Dental anomalies are caused by complex multifactorial interactions between genetic, epigenetic and environmental factors during the long process of dental development.
This process is multilevel, multidimensional and progressive. It involves multiple interactions and critical stages
4. Dental anomalies are
caused by complex
multifactorial
interactions between
genetic, epigenetic
and environmental
factors during the
long process of
dental development.
This process is multilevel,
multidimensional and
progressive. It involves
multiple interactions and
critical stages
5.
6. Teeth are typical examples of organs in which genes
determine the progress of development from
initiation to the final shape, size and structure,
whereas environmental factors play a minor role.
7.
8. Body organization requires cell differentiation and
morphogenesis which are controlled by gene expression.
Gene expression is defined as an
activation of a gene that results in
production of polypeptide/protein that
can activate/deactivate other genes with
the influence of transcription factors
(growth factors).
9. Every organism has a unique body pattern because
of the influence of Home box genes.
These seem to be the master genes that help in
development of individual structures from
different areas of the body
10. Human genes called the Hox
genes have the same pattern of
organization, follow the same
order of gene arrangement,
their expressions and functions
are also in sequences as
observed in Drosophila.
The genes HOX A, HOX B, HOX C
and HOX D are arranged on four
different chromosomes 7, 17, 12
and 2.
Homeobox genes are
characterized by a conserved
180-bp DNA sequence coding
for a 60-aminoacid DNA-binding
domain called the
‘‘homeodomain.’’
11. Hox Genes:
Genes
containing
Homeobox site.
During tooth
morphogenesis,
expression of
these
homeobox
genes is directly
under the
control of
signalling
cascades
initiated by the
interaction of
certain growth
factors and
receptors on
the surface of
the target cells .
HOX gene
influence
appears to
be in human
tooth buds
between 18
and 24 week
of
embryonic
developmen
t.
12.
13. Hox genes are critical regulators of embryonic development, being involved in
formation of the Skeleton and Limbs, Craniofacial morphogenesis, and in
development of the Central Nervous System, Gastrointestinal and Urogenital
tracts.
Aberrant expression of Hox genes have been described in developmental
abnormalities and solid tumors as well as in hematologic malignancies.
14. The subfamilies of Hox genes, which are of particular
interest in Craniofacial patterning and morphogenesis
include - muscle segment (Msx), distal less (Dlx),
orthodenticle (Otx), goosecoid (Gsc), Bar class{Barx),
paired-related {Prx, SHOT) & LIM homeoboxGaneS.
15. The expressions of these
genes are mediated
through two main groups
of regulatory proteins :
Growth factor
familyandsteroid/thyroid/
retinoic acid super family.
The vehicles through which
Hox gene information is
expressed for the regulation
of the growth process include
fibroblast growth factor(FGF),
Transforming growth factor a
and b (TGF a and TGF b) and
bone Morphogenetic protein
4 (BMP 4).
16. Tooth development is
complex phenomenon
between epithelium
and ectomesenchyme,
which is being
governed by the set of
these complex genes.
There are two classes
of homeobox genes:
Class1 genes called
Hox genes share a high
degree of identity in
their homeodomain.
Class2 genes share a
low degree of identity
their homeodomain.
17. Teeth form through a
series of reciprocal
interactions between
epithelium (derived
from oral ectoderm)
and mesenchyme
(derived from cranial
neural crest), which
begin at mid-
gestation in mouse
embryos.
[Tucker and Sharpe,
2004].
18. The interactions between oral epithelium and underlying
neural-crest derived mesenchyme are mediated by secreted
signaling molecules from the major signaling families (FGF,
TGF-β, WNT and HH), which lead to various intracellular
events, including expression of transcription factors (e.g.,
members of the Msx, Pax, and Runx families)
[Jheon et al., 2013; Jussila and Thesleff,
2012].
19.
