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2. INDIAN DENTAL ACADEMY
Leader in continuing dental education
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3.
INTRODUCTION
ROLE OF NEURAL CREST CELLS
VERTEBRATE HOX GENES
VERTEBRATE HOX CODE
PATTERNING THE BRANCHIAL REGION OF THE
HEAD
PATTERNING OF FACE AND JAWS
PATTERNING THE MIDLINE
PATTERNING OF THE DENTITION
GENETIC INFLUENCE ON TOOTH NUMBER, SIZE,
MORPHOLOGY, POSITION AND ERUPTION
HERITABILITY OF MALOCCLUSION
FAMILY AND TWIN STUDIES FOR HERITABILITY
OF DENTOFACIAL PHENOTYPES
GENETIC FACTORS AND HERITABILITY OF
VERTICAL DIMENSION MALOCCLUSION
HERIABILITY OF LOCAL OCCLUSAL VARIABLES
GENOMICS AND OROFACIAL CLEFTS
CRANIOFACIAL SYNDROMES
CONCLUSION
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4. INTRODUCTION
The advent of molecular biology has allowed
biologist to uncover, characterize, and ultimately
manipulate the genes. We can now study how genes
and proteins operate within their natural habitats.
This is significantly furthering our understanding of
the fundamental principles of development, how
genes control cell behavior and thus, how they
determine the pattern and form of an embryo.
Without this knowledge of gene activity and the
relevant cellular signaling pathway, elucidating the
mechanism that control development would be
impossible. These advances are now influencing
dentistry and clinical genetics with almost daily
progression in explaining the basis of multitude of
congenital malformation, skeletal and dental
abnormalities.
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5.
Generation of craniofacial complex is a process that
requires considerable organization. The vertebrate
head is a composite structure whose formation begins
early in development as the brain is beginning to
form. Central to the development of a head is a
concept of segmentation; manifest in the hindbrain
and branchial arch systems.
In conjunction with migrating neural crest cells these
systems will give rise to much of the head and neck
and their associated, individual compartments. It is
now becoming clear that the molecular control of
embryonic resides at the level of the gene, in
particular, within families of genes that encode
transcription factors capable of regulating
downstream gene transcription.
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6. ROLE OF THE NEURAL CREST CELLS
The neural crest is a highly pluripotent cell population that
plays a critical role in the development of the vertebrate head.
Unlike most parts of the body, the facial mesenchyme is
derived principally from the neural crest and not the mesoderm
of the embryonic third germ layer.
Neural crest cells migrates extensively throughout the embryo
in four overlapping domains (Cephalic, trunk, sacral and
cardiac) and in the developing head the cephalic neural crest
migrates from the posterior midbrain and hindbrain regions
into the branchial arch system.
The ectomesenchymal neural crest cells that interact with
epithelial and mesodermal population present within the
arches, leading to the formation of craniofacial bone, cartilage
and connective tissue.
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7. VERTEBRATE HOX GENES
In the early 1980s biologists began searching for genes
containing the Drosophila homeobox in vertebrates,
reasoning that the highly conserved nature of the
homeobox between homeotic genes might have been
preserved during evolution. In a landmark evolutionary
survey, using DNA from a variety of species, it was
shown that the homeobox is not confined to insects, but
is also found in vertebrates.
The first vertebrate homeobox was rapidly cloned in the
frog, Xenopus levis and this was soon followed by the
mouse. The degree of sequence similarity to the
Drosophila homeobox was remarkable, confirming that
the genetic control of development was more universal
than previously imagined. These vertebrate genes are
called Hox genes, and as more were cloned it became
clear that during the course of evolution considerable
duplication a divergence had occurred from the original
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ancestral cluster.
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8.
In the mouse and human genomes there are 39 Hox
genes related to Drosophila homeotic genes. These
Hox genes are arranged in four clusters (instead of one
in the fruitfly) on four different chromosomes: Hox a-d
in mice and HOZ A-D in man (Scott, 1992)
9. VERTEBRATE HOX CODE
The expression of Hox genes in the vertebrate embryo can be seen
along the dorsal axis with the CNS from the anterior region of the
hindbrain throughout the length of the spinal cord. The patterns of
these genes show a very precise spatial restriction. Each Hox genes
is expressed in and overlapping domain along the anteriorposterior axis of the embryo, but each gene has a characteristic
segmental limit of expression at its anterior boundary.
10.
In the developing head, this spatially
restricted limits of Hox gene expression
corresponding to rhombomeres boundaries at
two-segment intervals.
As the neural crest migrates from the
rhombomeres into specific branchial arches it
retains the particular combination or code of
Hox genes expression that is characteristic of
the rhombomeres from which it originated.
Thus, the neural crest from each axial level
conveys a unique combinatorial Hox code.
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11.
It should be noted that the neural crest destined
for the first brachial arch, from which the
maxillary and mandibular process develop,
doesn’t express Hox genes related to the
homeotic homeobox (Hunt et al 1991).
It is subfamilies of homebox genes, more
diverged from the ancestral Hox genes, that are
expressed in spatially restricted patterns within
the first brachial arch (MacKenzie et al
1992;Sharpe et al 1995).
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12.
Fundamental to the development of the
craniofacial complex is the central nervous
system (CNS). The CNS arises from the neural
plate, a homogenous sheet of epithelial cells
that forms the dorsal surface of the gastrula
stage embryo.
As the neural plate rolls up along its AP axis to
form the neural tube the enlarged anterior end
partitions into three vesicles. These vesicles are
the primordial of the developing forebrain
(prosencephalon), midbrain (mesencephalon),
and hindbrain (rhombencephalon).
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13. • It is the rhombencephalic-derived neural crest
that will give rise to the majority of the brachial
arch mesenchyme. Migration of these populations
of the neural crest cells from the regions of the
rhombecephalon results in a ventral relocation to
within the brachial arches.
• Development of the mid-brain and lower regions
of the craniofacial complex is intimately associated
with these branchial regions. It is clear, therefore,
that the neural crest derived from the hindbrain is
essential for normal formation of the face and neck.
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14.
The hindbrain itself
is known to be a
segment structure
composed of eight
subunits called
rhombomeres
(Lumsden and
Keynes, 1989).
Rhomomeres are
important segmental
unit of organization,
which have distinct
morphological
properties that vary
with a two-segment
periodically.
