Inheritance and malocclusion  / /certified fixed orthodontic courses by Indian dental academy
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Inheritance and malocclusion / /certified fixed orthodontic courses by Indian dental academy




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    Inheritance and malocclusion  / /certified fixed orthodontic courses by Indian dental academy Inheritance and malocclusion / /certified fixed orthodontic courses by Indian dental academy Presentation Transcript

    • INDIAN DENTAL ACADEMY Leader in continuing dental education
    •  Basic Principles in Genetics.  Recent advances in genetics and molecular biology.  Inheritance and Malocclusion.  Research objectives in Craniofacial Genetics.  Role of heredity in specific malocclusions.  Genetics and Craniofacial Syndromes  Orthodontic Implications.
    • Basic Principles and Terminology in Genetics: The science of genetics is concerned with the inheritance of traits, whether normal or abnormal, and with the interaction of genes and the environment. Consideration of the heritability of a particular feature or trait requires a consideration of the relationship between genotype and phenotype.
    • Genotype is defined as the genetic constitution of an individual, and may refer to specified gene loci or to all loci in general. Phenotype of an individual is the final product of a combination of genetic and environmental influences. Phenotype may refer to a specified character or to all the observable characteristics of the individual. Heritability: The proportion of the phenotypic variance attributable to the genotype.
    • Levels of Genetic Variation : I. Specific traits •Individual genotypes are readily identified and differences are qualitative (discrete), for example, the ABO blood antigen system. • Gene frequencies can be estimated and the Mendelian type of analysis can be applied.
    • II. Quantitative traits •Traits such as height, weight, or tooth size differences, characterized quantitatively between individuals. • More elusive to study because they are determined by the alleles of many gene loci and, therefore, the Mendelian type of analysis is not appropriate. •Further modified by environmental conditions which obscure the genetic picture.
    • Genetic differences caused by the segregation of many genes is referred to as polygenic variation and the genes concerned are referred to as polygenes. They are subject to the same laws of transmission and have the same general properties as the single genes involved in qualitative traits, but segregation of genes is translated into genetic variations seen in continuous traits through polygenes. If the genetic variation of a particular phenotypic trait is dependent on the simultaneous segregation of many genes and affected by environment it is referred to as being subject to multifactorial inheritance.
    • Difficulties in determination of heritability for multifactorial characters: A feature of continuous variation is that different individuals may occupy the same position on the continuous scale for different reasons. e.g. Micrognathia can occur in: Chromosomal disorders such as Turner's Syndrome •Monogenic disorders such as Treacher Collins or Sticklers Syndrome, Syndrome •An intra-uterine environmental problem, such as foetal alcohol syndrome.
    • Concept of etiological heterogeneity: The same gene defect can produce different phenotypic anomalies, and syndromes can be due to defective gene activity in different cells. Conversely, different gene defects or combinations of defective genes can produce a similar phenotypic abnormality. Genetic lethality or reduced reproductive fitness can also complicate the diagnostic picture and genomic imprinting can result in a gene defect `skipping' a generation.
    • Categorization of Multifactorial Traits I. Discontinuous multifactorial traits: Traits determined by multiple gene loci, which are present or absent depending on the number or nature of the genetic, and/or environmental factors acting. There is an underlying scale of continuous variation of liability to develop the condition resulting from a combination of all the genetic and environmental influences involved. The condition is present only when the liability exceeds a critical threshold value.
    • More than 20 discontinuous multifactorial traits have been described in humans. Cleft lip and palate is a congenital malformation inherited as a discontinuous multifactorial trait. In the mildest form the lip alone is unilaterally cleft, whereas in the most severe form the lip is bilaterally cleft and the palatal cleft is complete. The parents of a cleft lip and palate proband are often unaffected, and there may be no family history of cleft lip and palate, but by producing an affected child the parents are deemed to have some underactive genes for cleft lip and palate formation. Only when the balance exceeds a certain threshold will the malformation occur, and the further the threshold is exceeded, the greater the extent of the malformation.
    • II. Continuous multifactorial traits: Many normal human characteristics are determined as continuous multifactorial traits. These traits by definition have a continuously graded distribution e.g. for height there is a range from the very tall to the markedly short with the mean of 169 ± 6.5 cm in English males (Connor and Ferguson Smith, 1993). The majority of individuals are centered around the mean. Such distribution is characteristic of a continuous multifactorial trait. Malocclusion should be regarded not as abnormal or as a disease, but as a variation of occlusion in a continuous multi-factorial trait.