20. Fig. 2 Teeth form from oral epithelium (green)
and underlying mesenchyme (blue) and
interactions between these tissues regulate
development. The most important signal
molecules mediating this communication are
BMP (bone morphogenetic protein), WNT,
SHH (sonic hedgehog) and FGF (fibroblast
growth factor). They regulate the
expression of important transcription
factors indicated in boxes and numerous
transcription factors regulating gene
expression in the nucleus. Loss of
function of many of these genes arrests
the process of tooth development in
genetically modified mice, and their
mutations cause tooth agenesis in humans.
21. Fig. 4 Ectodysplasin (Eda) signalling is
necessary for tooth formation. (a). The
Eda pathway represents a typical
signal pathway. The signal (Eda) binds
to its cell surface receptor Edar
mediating the signal to the cytoplasm.
Edaradd and IKKgamma mediate the
signal to activate the transcription
factor NFkappaB which moves to the
nucleus and regulates gene
expression. (b). Severe tooth agenesis
(oligodontia) caused by lack of Eda in
XLHED (X-linked hypohidrotic
ectodermal dysplasia).
22.
23. Fig. 5 Stimulation of tooth
initiation by excess Eda and
Wnt signalling. (a). Three
molars in a wild type mouse.
(b). An extra premolar-like
tooth has been induced in a
mouse overexpressing Eda in
oral epithelium. (c). Forced
activation of Wnt signalling in
oral epithelium (ß-cat ex3K14/+)
results in
continuous initiation of new teeth. A tooth
bud of a mutant mouse embryo was
cultured ex vivo for 19 days.
24. Fig. 3 The placodes and enamel
knots are signalling centres
producing numerous signal
molecules. (a). The placodes
initiating the development of
incisors (I) and molars (M) in
the lower jaw of a mouse
embryo are visualized by the
expression of Shh (in situ
hybridization analysis). T,
tongue. (b). Histological section
of mouse embryonic molar at
the cap stage shows the
expression of FGF-4 in the
primary enamel knot.
25. Muscle Segment Box (Msx1, Msx2)
The Msx homeobox gene (Human ANTP class NKL
subclass) family plays a crucial role in the development
of craniofacial development.
Holland PWH, Booth HAF, Bruford EA. BMC
Biology, 2007
26. During the tooth development Msx 1 is expressed in the
bud stage and in the morphogenetic cap stage.
Msx 1 becomes localized in the
mesenchymal cells of the Dental follicle
and the papilla and Msx 2 becomes more
expressed in the enamel organ besides
expressing in dental papilla and the
follicles.
27. In the late stage of
morphogenesis, Msx 1
expression is absent in root
sheath epithelium indicating
that Msx does not plays a role in
root morphogenesis.
Msx1 also plays an
important role in the
development of the palate
specially the anterior
portion of the palatal
shelves.
Msx 2 plays role in the
expression in the formation of
the extracellular matrix and
ameloblast differentiation .
28. Msx1 is co- expressed with Msx2 at the site of epithelial
- mesenchymal interactions.
Its expression is increased in cap stage in enamel knot,
inner enamel epithelium and Dental papilla whereas
Msx2 expressed in odontoblasts, cuspal formation, and
root initiation.
Ahuja Rink, Agrawal Ankit, Tijare Manisha, Chouhan
Shweta . Indian J Dent Adv. 2013
29.
30. Wolf-Hirschhorn syndrome
(WHS) is a congenital human
syndrome resulting from a
deletion of Msx1locus on
chromosome 4. It manifests
as midline fusion defects, ear
defects, supernumery teeth
and microcephaly.
It may also cause
tooth agenesis, nail
dysgenesis, mental
retardation, cardiac
defects and variety of
skeletal deformities.
31. The BMP 4 mediated induction of Msx1expression and subsequent
Msx dependent activation and maintenance of BMP4 expression in
the Dental mesenchyme are the key steps in conferring odontogenic
potential to this tissues.
Activation of Msx1, Msx2, Dlx1
and Dlx2 in Dental mesenchyme
occurs in response to BMP4 and
FGF signals from the overlying
epithelium.