15. PATTERNING OF FACE AND JAWS
In humans a number of other homeobox-containing
genes are expressed in the maxillary and mandibular
arches, and developing facial primoridia. These
genes, which all encode homeodomain–containing
transcription factors, include Msx-1, Msx-2, Dlx1-6
and Barx-1. Again many of these homeoboxcontaining genes are related to the families of gene
found in Drosophila. Knockout studies have
confirmed that these genes perform essential roles
during the formation of the facial complex.
Members of the Msx gene family (Msx-1 and Msx-2)
are normally expressed strongly in the neural crest
derived mesenchyme of the developing facial
prominence, and there is now strong evidence for a
role of these genes in specification of the skull and
face (Ferguson 2000).
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16.
Targeted disruption of Msx-1 in the mouse produces
a number of defects in facial structures. There is
cleft palate associated with a loss of the palatine
bones, maxillary and mandibular hypoplasia, and a
highly penetrant arrest of tooth formation at the bud
stage of tooth development (Satokata and Maas).
In mice, defects in Msx-2 cause skull ossification
with persistence of calvarial foramen. This arises as
a result of defective osteoprogenitor proliferation
during calvarial morphogenesis (Satokata et al,
2000).
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17. • Members of the multi-gene Dlx family are
expressed in a complex pattern within the embryonic
ectoderm and mesenchyme of the maxillary and
mandibular processes of the first arch (Bulfone et al,
1993).
• Targeted mutation in Dlx-1, Dlx-2 and Dlx 1/2
provide evidence that these genes are required for
the development of neural crest derived skeletal
elements of the first and second branchial arches
(Qui et al, 1997).
• Analysis of these mutations reveals that Dlx-1 and
Dlx-2 regulate proximal first arch structures and
that, in the mandibular primordium, there is
considerable functional redundancy of Dlx-1 and
Dlx-2 with other members of the Dlx family.
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18. GOOSECOID GENE
Goosecoid is another homeobox-containing
transcription factor, originally isolated in
Xenopus from a dorsal blastopore lip cDNA
library. The dorsal blastopore lip has long been
known to be ultimately responsible for
organization of the complete body axis in the
early embryo.
However, when goosecoid was knocked out in
transgenic mice they formed a body axis
normally, but exhibited a number of craniofacial
defects (Rivera- Perez et al; Yamada et al, 1995).
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19. In wild type mice, goosecoid transcripts had been
detected at later stages of development in the
osteogenic mesenchyme of the developing mandible,
tongue and middle ear. In mutants, the mandible was
hypoplastic, and lacked coronoid and angular process,
whilst there were defects in several bones, including
the maxillary, palatine, and pterygoid.
As a homeobox–containing transcription factor it
would appear that goosecoid is involved in essential
inductive tissue interactions during the formation of
the head.
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20. ENDOTHELIN
Another gene that has produced an even more
perplexing phenotype is Endothelin-1 which
encodes a vasoactive peptide expressed in
vascular endothelial cells and is thought to play a
role in the regulation of blood pressure. Mice
with targeted disruption of Endothelin-1 have no
abnormalities of their cardiovascular system but
do have a marked reduction in tongue size,
micrognathia and cleft palate (Kurihara et al,
1994).
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21. •One of the two G protein-coupled endothelin
receptors, ET-A is expressed in the neural crest
derived ectomesechyme of the branchial arches,
whilst its primary ligand, ET-1 is expressed in arch
epithelium, pharyngeal pouch endothelium, and arch
core paraxial mesoderm. The ET-A/ET-1 pathway
appears to be important for proper patterning of the
caudal regions of the first arch (Tucker et al, 1999).
•Target disruption of ET-A or ET-1 in mice produce
craniofacial defects that resemble a human condition
called CATCH-22, which is characterized by
abnormal facies and cardiovascular defects (Wilson et
al, 1993).
•It has been recently been shown that the craniofacial
defects in ET-A mice are, in part, due to an absence of
the goosecoid transcription factor (Cloutheir et al,
1998).
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22. PATTERNING THE MIDLINE
Sonic hedgehog (Shh) is the vertebrate homologue of
the Drosophila hedgehog segment polarity gene.
Hedgehog morphogens are involved in the control of
left-right asymmetry, the determination of polarity in
the central nervous system, somites and limbs, and in
both organogenesis and the formation of the skeleton.
In the vertebrate embryo, Shh encodes a signaling
peptide that is involved in a number of wellcharacterized developmental signaling centers
(Hammer Schmidt et al, 1997).
Recently, clues about the regulation of craniofacial
morphogenesis have come from studies of Shh gene.
Mutations of Shh in the mouse (Chiang et al 1996) and
human (Belloni et al 1996) leads to profound
abnormalities in craniofacial morphogenesis
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23.
Loss of Shh produces defective patterning of the
neural plate resulting in holoprosencephaly, a failure
of cleavage in the midline forebrain and cylopia.
Later in development Shh is expressed in the
ectoderm of the fronto-nasal and maxillary
processes and has been shown to be essential for
their normal development (Wall and Hogan, 1995;
Helms et al 1997).
By manipulating developing chick embryos, it has
been shown that a transient loss of Shh signaling in
these regions of the developing face can result in
defects analogous to hypotelorism and cleft
lip/palate, which are characteristic features of the
milder form of holoprosencephaly. In contrast,
excess Shh leads to medio-lateral widening of the
fronto-nasal process resulting in hypertelorism. In
severe cases this can lead to facial duplication (Hu
and Helms, 1999).
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24. HOX CODE
The hindbrain region of the developing neural tube
from which the neural crest migrates is segmented
into eight rhombomeres. Segment specific
combinatorial Hox gene expression specifies each
rhombomeres identity. The migrating neural crest
carries this Hox code defined patterning which is
transferred to the branchial arches (Lumsden et al).
The hox code thus sets up regional diversity within
the branchial arch system. It is plausible therefore,
that the Hox code of those cells migrating to the
tooth forming regions is responsible for specifying
and patterning the dentition.
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25. • However, the genes are not expressed in region
rostral to rhombomeres 2, which means that no Hox
gene expression is seen in the neural crest that
migrates to the craniofacial region, including the
first branchial arch (Hunt et al 1991).
• In terms of patterning tooth development, we have
to look at a subfamily of homeobox genes that do
show temporal and spatial patterns of expression
within the first branchial arch.
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26. ODONTOGENIC HOMEOBOX CODE
Based upon such highly specific domains of
expression, it has been suggested that these
odontogenic homeobox genes provide a
homeobox code that specific regions of the
developing jaws to assume odontogenic potential
(Sharpe et al 1995).
