric differences in the mandible
exceeded those in the maxilla in most instances. Visual inspection of the root morphology
on the panoramic radiographs of the 47,XYY males did not reveal any major deviations
from normality.
Comparisons of the mean root lengths between nine 47,XYY males and their brothers
or fathers showed the former measurements to be larger, with only one exception. The
differences were significant in half of the comparisons, and the values for the relatives
came closer to those for the population controls than to those for the 47,XYY males
(Table 2 in paper I).
The root lengths of the population control men were in most cases larger than those of
the control women (Tables 4 and 5), the differences being significant in 15 out of the total
of 28 comparisons. The excess root growth in 47,XYY males relative to normal men was
47
in most cases greater than the difference between the normal men and women, except in
the upper incisors. The mean percentage difference in all root lengths between sexes was
four percent, and that between the 47,XYY males and normal men nine percent.
5.2 Root lengths in the permanent teeth of 46,XY females (II)
The mean permanent tooth root lengths in 46,XY females were larger than those for the
population control women (Tables 4 and 5), the difference being significant in eleven out
of the total of 28 comparisons, with values similar to those in the population control men.
The 46,XY females had significantly longer tooth roots than their sisters in nine out of
the total of 28 comparisons (Table 2 in paper II). Visual inspection of the root
morphology on the panoramic radiographs for the 46,XY females did not reveal any
major deviations from normality.
5.3 Root lengths in the permanent teeth of 45,X/46,XX females (III)
The mean root lengths of the permanent teeth in the 45,X/46,XX females were in most
cases less than those of the population control women (Tables 4 and 5), the differences
being significant in 23 out of the total of 28 comparisons, and the relative differences in
the maxilla exceeded those in the mandible in most instances. The mean percentage
difference for all root lengths between the 45,X/46,XX females and the population
control women was ten percent. The 45,X/46,XX females had shorter tooth roots than
their sisters or mothers, with only one exception (Table 2 in paper III). The differences
were significant in half of the comparisons, and the values for the relative women were
closer to those of the population controls than to those for the 45,X/46,XX females.
5.4 Root lengths in the permanent teeth of 47,XXY males (IV)
The mean permanent tooth root lengths in the 47,XXY males were larger than in the
population control men (Tables 4 and 5), the difference being significant in 12 out of 14
comparisons in the mandible and in the maxillary premolars and molars, and the absolute
values for the maxillary incisors were higher than those for the control men. The 47,XXY
males also had significantly longer tooth roots than the population control women in all
the measurements. The mean difference in all root lengths between the 47,XXY males
and the population control men and women was eight and eleven percent, respectively.
The 47,XXY males had longer tooth roots that their relative men in 22 out of the total
of 28 measurements (Table 2 in paper IV), the absolute lengths of the tooth roots in the
relative men falling mainly between those of the population control men and the 47,XXY
males. Visual inspection of the root morphology on the radiographs of the 47,XXY males
did not reveal any major deviations from normality, but a minor deviation in the form of
taurodontic teeth was observed in 30 percent of cases.