32. Distal-less
(Dlx)
The expression of Dlx 1 and Dlx 2 in the maxillary and
mandibular arch mesenchyme is restricted to the
region where the future molar teethwill develop
specially for the ectodermal and mesenchymal
compartments of the developing tooth.
33. Barx genes:
Bar expression becomes more localized exclusively to
the mesenchymal regions around the developing
molars to produce specific folding pattern of the
dental epithelium that produce molar cusps.
34. Barx 1 and Barx 2 show
complementary patterns in their
expression.
Barx1 appears in the mesenchyme of the
maxillary and the mandibular process where as
Expression of Barx 2 is most prominent in
mantle layer, where post- mitotic neurons are
located, the palatal floor and dorsal root
ganglia, mutations of which can produce cleft of
secondary palate hence, the association of Barx
1 with Barx 2 in the possible etiology of cleft lip
and palate.
35. LIM HOMEOBOX DOMAIN (Lhx)
These are found to be related with the expression of
the ectomesenchyme of the maxillary and the
mandibular process and also suggested to control
patterning of the first brachial arch.
Alappat S, Zhang ZY, Chen YP. Cell
Res, 2003
Lh x6, Lhx 7 are the earliest mesenchymal markers of
tooth development.
Ahuja Rink, Agrawal Ankit. Indian J
Dent Adv. 2013
36. Prx genes (Pair related gene)
Prx1 and Prx2 are closely related
members of Prx family of
homeobox genes.
Prx1 is expressed in central
nervous system derived
mesenchyme of Fronto nasal
process, first and second
branchial arches and group of
cells that form maxillary process.
Its expression decreases once
differentiation is initiated.
37. Prx1 in combination
with Prx2 is essential to
stabilize and maintain
cell fates in craniofacial
mesenchyme.
Holland PWH, Booth
HAF, Bruford EA. BMC
Biology, 2007
Pax a family of 9 genes. Regulators of
organogenesis, maintains pleuripotency
of stem cell. It is the earliest
mesenchymal gene which localizes site
of tooth bud.
38. Sonic Hedgehog (Shh) :
In facial development, Shh is expressed in the ectoderm of
frontonasal process (FNP) and maxillary process (MXP).
Transient loss of these signals can produce collapse of the
facial midline and hypotelorism. Disrupting Shh signaling in
FNP and MXP leads to interruption in their outgrowth,
resulting in clefting between the primordia; cleft lip/palate.,
Helms JA, Cordero D, Tapadia MD.
Development, 2005
Ganeshkar SV, Rai AK,
Rozario JE. IAIM, 2015
39. Shh expressed in Bud stage, cap stage
(enamel knot) and in hertwigs
epithelial root sheath for root
formation.
Ahuja Rink, Agrawal Ankit, Tijare
Manisha, Chouhan Shweta . Indian J
Dent Adv. 2013
. Occlusal view of developing mouse molars dissected from a 17-day-old
embryo. M1 is at the bell stage and M2 at the cap stage. The secondary
enamel knots marking future cusps in M1, and the primary enamel knot in M2
are visualized by Shh expression.
40.
41. Endothelin, dHAND and eHAND:
The endothelin family of signaling peptides has been
implicated in development and migration of neural crest
cells.
Appearance of marked
craniofacial and cardiac
abnormalities similar to those o
CATCH -22 syndrome (Cardiac
defects, abnormal facial
features, Thymic hypoplasia,
Cleft palate, Hypocalcaemia)
which is associated with
chromosome-22 deletion.
42. Msx1, which is implicated in growth of branchial
arches, was also found to be undetectable in the
mesenchyme ofd HAND null branchial arches, thus
suggesting the regulatory role played by endothelin
1 in stimulating mesenchymal expression of
dHAND thus regulating Msx1 expression in growing
distal branchial arch.
43. Lymphoid Enhancing
Factors (Lef-1) Lef-1 gene is involved in Wnt
signaling pathway and it may
function in hair cell
differentiation and follicle
morphogenesis. Expressed in
condensing mesenchyme in bud
stage &adjacent basal cells of
epithelium.