    • Recent advances in Genetics and Molecular Biology: Recent advances in molecular biology and in human genetics have had a considerable influence in the understanding of orofacial genetics. Some insight into the genetic mechanisms involved in craniofacial morphogenesis at the molecular level in the embryo assists our appreciation of the role of genetics, not only in the etiology of craniofacial abnormalities, but also in the regulation of maxillary, mandibular, and tooth morphology.
    • Facial development in the embryo is demarcated by the appearance of the pre-chordal plate (the cranial end of the embryo) on the 14th day of development. One of the most unusual features of vertebrate facial development is the origin of the facial mesenchyme, which arises from neural crest cells. Neural crest cells are a transient population of embryonic cells that originate from the dorsal aspect of the neural tube and migrate through the trunk and head in vertebrates to form a diverse set of cell types.
    • The Cranial Neural Crest Cells arise from the Rhombencephalon or hindbrain and migrate ventrolaterally taking three pathways to produce craniofacial mesenchyme, which get differenciated into cartilage, bone, cranial neurons, glia and connective tissue. Role of Homeobox genes: Edward Lewis was the first person to identify the homeotic genes in the fly, which help in controlling the developmental response of groups of cells along the body’s antero-posterior axis. In animals, these geneshomeobox genes, are regarded as master genes of the head and face.
    • The first vertebrate homeobox gene was cloned in the frog ( Xenopus levis) and was soon followed by cloning in mouse. The vertebrate genes are called HOX genes and consist of 39 genes in humans as well as mice. They are arranged in 4 different clusters- HOX A, HOX B, HOX C, HOX D, on 4 different chromosomes. As the neural crest cells migrate from the rhombomeres to the specific branchial arches, they retain a specific homeobox code, which specifies the form and pattern of different derived regions of the head and neck.
    • The sub-families of the HOX genes which are of particular interest in craniofacial patterning and morphogenesis, include: Muscle segment (Msx) Distal-less (Dlx) Goosecoid (Gsc) Otx gene. Bar Class Paired related genes (Prx and SHOT) LIM homeobox gene.
    • The expressions of these genes are mediated through two main groups of regulatory proteins-the Growth factor family and the Steroid/Thyroid/ Retinoic acid Super family. Some of the important regulatory molecules in the mesenchyme, through which homeobox genes information is expressed at the cellular level are: Fibroblast Growth Factor (FGF) Epidermal Growth Factor (EGF), Transforming Growth Factors (TGFα, TGFβ) Bone Morphogenetic Proteins (BMPs) . The most complex part of CNC migration is the understanding of how the combinations of HOX genes are expressed to specify the fate of the cells.
    • Inheritance and Malocclusion Familial tendencies are recognizable in the tilt of the nose, the shape of the jaw and the look of the smile. Certain types of malocclusions run in families. e.g. the Hapsburg jaw (the prognathic mandible of the German and Austrian-Hungarian royal families), as also the Class III malocclusion seen in some Eastern Aleut families.
    • King Charles II of Spain who had a Hapsburg jaw.
    • Past studies of population, families and twins have shown that genetic factors play an important role in almost every aspect of craniofacial growth and development, as also does environment. The important question is not whether there are inherited influences on the jaws and teeth, because they obviously are, but whether malocclusion is often caused by inherited characteristics ?
    • Malocclusion could be produced by inherited characteristics in two major ways: Inherited disproportion between the size of teeth and the size of the jaws: causing either crowding or spacing. Inherited disproportion between the size or the shape of the upper and lower jaws:causing improper occlusal relationships.
    • Dental anthropological evidence shows that population groups that are genetically homogeneous tend to have normal occlusion. E.g.In pure racial stocks, such as the Melanesians of the Philippine islands. In heterogeneous populations, the incidence of jaw discrepancies and occlusal disharmonies is significantly greater. . E.g. Modern U.S. society.
    • Stockard (1941) carried out breeding experiments with dogs and concluded that: Individual features of the craniofacial complex could be inherited according to Mendelian principles independently of other portions of the skull. Jaw size and tooth size could be inherited independently, and as genetically dominant traits.