Various odontogenic homeobox genes identified
were,
1) MSX genes → Msx-1, Msx-2
2) DLX genes → Dlx-1, Dlx-2
3) BARX genes → Barx-1, Barx-2
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27. • Each specific region of the homeodomain
expresses a unique combination of homeobox
genes, which monitor the development of specific
teeth. The molecular basis of this patterning is the
differential expression of the coded homeobox
nuclear proteins that regulate downstream gene
transcription.
• The proteins of this homeodomain act as
transcription factors that result in activation or
inhibition of other genes. These homeobox genes
also regulate the expression of other target genes.
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28. MSX genes
MSX is an important gene involved in tooth
formation. MSX stands for muscle segment
homeobox gene. Campbell et al (1989) reported
that MSX was homologous to mouse Homeobox
gene 7 (Hox 7) and Bell et al (1993) related it to the
Drosophila gene muscle-segment homeobox (msh).
Ivens et al (1990) localized this gene to
chromosome 4p16.1 and mutation of this gene has
been associated with facial and dental
abnormalities.
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29.
MSX-1 and MSX-2 genes:
MSX 1 gene is expressed in migrating neural crest
cells and later in mesenchymal cells of dental papilla
and follicle.
MSX-2 genes are involved in signaling interactions,
which are essential for the tooth development.
30.
Prior to the initiation of odontogenesis both Msx-1 and
Msx-2 exhibit very specific horseshoe-shaped fields of
corresponding mesenchymal expression in the anterior
regions of the first arch (McKenzie et al 1992).
These expression patterns are coincident except along
their posterior border where the expression of Msx-1
extends further than Msx-2.
This region of isolated mesenchymal Msx-1 expression
corresponds to the position of the future primary
epithelial thickening. As tooth development progresses
the expression of Msx-1 becomes localized in the
mesenchymal cells of the dental follicle and papilla.
The domains of expression of Msx-2 also become more
restricted to the dental follicle and papilla, but unlike
Msx-1, Msx-2 is also expressed strongly in the enamel
organ.
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31. DLX genes
Dlx genes are expressed in migrating neural crest
cells and in the first brachial arch. DLX stands for
distal-less homeobox gene.
McGuiness et al (1996) first reported the distal-less
Homeobox gene (Dlx2), which was localized at
chromosome 2q32 loci. The DLX genes have also
been conserved during evolution and bear homology
to the distal-less gene of Drosophila (Porteus et al,
1991).
DLX-1 and DLX-2 genes:
The expression of Dlx-1 and Dlx-2 in the maxillary
and mandibular arch mesenchyme is restricted to the
proximal regions where the future molar teeth will
develop.
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32. BARX genes
BARX stands for Bar class Homeobox gene
that includes Barx-1 and Barx-2. Barx-1 is
homeobox containing transcription factor that
exhibits regionalized expression within the
ectomesenchyme of the first branchial arch
(Tissier-Seta et al, 1995).
Bar class homeobox 2 genes (Barx-2) is also a
group of homeodomain transcription factors.
This group of Homeobox genes was first
located in Drosophila in the locus 11q25.
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33. • Prior to the appearance of the primary epithelial
thickening Barx-1 (along with Dlx-2) is expressed in
the posterior regions of the first branchial arch
mesenchyme, the region of future molar
development. There is no Barx-1 expression in the
anterior regions. As tooth development proceeds,
Barx-1 expression becomes localized exclusively to
the mesenchymal regions around the developing
molars (Thomas and Sharpe, 1998).
• Jones et al (1999) suggested that the mutation of
these genes could be associated with facial and
dental anomalies.
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34. PAX genes
Paired-box homeotic gene (PAX) is found in
2q35 locus. PAX gene products function by
binding enhancer DNA sequences and they
modify transcriptional activity of downstream
genes. There are nine PAX genes organized into
four groups (Pax1 to Pax9). Of these genes,
Pax9 is associated with the development of
teeth.
Nebuser et al (1997) associated PAX9
transcription factor with tooth bud positioning at
the mesenchymal level and mutations in this
gene results in conditions such as hypodontia,
transposition etc.
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35. HEDGEHOG GENE
Sonic Hedgehog gene (Shh) is located in 7q36
and is the vertebrate homologue of Drosophilia
hedgehog gene. Shh is expressed in the
epithelial thickenings of the tooth forming
regions. Shh along with bone morphogenetic
protein (BMP-4) determines the position of
future forming tooth germs.
Shh is necessary for initiation of tooth
development, epithelial signaling and cuspal
morphogenesis. The interaction of Shh gene
with other target genes like Gli is also
imperative for tooth formation.
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36. • Gli Zinc transcription factors are known to act
downstream of Shh gene. There are three subtypes
namely Gli-1, Gli-2 and Gli-3, which play a vital role in
tooth development. Mutant Gli-2 gene results in the
formation of abnormal incisors.
• When Gli-2 and Gli-3 were affected, maxillary incisor
development was absent and sizes of mandibular incisors
were reduced. When Gli-3 alone was affected, there was
no damage in the development of incisors.
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37. Inger kjaer (EJO 2001) reported that
less severe cases of holoprosencephaly
is characterized by a solitary median
maxillary central incisor (SMMCI)
38. ODONTOGENIC EPITHELIAL – MESENCHYMAL
INTERACTIONS THROUGH GROWTH FACTORS
The molecular basis for odontogenesis is dependent
upon many of the diffusible protein signaling
molecules and growth factors that are known to
mediate reciprocal signaling between cells groups in
epithelium and mesenchyme during tooth
development.
A number of intercellular protein molecules have
been identified in the developing tooth germ at
various stages of development. Among those factors,
Fibroblast growth factors (FGFs) and Bone
morphogenetic protein (BMPs) are essential for
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39. FIBROBLAST GROWTH FACTORS (FGFs)
FGFs are proteins involved in the growth and
differentiation of odontogenic cells during tooth
development. FGF is a family of heparin binding
proteins, which is expressed in tooth germs and regulates
epithelial-mesechymal interactions.
FGF-4, FGF-8 and FGF-9 play an important role in
odontogenesis.
FGF-4 and FGF-9 are essential for determing the coronal
morphology and FGF-8 and 9 are vital for initiation of
tooth development. FGF-4 has been suggested to play a
key role in stimulating the proliferation of dental
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and mesenchyme.