15.6
second molar
10 / 1.3
13 / 2.0
12 / 2.7
11 / 3.7
10 / 1.2
13 / 1.8
15 / 1.9
15 / 2.0
11 / 1.9
14 / 2.8
12 / 2.2
11 / 3.0
12 / 2.5
9 / 2.0
N / SD
15.1
14.7
19.5
19.1
22.7
19.0
21.1
21.7
19.8
23.9
18.0
19.9
14.9
16.4
Mean
3 / 3.0
4 / 3.9
3 / 4.3
4 / 4.5
4 / 2.7
3 / 1.5
5 / 2.4
4 / 2.3
4 / 0.9
4 / 4.1
4 / 1.9
2 / 1.8
3 / 1.6
3 / 2.3
N / SD
46,XY♀
17.4
16.8
19.7
19.9
23.4
20.0
21.1
21.0
19.8
23.3
19.9
19.5
17.4
17.1
Mean
27 / 2.4
21 / 1.7
24 / 2.4
24 / 1.9
25 / 2.7
28 / 2.0
32 / 2.4
33 / 2.4
28 / 1.9
30 / 2.9
29 / 2.2
18 / 2.6
23 / 1.8
24 / 2.2
N / SD
47,XXY♂
15.0
15.0
17.4
18.6
24.1
19.5
20.3
20.3
19.6
24.0
18.7
17.3
15.2
15.6
Mean
40 / 2.5
39 / 1.9
40 / 2.5
37 / 2.3
45 / 1.9
45 / 1.9
44 / 2.2
47 / 2.3
39 / 2.2
42 / 2.2
35 / 2.3
41 / 2.4
41 / 1.8
43 / 2.1
N / SD
46,XY♂
14.3
14.5
17.2
17.0
22.2
18.4
19.1
18.9
18.3
22.0
17.3
17.2
14.7
14.8
Mean
34 / 1.9
34 / 1.8
35 / 1.7
33 / 1.8
39 / 1.9
35 / 1.7
38 / 1.2
39 / 1.4
36 / 1.5
40 / 2.1
32 / 1.8
34 / 1.7
35 / 1.9
36 / 1.9
N / SD
46,XX♀
13.5
13.1
14.7
15.0
19.7
16.4
16.3
15.9
16.0
19.5
15.5
14.8
13.0
13.7
Mean
45,X/46,XX♀=a mosaic female in which a second cell line has the chromosome constitution 45,X (Turner women)
46,XY♂= population control men, relatives of all individuals grouped together; 46,XX♀=population control women, relatives of all individuals grouped together
47,XXY♂=an individual with an extra X or Y chromosome (Klinefelter men)
46,XY♀=a female with a male sex chromosome complement and complete form of androgen insensitivity syndrome (a female sex reversal)
47,XYY♂=a male with an extra Y chromosome
a) Root length refers to the longest root in the case of two roots on the top of the other and the mesial root in the case of multi-rooted teeth on the radiograph.
14 / 1.4
13 / 1.1
12 / 2.2
11 / 2.4
14 / 1.6
15 / 2.4
15 / 2.9
15 / 3.2
14 / 2.5
14 / 2.5
13 / 1.7
14 / 2.3
14 / 1.3
13 / 1.6
N / SD
45,X/46,XX♀
Mean=mean root length (mm), N=number of individuals with sex chromosome abnormalities and 46,XY females or normal controls, SD=standard deviation
16.0
lateral incisor
18.9
20.2
Left central incisor
first molar
20.9
central incisor
second premolar
20.7
lateral incisor
25.4
19.2
canine
18.1
24.6
first premolar
first premolar
18.6
second premolar
canine
16.4
20.2
first molar
16.4
Mean
47,XYY♂
Right second molar
Maxilla
Tooth root
Table 4. Summary table of permanent tooth root length (a) measurements of maxillary teeth for the individuals with sex chromosome
abnormalities, 46,XY females, and normal men and women (I-IV).