    • Chung, Niswander and Runck (1971) studied the effect of intermixing of European, Japanese and Chinese races with native Polynesians of Hawaii, on the malocclusion in their descendents. Their study showed that the effect of inter racial crosses on malocclusion is additive rather than multiplicative. No independent inheritance of discrete morphologic characteristics like tooth and jaw sizes.
    • Research Objectives in Craniofacial Genetics: Smith and Bailitt ( Angle Orthod 1977) listed 5 main research objectives in studying genetics and dental occlusion. Elucidating modes of inheritance. Detecting the effects of admixture and inbreeding Performing linkage analyses.  Estimating heritabilities. Comparing population differences.
    • Linkage Analyses: Linkage studies in humans have been mainly restricted to studies of the sex chromosomes. Cephalometric analysis of a sample of 47,XXY (Klinefelter) males indicates pronounced facial prognathism especially in the mandible. Mandibular corpus length is significantly increased and there is a tendency for reduction of the cranial base angle.
    •  Studies of 45, X females indicate a retrognathic face, with short mandible and flattened cranial base angle.  There is an increased prevalence of crossbite, large maxillary overjet, distal molar occlusion and a tendency to open bite.  The X chromosome is thought to influence growth of the cranial base at the synchondroses, and also exerts a direct effect on mandibular shape.
    • Estimation of Heritability:  There are two main analytic methods for estimation of heritability of genetic traits Twin studies and family line studies. The twin method , gives geneticists one of the most informative techniques available for analysis of complex.genetic traits The procedure is based on the fact that there are two different types of twin pairs: Monozygous or identical twins and dizygous or fraternal twins
    • Differences between members of a monozygous pair are entirely non-genetic (environmental ) in origin Differences between dizygous twins, who share 50 % of their total gene complement, are due to a combination of genetic and environmental influences. A prerequisite to the use of twins in studying the genetic contribution to observed variation is a reliable diagnosis of zygosity, and the accurate classification of twin pairs as either monozygotic or dizygotic.
    • Methods used to classify twins.  Blood and serum group matching  Use of DNA markers, especially micro satellites.  Methods from classic anthropology i.e. on the basis of hair color and texture, eye color, shape of chin, ears, nose and mouth, dermatoglyphics , as well as skin color and texture, as well as individual tooth morphology.  Comparison of anthropological and serological methods show no divergence between the two approaches.
    • Data on Craniofacial structure: Hunter (1965) analysed cephalometric data from 35 dizygotic and 37 monozygotic twins. Measurements of facial skeletal height demonstrated a significantly higher component of heritibility than did depth dimensions. Similar findings have been reported by Lundstrom and McWilliam (EJO 1987), Savoye et al (Angle Orthod. 1998) and Manfredi et al (AJO1997)
    •  Kraus et al (AJO DO 1959) found the shape and growth of the individual bones of the skull and face to be under strong genetic control, although environmental factors have an important role in determining the inter bone relationships.  Nakata et al (AJO 1973) also reported similar findings.  Naini and Moss (AJO DO 2004) used 3D optical surface scanning to assess genetic contribution to external facial features in twins, and reported significant genetic determination for the midface region, as well as for vertical facial dimensions.
    • Data on Occlusal structure:  Lundström (1948) used the difference between quantified occlusal variables in monozygotic (MZ) and dizygotic (DZ) twins to measure genetic and nongenetic variance ratios. Overjet was most highly heritable with a 3/1 ratio of genetic to nongenetic variance (75 percent heritability). Arch-width at Pl and Ml, buccal segment relation (sagittal overjet), and overbite were less heritable Generally, heredity and environment appeared about equally important, but heredity was the major etiologic factor in the severe malocclusions.
    •  Corrucini et al ( AJO 1980) studied occlusal relationships in 60 pairs of twins  They reported that significant heritability of overjet, buccal segment relationship, overbite, and total tooth rotation/displacement could not be documented.  Arch size, individual tooth displacement scores, and crossbite, however showed significant genetic variance.  They concluded that environmental determination of occlusal variation is roughly twice as important as was earlier thought.  Study by Corrucini and Sharma (EJO 1986) on Punjabi twins revealed significant genetic control for dental arch and palate dimensions, but environmental influences seemed important for occlusal traits.