It is Essential in initiation
and cytodifferentiation.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54. Familial, non-syndromic hypodontia:
A missense mutation in MSX1 on chromosome 4 was the first mutation
found to be associated with non-syndromic hypodontia.
The mutation was found in all affected members of a family with
missing second premolars and third molars.
Some also had missing maxillary first premolars,
mandibular first molars, one or both upper lateral
incisors or a single lower central incisor. All had normal
primary dentitions
55. a second gene—PAX9 on chromosome 14—was found to
be involved in hypodontia.
A frame shift mutation in PAX9 was identified in a family
with autosomal dominant hypodontia that had missing
permanent molars [Stockton et al., 2000].
56. More recently,
hypodontia associated
with AXIN2 mutations
has been identified to
affect a wider range of
tooth types.
In a four-generation
Finnish family, 11
members were found
to be missing at least
eight permanent teeth
along with an
increased risk of
developing colorectal
neoplasia
AXIN2 is a component
of the WNT signaling
pathway.
57.
58. Van der Woude syndrome:
VWS is inherited in an autosomal dominant fashion and is caused
by mutations in the interferon regulatory factor 6 (IRF-6) gene
VWS is the most common clefting syndrome and occurs in
approximately 2% of the population with facial clefts
Hypodontia is frequently seen in VWS, and a close association between
VWS and congenital absence of second premolars has been shown
59. Ectodermal dysplasia:
The ED syndromes can be inherited in an autosomal
dominant, autosomal recessive, or X- linked form. The
most common form of ED is X-linked hypohidrotic ED, or
XLHED (OMIM 305100) and is caused by mutations in
the gene encoding ectodysplasin-A (EDA), which is a
member of the TNF signaling pathway.
60. TNF signaling through EDA activates NFKB1, which is known to
play an important role in odontogenesis [Ohazama and Sharpe,
2004]. Affected males show severe oligodontia or anodontia in
both primary and permanent dentition.
61. Oral-facial-digital
syndrome type I:
OFD1 is an X-
linked disorder
caused by
mutations in the
gene OFD1. This
gene is important
for formation of a
cellular organelle
known as the
primary cilium.
Oral
manifestations of
OFD1 are seen in
the tongue,
palate, and teeth.
Cleft hard or soft
palate,
submucous cleft
palate, or highly
arched palate
occur in more
than 50% of
affected patients.
Dental
abnormalities
include missing
teeth, extra
teeth, enamel
dysplasia, and
malocclusion [Al-
Qattan, 1998;
Toriello and
Franco, 2007].
62. Rieger syndrome :
An autosomal dominant disorder characterized by
malformations in the anterior chamber of the eye,
umbilical anomalies, and hypodontia.
it is given the name Axenfeld-Rieger syndrome
ARS ,
Three genetic loci have been associated with ARS
so far.
FOXC1 and PITX2 encode transcription factors and
are located on chromosomes 6p25 and 4q25,
respectively [Tumer and Bach-Holm, 2009].
63. Dental features include hypodontia/oligodontia of
primary and permanent dentition.
The most commonly missing teeth are lower second
premolars and subsequently the central incisors and
upper second premolars
[Dressler et al., 2010].
A third locus for ARS was mapped to chromosome
13q14 but the gene has not yet been .
64. Holoprosencephaly:
HPE is caused by impaired midline cleavage of the embryonic
forebrain.
HPE is the most common defect of the forebrain and mid-face in
human [Wallis and Muenke, 2000].
The most severe form is cyclopia, and the mildest phenotype is a
single upper central incisor.
Several loci for HPE have been mapped. HPE3 is caused by mutations
in the Sonic hedgehog (SHH) gene, which was described above in the
context of tooth development [Lami et al., 2013].
65. Tooth anomalies associated with cleft lip and palate:
hypodontia is associated with clefts of the lip and palate.
Studies have found that hypodontia is
present in approximately 80% of
children with non-syndromic clefts
[Shapira et al., 1999], and the
prevalence of hypodontia increases
markedly with the severity of the cleft
[Ranta 1986].