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40. BONE MORPHOGENETIC PROTEIN (BMPs)
• Bone morphogenetic protein is a group of
dimeric proteins, which come under the
classification of Transforming Growth factor β.
Bone Morphogenetic Proteins, are responsible for
osteoinductive activity in bone matrix and
cartilage. BMPs are expressed in the condensed
mesenchymal cells of bone primordial, and
appear that different BMPs are expressed in
different bones.
• Nearly 20 modifications of BMPs with slightly
different modifications in small secondary
structure elements have been identified.
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41. In odontogenesis, epithelial-mesenchymal interactions
play a paramount role in the formation of hard tissue.
BMP’s are known to have a broad range of signaling
functions involving mediation of tissue interactions.
BMP-2, BMP-4 and BMP-7 have been associated
with epithelial mesenchymal interaction during the
morphogenesis stage of tooth formation.
BMP-4 is capable of inducing the expression of MSX1
and MSX-2. BMP-4 also determines the positions of
future forming tooth germs.
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42. GENETIC INFLUENCE ON TOOTH NUMBER,
SIZE, MORPHOLOGY, POSITION, AND
ERUPTION.
Various developmental dental disorders, which are
under the influence of genes, include,
1) Hypodontia
2) Supernumerary teeth
3) Abnormal tooth shape
4) Submerged primary molars
5) Ectopic eruption and Transposition of canines
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43. HYPODONTIA
The congenital absence of teeth may be referred to
as hypodontia, when one or several teeth are
missing, or anodontia when there is a complete
absence of one or both dentitions. Features
include,
More common in permanent than primary
dentition
Absence of primary teeth associated with absence
of permanent successors
May be associated with other developmental
anomalies
Grahnen (1956) in his familial and twin studies
revealed the hereditary nature of hypodontia and
concluded that in children with missing teeth, up
to half of their siblings or parents also had missing
teeth.
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44. • Osborne et al (1958) in his twin studies have shown
that tooth crown dimensions are strongly determined by
heredity..
• Gruneberg (1965) suggested that a tooth germ must
reach a critical size during a particular stage of
development or the structure will regress, and Suaraz and
Spence (1974) showed that hypodontia and reduction in
tooth size are in fact controlled by the same or related
gene loci. It is apparent from all the evidence in this
respect that tooth size fits the polygenic multifactorial
threshold model.
• Markovic (1982) found a high rate of concordance for
hypodontia in monozygous twin pairs, while zygous twin
pairs he observed discordant. These and other previous
studies concluded that a single autosomal dominant gene
could explain the mode of transmission with incomplete
penetrance.
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45. Dermaut and Smith (AJO1997) studied the
prevalence of tooth agenesis correlated with jaw
relationship and dental crowding in 185 patients
and found that,
• Hypodontia occurred more often in girls than in
boys.
• The upper lateral incisors and lower premolars
were the most frequently missing teeth.
• Class I skeletal relationships were found more
often in patients with agenesis than in patients
without missing teeth and are associated with
deep-bite growth patterns
• The molecular genetics of tooth morphogenesis
with the homeostatic Hox 7 and Hox 8 (now
referred as Msx-1 and Msx-2) genes are being
responsible for stability in dental patterning.
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46.
Clinical evidence suggests that congenital absence
of teeth and reduction in tooth size are associated
e.g., hypodontia and hypoplasia of maxillary
lateral incisors frequently present simultaneously.
Numerous pedigrees have been published linking
the two characteristics and implying that they are
different expressions of the same disorder
Vastardis (Nature Genetics 1996) studied the cause
for selective tooth agenesis in human, where
missense mutation occurred in the MSX-1
homeodomain. This occurs as a consequence of
replacement of arginine with proline protein
(Arg31Pro mutation) in the homoedomain of
MSX1. Tooth agenesis was reported in a family
with a ser105 stop mutation of MXS-1 gene
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47. Research work by Cobourne (BJO 1999) on
families affected with hypodontia has revealed that
it is transmitted as an autosomal dominant disorder
with variable expressivity and incomplete
penetrance. Missing maxillary laterals and
mandibular second premolars have been associated
with defects in MSX-1and MXS-2 genes.
Van den Boogard et al (Nature Genetics 2000)
observed a genetic aberration in a Dutch family
with tooth agenesis. A stop codon in MSX-1
mutation was identified implying the involvement
of this gene in tooth agenesis.
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48.
Nieminen (Eu J of Human Genetics 2001) found that, a
non-sense mutation in the PAX-9 gene was associated
with molar tooth agenesis in a Finnish family. The
A340T transversion creates a stop codon at lysine 114,
and truncates the coded PAX-9 protein at the end of the
DNA-binding paired box. The tooth agenesis
phenotype involved all permanent second and third
molar and most of the first molars.
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49. Lidral (JDR 2002) concluded that a mutation in MSX-1
gene in chromosome 4 has been identified as the
causative factor for oligodontia involving the absence of
all second premolar and third molar. Missing first molar
and second molars have been linked with a substitution
mutation of MSX-1 gene.
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50.
With the help of molecular genetics techniques, Peck
and Peck (AJO 2002) assessed a family exhibiting an
autosomal dominant trait of missing second premolar
and third molars. The affected chromosome was
isolated to be in a chromosome 4p and many genes
were considered to be responsible for this tooth
agenesis. A point mutation was detected in the MSX 1
gene in all affected family.
Also mutation of PAX-9 transcription factors has been
observed in familial tooth agenesis and also in missing
mandibular second premolars and central incisors.
Recently Viera (JDR 2003) suggested that a fourth
mutation has been found in MXS-1 gene, which was
Met611Lys and was associated with missing second
premolar and third molars.
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51. SUPERNUMERARY TEETH
These are teeth additional to those of the normal series.
A mesiodens is a supernumerary tooth occurring
between the maxillary central incisors and is the most
common of all supernumerary teeth. Supernumerary
teeth most frequently seen in the pre-maxillary region
and with a male sex prediction also appear to be
genetically determined.
Niswander and Suguku (1963) analyzed the data from
family studies and have suggested that, like
hypodontia, the genetics of the less prevalent condition
of supernumerary teeth in under the control of number
of different loci.
Brook (1980) found that mesiodens is more commonly
present in parents and siblings of patients who present,
although inheritance does not follow a simple
Mendelian pattern. Evidence from twins with
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supernumerary teethmalso supports this theory (Jasmin
52. ABNORMAL TOOTH SHAPE
Alvesalo and Portin (1969) provided substantial
evidence supporting the view that missing and
malformed lateral incisors may be the result of a
common gene defect.