48
18.5
second molar
6 / 1.9
10 / 1.8
9 / 2.7
10 / 1.5
13 / 2.4
14 / 2.1
12 / 2.4
13 / 1.8
12 / 1.9
12 / 2.5
13 / 1.8
5 / 1.9
11 / 2.2
9 / 2.8
N / SD
19.2
19.2
19.8
19.0
22.6
17.4
17.0
16.1
16.7
21.7
19.1
20.8
18.3
19.5
Mean
3 / 0.8
3 / 3.2
4 / 2.8
6 / 1.6
7 / 1.8
7 / 1.3
8 / 1.7
6 / 0.8
8 / 1.2
7 / 1.8
6 / 0.9
4 / 1.2
4 / 2.0
4 / 0.9
N / SD
46,XY♀
18.9
20.3
21.1
19.4
22.5
18.7
17.9
17.6
18.6
22.6
19.9
20.7
19.7
18.5
Mean
22 / 2.0
19 / 1.6
20 / 2.1
37 / 1.9
42 / 2.7
43 / 2.0
41 / 1.9
41 / 1.8
41 / 1.9
39 / 2.2
39 / 2.0
22 / 2.3
24 / 1.7
22 / 2.0
N / SD
47,XXY♂
17.2
18.9
19.3
18.9
21.7
17.6
15.6
16.1
17.6
22.5
18.9
19.3
18.9
17.8
Mean
32 / 2.3
35 / 1.7
45 / 2.8
54 / 2.5
54 / 2.8
53 / 2.3
51 / 2.1
52 / 2.1
56 / 2.0
54 / 2.3
52 / 2.5
44 / 2.6
35 / 2.1
33 / 2.2
N / SD
46,XY♂
17.2
17.8
18.8
17.9
19.5
15.7
14.5
14.5
15.7
19.8
17.6
18.2
17.7
17.2
Mean
30 / 1.5
29 / 1.5
39 / 1.7
42 / 1.8
40 / 1.7
44 / 1.8
45 / 1.7
46 / 1.7
45 / 1.7
42 / 2.0
41 / 1.8
36 / 1.9
28 / 1.3
33 / 1.4
N / SD
46,XX♀
15.6
16.2
17.2
16.6
17.7
14.2
13.8
13.5
14.0
17.6
16.2
16.5
16.4
16.0
Mean
To specify the different study groups see Table 5.
a) Root length refers to the longest root in the case of two roots on the top of the other and the mesial root in the case of multi-rooted teeth on the radiograph.
13 / 1.8
12 / 1.3
13 / 2.0
13 / 2.0
14 / 2.2
14 / 1.4
14 / 1.7
13 / 1.7
14 / 1.1
13 / 1.6
14 / 1.3
11 / 2.9
9 / 2.5
13 / 2.0
N / SD
45,X/46,XX♀
Mean=mean root length (mm), N=number of individuals with sex chromosome abnormalities and 46,XY females or normal controls, SD=standard deviation
20.3
lateral incisor
21.7
18.9
Left central incisor
first molar
16.8
central incisor
second premolar
17.8
lateral incisor
24.0
18.8
canine
20.0
23.8
first premolar
first premolar
19.8
second premolar
canine
20.2
20.9
first molar
19.5
Mean
47,XYY♂
Right second molar
Mandible
Tooth root
Table 5. Summary table of permanent tooth root length (a) measurements of mandibular teeth for the individuals with sex chromosome
abnormalities, 46,XY females, and normal men and women (I-IV).
49
6 Discussion
In addition to the population controls, the present study groups included the first-degree
relatives of the individuals with sex chromosome abnormalities and 46,XY females as
controls. This allowed consideration of the possibility that the mean root lengths in
relatives may deviate from the mean values for the population. One relative of the same
phenotypic sex for each individual was chosen and the comparisons were also extended
to the opposite sex if possible. The other criteria were age, generation and the number of
teeth available. The relatives’ values were in most cases closer to the values for the
population controls than to those for the individuals with extra sex chromosomes, such as
47,XYY and 47,XXY males and 45,X/46,XX females with a shortage of sex chromosome
material. The 46,XY individuals who are insensitive to androgens and phenotypically
females had in most cases significantly longer tooth roots than their female relatives. All
in all, the root lengths of the relatives fell within the normal range of variation.
The beam in a dental panoramic radiograph is not perpendicular to the labiolingual
direction of the tooth in most instances, and the inclination of the tooth varies between
dentitions and individuals. Lind (1972), having studied the effect of varying inclination
and slight to moderate rotation of the tooth in relation to the film or beam, found that
these factors did not influence the root/crown ratio by more than 0.1. An even distribution
in these variables was assumed between the study groups. The magnitude of the tooth
inclination in relation to the beam and film can be considered here to lie between the
limits suggested by Tronje et al. (1981): -20 and 30 degrees in the mandible and -15 and
45 degrees in the maxilla.