66. A recent meta-analysis concluded that patients with
cleft lip and palate experience not only more tooth
agenesis, but also supernumerary teeth and
anomalous tooth morphology in comparison to non-
cleft patients [Tannure et al., 2012].
67. Delayed formation and eruption of teeth:
Several syndromes have delayed formation and eruption
of teeth, including Apert syndrome [Kaloust et al.,
1997],
cleidocranial dysplasia,
Dubowitz syndrome, Goltz
syndrome, progeria,
Menke syndrome and
oculofaciocardiodental
syndrome (OFCD).
68. In Apert syndrome, there are
delays in both development and
eruption, and there can also be
ectopic eruption and
abnormalities in incisor and molar
shape [Kaloust et al., 1997].
Erupting teeth remain
buried in thickened
gingival tissues for
long periods of time.
The alveolar swellings of
the maxillary arch are
characteristic of the Apert
syndrome.
Activating mutations in genes
encoding receptors for Fibroblast
Growth Factors, which were
discussed above in the context
of tooth development, cause
Apert syndrome.
69. Oculofaciocardiodental syndrome (OFCD) Mutations
in the BCOR gene have been found in this condition
Delayed tooth eruption has also been found in the
upper jaw of patients with orofacial clefts [Peterka et
al., 1996].
70. Abnormalities in tooth
size, shape and form:
Abnormalities in tooth size and shape
are thought to result from disturbances
in the morphodifferentiation (cap-bell)
stage of development.
In the upper jaw of cleft patients,
where the permanent teeth have
normal mesio-distal dimension,
while the upper jaw arch is
significantly shorter.
joined at the dentin or
teeth with a common pulp
chamber.
71. Sometimes, tooth germs may
fuse or germinate during
development [Guttal et al.,
2010], resulting in teeth with
separate pulp chambers
72. A taurodontic tooth is thought to result from a
disturbance in growth of Hertwig’s epithelial root
sheath.
Based on this hypothesis, there may be
an association between taurodontism
and hypodontia, as both conditions may
be attributed to defects in the growth of
dental epithelium [Hu and Simmer,
2007].
74. Lastly, there may be a common genetic etiology
between VWS, hypodontia, and taurodontism
[Nawa et al., 2008]. The frequency of taurodontism
in VWS subjects was almost 50% [Nawa et al.,
2008].
75.
76. Supernumerary
teeth:
Supernumerary teeth result from
disturbances during the initiation and
proliferation stages of dental
development.
Supernumerary teeth may be unilateral or
bilateral, single or multiple, and may be found in
one or both jaws. there are over 20 syndromes
with supernumerary teeth, the most common
being cleidocranial dysplasia and Gardner
syndrome [Moore et al., 2002].
77. The frequency of supernumerary
teeth in individuals with unilateral
cleft lip and/or palate was found
to be 22.2% , with males affected
twice as often as females in the
permanent dentition.
There are various
hypotheses regarding
the etiology of
supernumerary
teeth.
According to one, a
supernumerary tooth is
created as a result of
dichotomy of the tooth
bud.
Another theory is that
supernumeraries are
formed as a result of local,
independent conditioned
hyperactivity of the dental
lamina
78. Some problems associated with supernumerary teeth
include failure of eruption, displacement.
crowding, and formation of dentigerous cysts.
Root resorption of adjacent teeth is a rare occurrence as
well .
79. Cleidocranial
dysplasia—
The best-known
syndrome associated
with supernumerary
teeth is cleidocranial
dysplasia (CCD).
CCD is an autosomal
dominant skeletal
dysplasia associated
with clavicle
hypoplasia and
dental abnormalities
and has a prevalence
of 1 in 1,000,000.
It is caused by mutations in
RUNX2, which encodes a
transcription factor that
activates osteoblast
differentiation. One third of
CCD cases are sporadic and
represent new mutations
[Otto et al., 2002].