Abnormalities in the lateral incisor region varies from
peg shaped to microdont to missing teeth, all of which
have familial trends, female preponderance, and
association with other dental anomalies, such as other
missing teeth, ectopic canine, and transpostion,
suggesting a polygenic etiology.
Aspects of tooth morphology such as the Carabelli
trait also seem to be strongly influenced by genes as
evidenced by Australian twin study (Townsend and
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Martin, 1992).
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53. SUBMERGED PRIMARY MOLARS
Primary molar submergence occurs most often in the
mandibular arch with a wide variation in the reported
population (Kurol, 1980).
Helpin and Duncan (1986) found that, the siblings of
children with submerged primary molars are likely to
also be affected and in monozygous there is a high rate
of concordance indicating a significant genetic
component in the etiology. It is also of interest that a
variety of abnormalities are also associated with tooth
submergence with a suggestion that this may
encompass different manifestations of one syndrome,
each manifestation having incomplete penetrance and
variable expressivity.
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54. ECTOPIC ERUPTION AND TRANSPOSITION OF
CANINES
Various studies in the past have indicated a genetic
tendency for ectopic maxillary canines.
Zilberman et al (1990) and Peck et al (1994) concluded
that palatally ectopic canines were an inherited trait,
being one of the anomalies in a complex of genetically
related dental disturbances often occurring with
missing teeth, tooth size reduction, and other
ectopically positioned teeth.
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55. Peck et al (1993) classified a number of different
types of tooth transposition in both maxillary
and mandibular arches, with maxillary
canine/first premolar class position being the
most common.
• They also provided strong evidence of a
significant genetic component in the cause of
this most common type of transposition in that
there was,
• A familial occurrence
• Bilateral occurrence in a high percentage of
cases
• Female predominance and a difference in
different ethnic groups
• An increased frequency of associated dental
anomalies; tooth agenesis and peg-shaped
maxillary lateral incisors were also reported.
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56. • Previous studies by Mossey et al (1994) have also
shown an association between ectopic-maxillary
canine and Class II div 2 malocclusion, a genetically
inherited trait.
• Neubuser et al (1995) found that PAX-9
transcription factor is associated the genetic
mechanism for tooth displacement anomalies, such as
palatally displaced canines and canine transposition.
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57. HERITABILITY OF MALOCCLUSION
Malocclusion may be defined as a significant
deviation from what is defined as normal or ideal
occlusion – Andrews 1972.
There is dental anthropological evidence that
population groups that are genetically homogenous
tend to have normal occlusion. In pure racial
stocks, such as a Melanesians of the Philippine
islands, malocclusion is almost non-existent.
However, in heterogeneous population the
incidence of jaw discrepancies and occlusal
disharmonies is significantly greater.
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58.
Stockard (1941) carried out breeding experiments
with dogs and produced gross orofacial deformities
and associated malocclusions. He concluded that
individual features of the craniofacial complex could
be inherited independently of other portions of the
skull, and that jaw size and the tooth size could be
inherited independently, and as genetically dominant
traits.
Harris et al (1963) recommended that any study of
genetic examination using line and angles requires
the use of multitriate analysis in order to identify
relationship while Kraus et al (1959) criticized the
use of lines and angles to study heredity, and
preferred superimpositions of bony profiles to
illustrate genetic control of craniofacial morphology.
Their study involved superimposition of lateral
cephalograms of a sample of identical twins and
showed that many bony contours are in almost
perfect concordance. This applied equally to contours
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across sutures and to individual bony contours such
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as the mandible.
59. • Fernex et al (1967) found boys to show more
similarities to their parents than girls. Facial skeletal
structures were more frequently transmitted from
mothers to sons than from mothers to daughters.
• Female twins showed greater concordance in
facial features than male twins. While the profile
outline coincided most frequently, this was not true
of the cranial base and differences increased with
age.
• Littons et al (1970) concluded that siblings usually
show similar types of malocclusion and examination
of older siblings can provide a clue to the need or
interception and early treatment of malocclusion.
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60. FAMILY AND TWIN STUDIES FOR HERITABILITY
OF DENTOFACIAL PHENOTYPES
The twin method, when appropriately applied, provides
geneticists with one of the most informative technique
available for analysis of complex genetic traits.
Alternative method for investigating the role of heredity
in determining craniofacial and dental morphology is by
familial studies.
Heritability in such studies is normally expressed in
terms of parent/offspring correlation coefficients or
correlation coefficients with sibling pairs, of which twins
are a special kind.
The study of craniofacial relationship in twins has
provided much useful information concerning the role of
heredity in malocclusion.
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61.
The procedure is based on the underlying principle that
observed differences within a pair of monozygotic twins
(whose genotype is identical) are due to environment and
those differences within a pair of dizygotic twins (who
share 50% of their total gene complement) are due to
both genotype and environment.
A comparison of the observed within-pair differences for
twins in the two categories should be provide a measure
of the degree to which monozygotic twins are more alike
than dizygotic twins. The larger this differences between
the two twin categories, the greater the genetic difference
effect on variability of the trait. This model implies the
zygosity is accurately determined and that environment
effects are equal in the two twin categories
The bulk of the evidence for the heritability of various
types of malocclusion arises from family and twin
studies.
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62. CLASS II MALOCCLUSION
Class II Division I Malocclusion:
Extensive cephalometric studies have been carried out to
determine the heritability of certain craniofacial
parameters in class II division I malocclusion (Harris
1975). These investigation have shown that in the class II
patients, the mandible is significantly more retruded than
in class I patients, with the body of the mandible length
smaller and overall mandibular length reduced.
These studies also showed a higher correlation between
the patient and his immediate family that data from
random pairings of unrelated siblings, thus supporting
the concept of polygenic inheritance for class II division
I malocclusion.
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63. Class II Division 2 malocclusion:
Class II division 2 is a distinct clinical entity and is a
more consistent collection of definable morphometric
features occurring simultaneously i.e., syndrome than
the other malocclusion types put forward by Angle in
the early 1900’s.
Class II division-2 malocclusion along with
characteristic skeletal features is often accompanied
by particular morphometric dental feature also, such
as a poorly developed cingulum on the upper incisors
and a characteristic crown angulation.
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64. • Markovic (EJO1992) carried out a clinical and
cephalometric study of 114 Class II division-2
malocclusions, 48 twin pairs and six sets of triplets.
