GENETICS AND MALOCCLUSION
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INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com
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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 www.indiandentalacademy.co m
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.
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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. www.indiandentalacademy.co m
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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.
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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. www.indiandentalacademy.co m
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. www.indiandentalacademy.co m
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.
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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 www.indiandentalacademy.co ancestral cluster. m
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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)
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.
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In the developing head, this spatially restricted limits of Hox gene expression corresponding to rhombomeres boundaries at two-segment intervals.
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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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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).
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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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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.
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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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• 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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The hindbrain itself is known to be a segment structure composed of eight subunits called rhombomeres (Lumsden and Keynes, 1989).
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Rhomomeres are important segmental unit of organization, which have distinct morphological properties that vary with a two-segment periodically.
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). www.indiandentalacademy.co m
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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).
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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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• 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. www.indiandentalacademy.co m
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.
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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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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窶田ontaining transcription factor it would appear that goosecoid is involved in essential inductive tissue interactions during the formation of the head.
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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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•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). www.indiandentalacademy.co m
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 www.indiandentalacademy.co m
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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).
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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). www.indiandentalacademy.co m
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).
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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. www.indiandentalacademy.co m
• 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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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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• 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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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).
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Ivens et al (1990) localized this gene to chromosome 4p16.1 and mutation of this gene has been associated with facial and dental abnormalities. www.indiandentalacademy.co m
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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.
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. www.indiandentalacademy.co m
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. www.indiandentalacademy.co m
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).
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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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• 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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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.
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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. www.indiandentalacademy.co m
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.
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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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• 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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Inger kjaer (EJO 2001) reported that less severe cases of holoprosencephaly is characterized by a solitary median maxillary central incisor (SMMCI)
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 www.indiandentalacademy.co development of teeth. m
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 epitheliumwww.indiandentalacademy.co and mesenchyme. m
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. www.indiandentalacademy.co m
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. www.indiandentalacademy.co m
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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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. www.indiandentalacademy.co m
• 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. www.indiandentalacademy.co m
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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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
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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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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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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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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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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.
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Also mutation of PAX-9 transcription factors has been observed in familial tooth agenesis and also in missing mandibular second premolars and central incisors.
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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. www.indiandentalacademy.co m
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 www.indiandentalacademy.co supernumerary teethmalso supports this theory (Jasmin
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.
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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.
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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 www.indiandentalacademy.co Martin, 1992). m
SUBMERGED PRIMARY MOLARS 
Primary molar submergence occurs most often in the mandibular arch with a wide variation in the reported population (Kurol, 1980).
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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. www.indiandentalacademy.co m
ECTOPIC ERUPTION AND TRANSPOSITION OF CANINES 
Various studies in the past have indicated a genetic tendency for ectopic maxillary canines.
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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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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. www.indiandentalacademy.co m
• 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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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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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.
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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 www.indiandentalacademy.co across sutures and to individual bony contours such m as the mandible.
• 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. www.indiandentalacademy.co m
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. www.indiandentalacademy.co m
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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. www.indiandentalacademy.co m
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.
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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. www.indiandentalacademy.co m
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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• 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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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.
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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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• 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. www.indiandentalacademy.co m
• 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. www.indiandentalacademy.co m
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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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.
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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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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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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.
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High genetic determination was found for the vertical proportions. www.indiandentalacademy.co m
Yamaguchi (AJO 2001) studied the association of the growth hormone receptor gene variant and mandibular height in the normal Japanese population. •
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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. www.indiandentalacademy.co m
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.
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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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• 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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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.
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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. www.indiandentalacademy.co m
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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.
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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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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
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
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. www.indiandentalacademy.co m
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. www.indiandentalacademy.co m
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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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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Various transcription factors and growth factors are involved in non syndromic cleft lip/cleft palate where mutations in these factors results in the disorder FACTORS TRANSCRIPTION GROWTH FACTORS Genes
Loci
Homeobox genes
Genes
Loci
Transforming Growth Factor α (TGF α)
2p11-13
Transforming Growth Factor β (TGF β)
14q23-24
Retinoic Acid Receptor Alpha (RARA)
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) www.indiandentalacademy.co 2q31 m
19q13.1
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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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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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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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.
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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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Congenital healed cleft lip (CHCL) 
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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. www.indiandentalacademy.co m
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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ALVEOLAR CLEFTS
Alveolar clefts are associated with oral- facial digital syndromes
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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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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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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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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. www.indiandentalacademy.co m
There is hypertelorism, strabismus, midface hypoplasia, a prominent beaked nose, high arched palate, mandibular prognathism and dental malocclusion.
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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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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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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. www.indiandentalacademy.co m
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 m
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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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. www.indiandentalacademy.co m
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’. www.indiandentalacademy.co m
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. m
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. www.indiandentalacademy.co m
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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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. www.indiandentalacademy.co m
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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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. www.indiandentalacademy.co m
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