The fact that the mean root lengths of antimeric teeth differed to some extent may be
due to the sample sizes, the varying numbers of measurements available and general
technical reasons. Certainly, the measurements of natural tooth roots also show
differences between the mean lengths for antimeric teeth (Selmer-Olsen 1949).
Permanent tooth root lengths may be affected by several external factors, which could
bias the results. According to anamnestic information (gathered during the years 19741987), the individuals or their relatives had not had any orthodontic treatment, at least not
with fixed appliances, before the examination procedures. Similarly, anamnestic
information on the population controls suggested that they had not undergone orthodontic
therapy. This is supported by the fact that at the time in question there were only very few
51
dental offices in Finland where fixed appliance orthodontics, or orthodontics in general,
were carried out. Regarding the possible effects of other external factors, the assumption
was made of an even distribution between the study groups.
The main source of error in tooth length measurements in repeated dental panoramic
radiographs has been found to lie in the recognition of the reference points. Larheim et al.
(1984) found only small differences between the tooth groups and between the right and
left sides in tooth lengths in repeated dental panoramic exposures, but they felt that it was
necessary to mark some reference points with a pencil because of difficulties in
recognition. The vertical plane in an orthopantomograph was considered trustworthy
under standardized circumstances (Larheim et al. 1984; Tronje et al. 1981). The problem
in finding the reference points was handled here by marking the outlines of the teeth
directly on the radiograph, with special emphasis on the apical dentin/cementum border,
where there is a slight difference in radiodensity. Furthermore, all the radiographs were
taken using the same machine and by same person, which is important for obtaining
comparable radiographs with this method, where the positioning of the patient in the
machine is most important. Measurement of the tooth length on a panoramic dental
tomogram has been considered a suitable method and permitted us to compare root
lengths between the study groups.
The accuracy of marking the cervical line on a dental panoramic radiograph to
measure the root length was evaluated by performing the measurements twice and
rubbing the cervical line out after the first measurement and re-drawing it for the second.
The coefficients of intra-class correlation of the root lengths between the first and second
measurements were considered reliable for further measurements.
The root lengths were measured as projections of the root apex to the film. Only the
mesial root was included in the calculations in the case of multi-rooted teeth with mesial
and distal roots. In the case of two roots on the top of each other on the radiograph, the
longest dimension was chosen for measurement, as it is impossible to define the labiolingual order in this kind of panoramic radiograph. Mineralization of the hard tissues
during tooth development starts in the mesial part of the crown and it is evident that the
same order continues during root development, expressing a more invariable part of the
tooth.
All in all, the results showed longer final permanent tooth roots in the 47,XYY and
47,XXY males, while the roots in the 45,X/46,XX females were shorter than in normal
men and women, respectively. The root lengths of the 46,XY females were longer than in
normal women and similar to those for normal men. The differences in all measured tooth
root lengths between the individual and control groups were very clear according to the
analysis of ANOVA. When the Duncan test was used to compare the individuals with sex
chromosome abnormalities and population controls, the root lengths of the canines,
maxillary central incisors, and mandibular lateral incisors clearly differed between the
normal men, women and 45,X/46,XX females with a shortage of sex chromosome
material, the men having the longest roots, the mosaic females the shortest and the
normal women lying between them. The root lengths in all the teeth measured clearly
differed between the mosaics (45,X/46,XX females) and the trisomies (47,XXY and
47,XYY males).
The root lengths in the population control men were longer than those in the
population control women, as observed previously (Selmer-Olsen, 1949). Extremely
52
short roots are found more frequently in girls and extremely long roots in boys. The mean
difference between the sexes in the present root lengths was five percent, which is
parallel with the six percent reported by Garn et al. (1978) in mandibular canines,
premolars and molars. The present results regarding tooth root lengths in individuals with
extra and shortage of sex chromosome material and population controls strongly indicate
that the promoting effect of the Y chromosome on growth in root length is greater than
that of the X chromosome. This differential effect may lead to the expression of sexual
dimorphism in root size.