Intra- and Inter- pair comparisons were made to
determine concordance-discordance rate for
monozygotic and dizygotic twins.
• Of the monozygotic twin pairs, 100% demonstrated
concordance for the Class II division-2 malocclusion,
whilst almost 90% of the dizygotic twin pairs were
discordant. This is strong evidence for genetics as the
main etiological factor in the development of class II
division2 malocclusion.
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65. CLASS III MALOCCLUSION
Probably the most famous example of a genetic
trait in humans passing through several generations
is the pedigree of the so-called Hapsburg jaw. This
was the famous mandibular prognathism
demonstrated by several generations of the
Hungarians/Austrian dual monarchy.
Strohmayer (1937) concluded from his detailed
pedigree analysis of the Haspburg family line that
the mandibular prognathism was transmitted as an
autosomal dominant trait. This could be regarded
as an exception and in itself, does not provide
sufficient information to predict the mode of
inheritance of mandibular prognathism.
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66. • Hughes and Moore (1942) suggested that the mandible
and maxilla are under separate influence of genetics
control, and that certain portions of individual bones,
such as the ramus, body, and symphysis of the mandible
are under different genetic and environmental
influences.
• The polygenic multifactorial threshold model put
forward by Edward et al (1960), however, did fit the
data and accordingly proposed a polygenic model with a
threshold for expression to explain familial distribution,
and the prevalence both within general population and in
siblings of affected persons.
• Polygenic inheritance implies that there is scope for
environmental modification and many familial and twin
studies bear this out.
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67. • Schulze and Weise (1965) also studied mandibular
prognathism in monozygotic and dizygotic twins. They
reported that concordance in monozygotic twins was six
times higher than among dizygotic twins.
• Watnick (1972) studied 35 pairs of monozygotic and 35
pairs of dizygotic like-sexed twins using lateral
cephalometry. He concluded that the analysis of unit areas
with the craniofacial complex represents local growth
sites and revealed different modes of control within the
same bone.
• Certain areas, such as the lingual symphysis, lateral
surface of the ramus and frontal curvature of the mandible
are predominantly under genetic control.
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68. Nakasima and Nakata (AJO 1982) assessed the
craniofacial morphologic differences between parents
of Class II patients and parents of Class III patients,
as well as parent-offspring correlations, and the
genetic and environmental components of variation
within the craniofacial complex in these
malocclusions. The results showed that,
• Both Class II and Class III malocclusions have a
genetic basis.
• The skeletal pattern was more directly related to
genetic factors.
• Parent-offspring correlation data were in good
agreement with the expected level under the
polygenic model of inheritance.
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69. GENETIC FACTORS AND HERITABILITY OF
VERTICAL DIMENSION MALOCCLUSION
Howoritz et al (1960) studied fraternal and identical
adult twin pairs using only linear cephalometric
measurements and he demonstrated highly
significantly hereditary variations in the anterior
cranial base, mandibular body length, lower facial
height and total facial height.
Hunter et al (1965) also used linear measurements
on lateral cephalograms and concluded that there is
a stronger genetic component of variability for
vertical measurements, rather than for
measurements in the anteroposterior dimension.
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70. Lobb et al (Angle 1987) studied the variation within
the craniofacial skeletons, the anterior upper face
height to anterior lower face height in monozygous
and dizygous twins in terms of shape and spatial
arrangement of the component parts, and related
this variation to the occlusion of the teeth. He
summarized the following findings:
• Both the monozygous and dizygous twin pairs
revealed intra-pair variation in terms of relative
size, shape, and spatial arrangement of the bony
components of the craniofacial skeleton.
• Even though the monozygous twins had identical
occlusions, their craniofacial complexes were not
identical in every detail.
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71. Savoye and Loos et al (Angle 1998) used Lateral
cephalograms of 33 monozygotic and 46 dizygotic
twins to evaluate the genetic and environmental
contribution to facial proportions and to compare
them with earlier genetic analyses of the different
facial components using model-fitting and path
analysis. They concluded that,
•
The analysis indicated that additive genes and the
specific environment and the specific environment
influence all the facial proportions. The
heritability was 0.71 for upper to lower facial
height and 0.66 for anterior to posterior facial
height.
•
High genetic determination was found for the
vertical proportions.
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72. Yamaguchi (AJO 2001) studied the association
of the growth hormone receptor gene variant and
mandibular height in the normal Japanese
population.
•
•
•
Pro561Thr (P561T) variant in the growth hormone
receptor gene (GHR) is considered to be an important
factor in craniofacial and skeletal growth.
Patients who did not have the GHR P561T allele had a
significantly greater mandibular ramus length
(condylion-gonion) than did those with the GHR
P561T allele.
He concluded that the GHR P561T allele may be
associated with decreased growth of mandibular
height and can be a genetic marker for it, it is not clear
if the effect is directly on the mandible and/or on
another nearby tissue or matrix.
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73. HERITABILITY OF LOCAL OCCLUSAL
VARIABLES
It has been thoroughly documented that measurements
of the skeletal craniofacial complex have moderate to
high heritability, while measures of the dento-alveolar
portions of the jaws i.e., tooth position and dental
relationships are given much less attention in the
literature.
Because of the adaptability of the dentoalveolar region
when subjected to environmental factors, local
malocclusions are primarily acquired and would be
expected to have low heritablities.
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74. • In an analysis of the nature versus nurture in
malocclusion Lundstrom (1984) concluded that
the genetic contribution to anomalies of tooth
position and jaw relationship overall is only 40%,
with a greater genetic influence on the skeletal
pattern than on the dental features.
• Lundstrom (1948) studied 50 pairs of
monozygotic and 50 pairs of dizygotic twins and
concluded that heredity played a significant role
in determining, among other factors, width and
length of the dental arch, crowding and spacing of
the teeth and degree of overbite.
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75.
Van der Linden (1966) described the concept
that, the balance between the internal and
external functional matrices existed. For
example, in a Class II division 1 malocclusion a
short upper lip and low lip level with flaccid lip
tone will reduce the external influence and
balance will favour proclination of the upper
incisors. On the other hand, a high lip level and
more expressive lip behaviour will tend to
produce a Class II division-2 incisior
relationship.
This external matrix is thought to be strongly
genetically determined. The internal matrix
determined mainly by tongue posture and
behavior that can be influenced by
environmental, as well as genetic factors.
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76.