80. Individuals with CCD have growth retardation with
moderate short stature, delayed fontanelle closure
with parietal and frontal bossing, midface hypoplasia,
hypertelorism, low nasal bridge, and hearing loss. They
may have cleft palate or a narrow, high palate.
81. Dental manifestations are
found in more than 90%
of individuals with CCD
and include delayed
eruption of deciduous and
permanent teeth,
supernumerary teeth,
retention cysts and
enamel hypoplasia .
Formation and eruption of
the deciduous teeth are
usually normal.
One suggested
explanation for the
delayed or non-eruption
of many permanent and
supernumerary teeth is
the lack of cellular
cementum in the apical
region of impacted teeth.
82. Because of challenges in dental management of these
individuals with CCD, comprehensive orthodontic and
surgical treatment is required.
Additionally, there is a
wide variation in
supernumerary tooth
development, including
asymmetrical development
of supernumerary teeth in
the upper and lower jaw
[Soni et al., 2012].
83.
84.
85. Gardner syndrome—
a variant of familial adenomatous polyposis (FAP), is a
rare autosomal dominant condition characterized by
gastrointestinal polyps, multiple osteomas, and skin and
soft tissue tumors including a characteristic retinal
lesion.
Approximately 10% of FAP individuals are affected by
Gardner syndrome [Ramaglia et al., 2007].
86. Gardner syndrome and
FAP are caused by
mutations in APC at
5q21.
APC is a multidomain
protein that plays a
major role in tumor
suppression by
antagonizing the WNT
signaling pathway
Dental anomalies are
present in 30% to 75%
of patients with
Gardner syndrome,
and may include
impacted or unerupted
teeth, hypodontia,
abnormal tooth
morphology,
87. supernumerary teeth, hypercementosis, compound
odontomas, dentigerous cysts, fused molar roots,
long and tapered molar roots, and multiple caries .
Osteomas occur in 68–82%
and are generally located
in the paranasal sinuses
and mandible They can
also affect the skull and
long bones .
88.
89.
90. Yin et al. found an epigenetic control of EDA (via
cytosine methylation) was due to large CpG
islands(regions of DNA where a cytosine nucleotide is
followed by a guanine nucleotide in the
linear sequence of bases along its 5' → 3' direction
Cytosines in CpG dinucleotides can be methylated to
form 5-methylcytosine.
In mammals, methylating the cytosine within a gene
can change its expression, a mechanism that is part of
a larger field of science studying gene regulation that is
called epigenetics. Enzymes that add a methyl group
are called DNA methyltransferases.)
91. large CpG island within the promoter of EDA; its
transcription can be significantly modulated
depending by the degree of methylation.
The CpG rich EDA promoter region
was found to be hypermethylated in
~78% of carriers of XLHED , a
modification which could presumably
inhibit expression of the mutated
gene product.
92. A similar finding was
reported when
investigators completed
a DNA methylation
profiling of patients with
non-syndromic tooth
agenesis.
They found a group of
differentially meth-
ylated promoters in
novel genes in affected
patients compared to
controls.
Another level of
epigenetic control can be
found in gene regulation
via microRNAs (miRNAs),
and it is thought to
influence the expression
of almost 30% of all
protein-coding genes .
93. miRNAs have been found to be differentially
expressed in dental epithelial and mesenchyme
tissues of different tooth types and participate in the
differentiation of odontogenic cells including
ameloblasts, odontoblasts, dental follicular, and pulp
cells.
94. Abnormal dental phenotypes
have also been found in
mouse studies where
microRNA function is
disrupted by knockout of
Dicer1, which is required for
miRNA maturation.
Fan et al.injected a
soluble miR-224 agomir
(miRNA mimics) into
incisors of neonatal
mice and found
significant structural
differences in enamel,
including
disorganization of
enamel prism structure,
deficient crystal growth,
and reduced
microhardness.
Studies such as these
highlight the role of
microRNAs in tooth
development and
suggest that
disturbances in
microRNAs may result in
tooth developmental
abnormalities.