It is known that the crown sizes of the canines show the greatest difference between
the sexes. The root length difference between the present normal men and women in the
canines was found to be twice as great as the mean root length difference between these
groups, being significant according to the test of Duncan. The roots of the canines were
longer in the 47,XYY males, with an extra Y chromosome, than in the normal men, while
in the 47,XXY males and 46,XY individuals (insensitive to androgens and phenotypically
females), the mean root lengths of the canines were close to those in the normal men. On
the other hand, the roots of the canines in 45,X/46,XX females, with a shortage of sex
chromosome material, were very much shorter than in the normal women, which is
parallel with earlier reports based on this and other Turner female groups (Midtbø &
Halse, 1994b).
The root morphology did not reveal any major deviations from normality in either of
the study groups. The 45,X/46,XX females showed the same tendency in root
morphology as described in the 45,X females. A mild form of taurodontism was found in
one third of the roots of the second molars of the 47,XXY males, which is parallel with
the earlier findings that the incidence of taurodontism increases in the presence of an
extra X chromosome. The plump shape of the roots, especially in the maxillary central
incisors, found in a normal population with short roots (Lind 1972) does not appear in the
form of reduced root length in the case of Turner females.
Earlier results regarding tooth crown sizes in 47,XXY males had indicated smaller
mesio-distal crown dentin thickness than in normal men, which was considered to result
from the “retarding” effect of an extra X chromosome (Alvesalo et al. 1991). However,
root dentin formation in the 47,XXY males was greater than that in normal men or
women. Only the root lengths of the canines in the present normal men exceeded the
values for the 47,XXY males. On the other hand, the enamel layer in the tooth crowns of
the 47,XXY males was markedly thicker than in the normal men or women, as is also the
case in 47,XXX females. The mesio-distal crown dentin size in the canines of 47,XXX
females has been shown to be slightly decreased, too (Alvesalo et al. 1987). These
findings need further discussion. Patients with dentinogenesis imperfecta type I with
normal enamel formation but defects in the formation of dentin appear to have smaller
tooth crowns and surely show shorter than normal roots (J. Waltimo-Sirén, personal
communication), which is suggesting of a mesenchymal participation in the crown
growth.
Turner females, including mosaics, 45,X/46,XX females, have smaller tooth crown
sizes with simplified tooth crown shapes and a tendency towards less ordinary cusps in
the molars and shorter roots, due to shortage of sex chromosome material by comparison
with normal women. On the other hand, they have extra cusps and nippled cusp tips in
the premolars and a mamelon pattern of the incisal edges of the lateral incisors and
53
molariform mandibular premolars, and the incidence of root components in dissimilar
variants is increased. It may be that this diversity in the morphology of the tooth crown
and root associated with a shortage of sex chromosome material is affected by different
genetic information than the small and reduced crown size and short roots.
A relationship between tooth size and body size has been suggested (Garn et al.1968).
There is a clear size difference in stature, tooth crown dentin mesio-distal diameter and
root length between normal men and women, with normal men showing larger values. In
individuals with a shortage of sex chromosome material, stature, the enamel layer in the
tooth crowns and tooth root lengths are all smaller than in normal women. On the other
hand, an extra X chromosome increases stature, with modified body proportions, the
enamel becomes thicker and the tooth roots are longer. An extra Y chromosome has the
greatest influence on stature, resulting in similar body proportions as in normal men,
bigger tooth crown sizes and longer roots.