In a recent study by King et al (AJO 1993), initial
treatment records of 104 adolescent sibling pairs, all
whom subsequently received orthodontic treatment,
were examined. Heritability estimates for occlusal
variations such as rotations, crossbites and
displacements were significantly higher than in a
comparable series of adolescents with naturally good
occurring occlusions. The explanation offered was
that a genetically influenced facial types and growth
patterns of the siblings are likely to respond to
environment factors.
It is also important to remember the soft tissue
morphology and behaviour have a genetic component
and they have a significant influence on the
dentoalveolar morphology.
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77.
GENOMICS AND OROFACIAL CLEFTS
Orofacial clefts, the most common craniofacial
malformation ranks second among all the
craniofacial anomalies, among all the congenital
malformation affecting human.
These include,
1) Cleft lip and Cleft palate
• Cleft lip with or
without cleft palate
• Cleft palate only
1) Median clefts
2) Alveolar clefts
3) Facial clefts
78. Etiology of orofacial clefts appears to be complex with
involvement of genetic, environmental and tetragenic
factors complicating the process.
Etiological factors:
Monogenic or single gene disorder
Polygenic or multifactorial inheritance
Chromosomal abnormalities
Familial
Sex predominance
Racial incidence
79. Monogenic or single gene disorders
Approximately half of the recongnized syndromes
associated with cleft lip and palate are due to single
gene disorders with equal distribution between
autosomal dominant and autosomal recessive.
Single gene defect may give rise to Mendelian
pattern of inheritance, either of isolated cleft lip
(palate) or in multiple malformations associated
with cleft lip with or without cleft palate.
Polygenic or multifactorial inheritance
Several genes, each with a relatively small effect,
act in concert with poorly defined environmental
triggering mechanisms leading to the expression of
the abnormality. Thus, such cases show a slight
familial tendency but do not confirm to simple
Mendelian inheritance patterns.
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80. Chromosomal abnormalities
Chromosomal abnormalities account for 18% of the
clefting syndromes and would invariably be associated
with other malformations, delayed development and
poor prognosis. Chromosomal abnormalities notably
trisomy D and also less frequently trisomy E, may
cause multiple malformations including cleft lip
(palate).
Familial
Fogh-Anderson’s family studies showed that siblings
of patient with cleft lip had increased frequency of cleft
lip and cleft palate, but no increased frequency of cleft
palate alone. Siblings of patients with cleft palate had
increased frequency of cleft palate, but not CL and CP.
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81. Sex predominance
More males are born with cleft lip and cleft
palate than females and more females than
males have cleft palate alone.
Racial incidence
The incidence of cleft lip and cleft palate is
greatest in the Mongoloid population being
greater than that in the Caucasian population,
which is in turn greater than in the Negroid
population. In contrast, the racial differences
for cleft palate or not significant.
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82. Cleft lip and cleft palate can be broadly categorized
as,
1)
2)
3)
4)
5)
Non-syndromic CLP/CP
Syndromic CLP/CP
Syndromic isolated CP
Sex-linked CP (CPX)
Congenital healed cleft lip (CHCL)
Non-syndromic CLP/CP
Non-syndromic CLP/CP in humans seems to be
etiologically distinctive and still constitute majority
of all classes with clefting disorder.
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83. Various transcription factors and growth factors are involved in non
syndromic cleft lip/cleft palate where mutations in these factors results
in
the disorder
TRANSCRIPTION FACTORS
GROWTH FACTORS
Genes
Genes
2p11-13
Transforming Growth
Factor β (TGF β)
14q23-24
Retinoic Acid Receptor
Alpha (RARA)
Homeobox genes
Loci
Transforming Growth
Factor α (TGF α)
Loci
17q21
Muscle segment
(MSX1)
4p16.1
Lim Homeobox
(Lhx8)
4q2531
Bar class
(Barx)
11q25
GABA Receptor β 3
(GABRB3)
15q11.2-12
Distal less
(Dlx2)
2q32
B-cell leukemia/
Lymphoma (3 BCL3)
19q13
Jagged 2
(Jagg2)
14q32
Other Genes
Endothelin 1
Glutamate
Decarboxylase
(GAD 67)
6p2324
Apolipoprotein C II
(APOC2)
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2q31
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19q13.1
84. Syndromic CLP
Over 300 syndromes are known to have clefting
of the lip or palate as an associated feature. As
with all clinically recognizable syndromes,
cases of syndromic CLP or CP can be broadly
subdivided into,
Those that occur as part of characterized
Mendelian disorder (Single Gene defects)
Those arising from structural abnormalities of
the chromosomes
Syndromes associated with known Teratogens
Those whose causation remains obscure and are
therefore currently uncharacterized.
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85.
One of the most common human autosomal
dominant disorders associated with CLP is van der
Woude syndrome.
Twin studies by Kondo et al (2002) revealed that a
non-sense mutation in the interferon regulatory
factor-6 (IRF6) gene resulted in van der Woude
syndrome.
Some of the syndromes associated with CLP are,
Pierre Robin syndrome
CLP-ectodermal dysplasia syndrome (CLPED-1)
Ectrodactyly, ectodermal dysplasia, orofacial
cleft (EEC syndrome)
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86. Syndromic CP
In addition to syndromic CLP, progress has also
been made in elucidating the genetic mechanisms
behind several syndromic causes of isolated CP.
Some of the syndromes associated with CP are,
Mandibulofacial dysostosis (Treacher Collins
syndrome)
Holoprosencephaly, type-3
Stickler syndrome
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87. Sex-linked CP (CPX)
•
Philip Stainer and Gudrun Moore (1995) found the
Sex (X) chromosome linked form of cleft palate
(CPX) and an associated disorder ankyloglossia can
occur due to mutations in a particular gene → T Box
22. T-Box genes are members of a family of
transcription regulators that share a common DNAbinding domain, the T-box.
•
Laugier et al (2000) through silico analysis identified
the gene loci at chromosome Xq12-q21.
Bay brook et al (2001) identified six different
mutations including missense, splice site and non
sense in the TBX22 gene families segregating Xlinked cleft palate and ankyloglossia.
•
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88. Congenital healed cleft lip (CHCL)
CHCL is an unusual anomaly consisting of
paramedian scar of upper lip with
appearance suggestive of typical cleft lip
corrected in utero. It is usually associated
with an ipsilateral notch in the vermillion
border and a collapsed nostril.