Earlier dental studies have shown that the Y chromosome genes promote growth of the
permanent tooth crown, both the enamel and the dentin, whereas the effect of the X
chromosome genes on crown formation seems to be restricted mainly to the enamel. The
formation of enamel is decisively influenced by the cell secretory function, and dentin
formation in the crown by cell proliferations or mitotic activity. It has been suggested that
the effect of the Y chromosome, particularly in increasing cell proliferations, explains the
expression of sexual dimorphism in crown size and shape, maturation and the number of
teeth, i.e. supernumerary permanent teeth are approximately twice as common in normal
males as in normal females and permanent ordinary teeth are more frequently missing in
females than in males. Moreover, assuming genetic pleiotropy, the expression of the torus
mandibularis, statural growth and the sex ratio (the ratio of the number of males to that of
females) at birth and in the earlier stages of development are explained by this effect of
the Y chromosome (Alvesalo 1985; Alvesalo 1997). The present results show that the
effect of an extra X and Y chromosome on the promotion of dental development
continues in the form of root dentin, which is influenced by cell proliferations, as was the
formation of crown dentin before it. In accord, the tooth roots remain shorter than normal
in individuals with a shortage of sex chromosome material. It is suggested that root
formation may be affected by the same genes on the X and Y chromosomes that promote
crown development.
In terms of population dental developmental standards (Haavikko 1970), the final size
of the permanent tooth roots (excluding the third molars) becomes evident during a
period beginning eight years after birth and continuing up to the age of 14 years, at least.
Consequently, the present results indicate that the changes in tooth root lengths in all
study groups become evident in final form within these time limits. Previous results
regarding tooth crowns indicate that they reach their final size and shape between the
ages of two months and eight years.
The possible effect of hormones as causative factors leading to changes in root growth
in these groups of patients was considered. The hormone levels of 47,XYY males can be
considered normal, but 47XXY males have insufficient testosterone production.
45,X/46,XX females with a shortage of sex chromosome material lack primary oestrogen.
Because of the androgen insensitivity of 46,XY females, dental growth excesses in this
group of individuals conceivably would develop independently of the possible influence
of the androgens. All in all, it is difficult to explain that the differences in root lengths
54
between the individuals result from hormone production, hormone balance, hormone
treatment or insensitivity to hormone.
It became clear that the effect of the Y chromosome on tooth root growth is greater
than that of the X chromosome, and it is conceivable that this may lead to the sexual
dimorphism observed in root length, men having longer roots than women. The location
of the crown growth-promoting region is apparently on the long arm of the Y
chromosome and the short arm of the X chromosome (Alvesalo & Chapelle 1981;
Mayhall et al. 1991) as is also the location of the tooth root growth-promoting region, as
suggested. It is of interest that the gene for amelogenin, which is the main protein
component of the enamel matrix, has been located on either the long or short arm of the Y
chromosome and on the short arm of the X chromosome (Lau et al. 1989).
Future work will be devoted to tooth root growth in 47,XXX, 48,XXXX, and
46,X,i(Xq) females, focusing on varying X chromosome constitutions. Another topic of
interest will be heights of the tooth crowns.
7 Conclusions
The results pointed to longer tooth roots in humans due to additional sex chromosomes
and shorter roots due to a shortage of sex chromosome material by comparison with the
normal population. In 46,XY females, who are insensitive to androgens and
phenotypically women, root size was considered similar to that of normal men.
It is also concluded that:
− final tooth root size changes in these groups of individuals apparently become evident
during a period beginning at the age of eight years after birth and continuing at least
up to the age of 14 years.
− the effect of the Y chromosome on root growth is greater than that of the X
chromosome.
It is suggested that the genes on the X and Y chromosome that affect tooth crown growth
are also expressed in the following root growth and may lead to sexual dimorphism in
root length, men having longer roots than women.
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Original articles
I
Lähdesmäki R, Alvesalo L (2004) Root lengths in 47,XYY males’ permanent teeth. J
Dent Res 83: 771-775.
II
Lähdesmäki R, Alvesalo L (2005) Root growth in the teeth of 46,XY females. Arch
Oral Biol 50: 947-952.
III Lähdesmäki R, Alvesalo L (2006) Root growth in the permanent teeth of
45,X/46,XX females. Eur J Orthod 28: 339-344.