Castilla presented 25 cases of CHCL and
suggested this condition to be most
common among males and preferentially
affects left side. They further suggest a
familial predisposition to this phenomenon
and may result from a defective fusion of
frontonasal and maxillary process or from
spontaneously repaired open cleft with
visual scar later on development.
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89. MEDIAN CLEFTS
True median cleft lip occurs with premaxillary
agenesis and failure of completion of the nose.
Median clefts may occur with
holoprosencephaly or may occur as an isolated
malformation (Cohen 1997).
Other types of median clefts are associated with
syndromes such as,
Treacher Collins syndrome
Stickler dysplasia
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91. CRANIOFACIAL SYNDROMES
A syndrome is recognised to represent multiple
malformations occuring in embryonically noncontigeous areas.
Some of the syndromes with dental importance are,
Crouzons syndrome
Aperts syndrome
Pfeiffer syndrome
Treacher collins syndrome
Craniofacial microsomia
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92. CROUZON SYNDROME
• It is a frequent form of craniofacial dysostosis.
• It is characterized by mutiple anomalies of the
craniofacial skeleton with a autosomal dominant
inheritance.
• Its manifestations are usually less severe than Apert
syndrome and there are no malformations of the
extremities.
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93. Genetic etiology:
At the molecular level, it is caused by mutiple
mutations in the fibroblast growth factor receptor 2
(FGFR2). Mutation occurs at Tyrosine kinase
receptor, at Ig II – Ig III domain.
Chromosome and region: 10q25.3 -q 26
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94. Clinical features:
• They are limited to the head and neck region in contrast
to other craniosynostosis syndrome in which hand, feet
involvement or both are common.
• Forehead is often high and prominent.
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95. There is hypertelorism, strabismus, midface hypoplasia,
a prominent beaked nose, high arched palate,
mandibular prognathism and dental malocclusion.
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96. APERT SYNDROME
Apert syndrome also known as Apert-Crouzon
disease is characterized by skull malformation
(Bicoronal synostosis) and syndactyly of the hands
and feets.
It is associated with an autosomal dominant
inheritance pattern.
Chromosome and location: 10q 25.3 – q26
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97. Genetic etiology:
At the molecular level, one of the two fibroblast
growth factors 2 gene (FGFR2) mutations
involving amino acids (Ser252 trp and pro 253
Arg) are found to cause Apert syndrome.
Tyrosine kinase receptor is affected at
extracellular Ig II – Ig III.
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98. Clinical features:
Bicoronal syostosis with
a widely patent midline
calvarial defect.
The facial apperance in
Apert syndrome is
characterized by a high
and prominent forehead.
Mid-face hypoplasia
giving the appearnce of
mandibular prognathism,
and a prominent beaked
nose.
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99. Cleft palate is
common.
The palate is typically
high arched, and quite
narrow, giving a
“Byzantine arch”
appearance.
Crowding of the
dentition is common.
Of all other features, it is the hands and feet
which are most characteristic of Apert
syndrome. www.indiandentalacademy.co
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100. PFEIFFER SYNDROME
Characterized by deformation of head and neck, hand and
feet.
It is associated with an autosomal domimant inheritance.
Genetic etiology:
At the molecular level, mutation of fibroblast growth factor
receptor (FGFR1 & FGFR2) involving aminoacid (Pro 252
Arg) is found to cause pfeiffer syndrome. Tyrosine kinase
receptor is affected at extracellular Ig II – Ig III.
Chromosome location: 8 p 11.2 – p12
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101. Pfeiffer syndrome has 3 clinical subtypes
Clinical features:
Cranial features include synostosis of the
coronal sutures producing brachycephaly,
midface hypoplasia, and relative
prognathism.
Other feaures include, Hypertelerosim,
prominent beaked nose, high arched palate
with dental malocclusion.
Hand and feets shows a characteristic
pattern of malformation.
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102. TREACHER COLLINS SYNDROME
Treacher collins syndrome is characterized by
bilaterally symmetrical abnormalities of structures
within the first and second branchial arches.
It is inherited as autosomal dominant trait.
Genetic etiology:
Treacher collins syndrome occurs as result of
mutation of Treacle gene (TCOF1 gene) located in
chromosome 5q 32 – q 33.1. TCOF1 encodes a
protein that is 1411 amino acids in length and has
been named ‘treacle’.
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103. Clinical features:
The facial appearance is sticking, with downward slanting
palpaberal fissures, depressed zygoma, displastic ears and
receding chin.
Zygomatic arches may be absent but more often are
symmetricallywww.indiandentalacademy.co
underdeveloped.
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104. Poor development of the maxilla and frequent high arch or
cleft lip and cleft palate.
Hypoplastic changes in muscle of mastication and weakness
of facial muscles.
Paranasal sinuses are often small and may be completely
absent.
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105. CRANIOFACIAL MICROSOMIA
Also known as, First and
Second Brachial arch
Syndrome/ Oralmandibular-auricular
Syndrome.
The clinical expression
of the syndrome was in
the structures derived
from the first and the
second brachial arch.
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106. Jaw deformity: The most conspicuous deformity of
unilateral microsomia is a hypoplasia of the mandible
on the affected side. The ramus is short or virtually
absent and the body of the mandible curves upward to
join the short ramus. The chin is deviated to the affected
side; the body of the mandible on the normal or less
affected side is also characterized by abnormalities in
the skeletal soft tissue anatomy.
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107. Body of the mandible shows
increased horizontal length
and an increase in the gonial
angle.Ramus and the condyle
malformations vary from
minimal hypoplasia of the
condyle to its complete
absence in association with
hypoplasia or agenesis of the
ramus. Condylar anomalies
are the pathognomic
hallmark of the syndrome.
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108. CONCLUSION
At the present time successful orthodontic interception and
treatment of hereditary malocclusion are limited by the extent of our
knowledge because of,
1) lack of research dedicated to this particular problem e.g.,
prospective randomized clinical trials
2) relative blunt measurement tools
3) limited knowledge about the genetic mechanisms involved and
the precise nature and effects of environmental influences, we
are unable to predict with a satisfactory degree of certainty the
final manifestation of the growth pattern or the severity of the
malocclusion conferred by a particular genotype.
On the genetics side the advent of diagnostic techniques in the field
of molecular genetics make it possible to identify relevant
morphogenes or genetic markers such as those for mandibular
prognathism or to influence the development of malocclusion.
It is therefore incumbent on the orthodontic speciality to keep
abreast of developments in molecular genetics.
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