IV Lähdesmäki R, Alvesalo L. Root growth in the teeth of Klinefelter (47,XXY) men
(manuscript).
I thank International & American Associations for Dental Research (I), Elsevier Ltd. (II),
and Oxford University Press (III) for their permission to reprint the original papers in this
thesis.
Original publications are not included in the electronic version of the dissertation.
D855etukansi.fm Page 2 Thursday, September 7, 2006 9:03 AM
ACTA UNIVERSITATIS OULUENSIS
SERIES D MEDICA
870.
Hinkula, Marianne (2006) Incidence of gynaecological cancers and overall and
cause specific mortality of grand multiparous women in Finland
871.
Syrjäpalo, Kyllikki (2006) Arvot ja arvostukset psykiatrisessa hoidossa.
Henkilökunnan ja potilaiden näkemyksiä hoidon nykytilasta
872.
Karinen, Liisa (2006) Chronic chlamydial infection: impact on human reproductive
health. Reproductive health research in the Northern Finland 1966 Birth Cohort
(NFBC 1966)
873.
Silvennoinen, Laura (2006) ERp57—Characterization of its domains and
determination of solution structures of the catalytic domains
874.
Sorppanen, Sanna (2006) Kliinisen radiografiatieteen tutkimuskohde.
Käsiteanalyyttinen tutkimus kliinisen radiografiatieteen tutkimuskohdetta
määrittävistä käsitteistä ja käsitteiden välisistä yhteyksistä
875.
Erola, Tuomo (2006) Deep brain stimulation of the subthalamic nucleus in
Parkinson's disease. A clinical study
876.
Mäkinen, Tiina M. (2006) Human cold exposure, adaptation and performance in a
northern climate
877.
Autio, Reijo (2006) MRI of herniated nucleus pulposus. Correlation with clinical
findings, determinants of spontaneous resorption and effects of anti-inflammatory
treatments on spontaneous resorption
878.
Laurila, Jouko (2006) Surgically treated acute acalculous cholecystitis in critically
ill patients
879.
Pakkanen, Outi (2006) Assembly and secretion of recombinant human collagens
and gelatins in the yeast Pichia pastoris, and generation and analysis of knock-out
mice for collagen prolyl 4-hydroxylase type I
880.
Neubauer, Antje (2006) Expression and analysis of recombinant human collagen
prolyl 4-hydroxylase in E. coli and optimization of expression
881.
Koivula, Marja-Kaisa (2006) Autoantibodies binding citrullinated type I and II
collagens in rheumatoid arthritis
882.
Kervinen, Marko (2006) Membranous core domain of Complex I and
mitochondrial disease modeling
883.
Rytkönen, Jani (2006) Effect of heat denaturation of bovine milk beta-lactoglobulin
on its epithelial transport and allergenicity
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D 885
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UNIVERSITY OF OULU P.O. Box 7500 FI-90014 UNIVERSITY OF OULU FINLAND
U N I V E R S I TAT I S
S E R I E S
SCIENTIAE RERUM NATURALIUM
Professor Mikko Siponen
HUMANIORA
Professor Harri Mantila
TECHNICA
Professor Juha Kostamovaara
MEDICA
Professor Olli Vuolteenaho
ACTA
U N I V E R S I T AT I S O U L U E N S I S
Raija Lähdesmäki
E D I T O R S
Raija Lähdesmäki
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O U L U E N S I S
ACTA
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SEX CHROMOSOMES
IN HUMAN TOOTH ROOT
GROWTH
RADIOGRAPHIC STUDIES ON 47,XYY MALES,
46,XY FEMALES, 47,XXY MALES AND
45,X/46,XX FEMALES
SCIENTIAE RERUM SOCIALIUM
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ISBN 951-42-8169-1 (Paperback)
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ISSN 0355-3221 (Print)
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FACULTY OF MEDICINE,
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