    • Data on Tooth structure and dimensions:  Potter and Nance (1976) showed that tooth crown dimensions were largely under genetic control. Larger discordance in dizygotic twins than in monozygotic twins provides strong evidence for the existence of genetic control of individual buccolingual and mesiodistal dimensions. Studies on Punjabi twins showed substantial and complex environmental determination for some dental dimensions, especially in incisors and second molars.
    •       Family line studies:  Korkhaus in 1931 showed a 4 generation family line which exhibited mandibular protrusion.  Downs in 1928 reported on the heritability of Angle’s Class II type of malocclusion.  Lebow and Swain in 1941 presented facial photographs of 7 generations of a family and concluded that repeated appearance of long faces in successive generations cannot be from environmental factors but from hereditary factors.  James Harris et al (AJO 1975) studied 77 families to investigate and identify th mode of transmission of Class II division 1 malocclusion. Results showed that there is a polygenic mode of inheritance.
    •  Nakasima et al (1986) found that the parents of those with a pseudo mesioocclusion had a similar prognathic skeletal profile as do the parents of true mesioocclusion patients.  This indicates a familial tendency in the development of pseudo as well as true mesio-occlusion.
    • Population differences:  Relatively high frequency of Class II and low frequency of Class III occlusion in North American Caucasian and European populations.  Presence of the reverse situation in some groups of Asian origin, including Polynesians, Alaskans, Aleuts, American Indians and Pacific islanders.  Grewe (1968) showed that the tendency toward Classs II relationships in North American Indians increased in relation to the proportion of Caucasian ancestry. A similar effect was seen in Polynesian-Caucasian hybrids. Higher prevalence of bimaxillary protrusion of the jaws in African people as compared to Caucasians.
    • Role of Heredity in Specific Malocclusions:  Etiology of Crowding and Malalignment: Continuing evolutionary reduction in jaw size. Additive effects on malocclusion due to out breeding. Other important factors may be environmental e.g. alterations in diet, mouth breathing.
    •  Class II Division 1 Malocclusion:  The mandible is significantly more retruded than in Class I patients, with the body of the mandible smaller and overall mandibular length reduced.  Higher correlation between the patient and his immediate family than among random pairings of unrelated siblings.  This supports the concept of polygenic inheritance for Class II division 1 malocclusion.  Environmental factors can also contribute to the etiology e.g. lip/tongue contact for an anterior oral seal, digit sucking habits, lip incompetence
    • Class II Division 2 Malocclusion:  Distinct clinical entity which may be considered as a syndrome  Unique combination of deep overbite, retroclined incisors, Class II skeletal discrepancy, high lip line with strap-like activity of the lower lip, and active mentalis muscle.  Often accompanied by a poorly developed cingulum on the upper incisors and a characteristic crown root angulation. Peck et al. (1998) also describe characteristic smaller than average teeth when measured mesio-distally.   Tendency to a forwardly rotating mandibular development which in turn, has an influence on the position of the lower lip relative to the upper incisors, and an increase in masticatory muscle forces
    •  Familial occurrence of Class II division 2 has been documented in several published reports including twin and triplet studies e.g. Korkhaus (1930), Markovic (1992), Peck et al. (1998).  Markovic (1992) carried out a clinical and cephalometric study of 114 Class II division 2 malocclusions (48 twin pairs and six sets of triplets)  Of the monozygotic twin pairs, 100 per cent demonstrated concordance for the Class II division 2 malocclusion, while almost 90 per cent of the dizygotic twin pairs were discordant.  This is strong evidence for genetics as the main etiological factor
    •  Genetic influence is probably autosomal dominant with incomplete penetrance and variable expressivity.  It could also be explained by a polygenic model with a simultaneous expression of a number of genetically determined morphological traits acting additively.  Controversy regarding the etiology arises from a failure to appreciate the synergistic effects of genetics and environment.  Ballard (1963), Houston (1975) Mills (1982), and others considered that a high lip line, and a particular lip morphology and behavior were the main etiologic factors.  (Lauweryns et al. (1995) found strong genetic factors in certain aspects of masticatory muscle behavior.
    • Class III Malocclusion:  Strohmayer (1937) concluded from pedigree analysis of the Hapsburg family line that the mandibular prognathism was transmitted as an autosomal dominant trait.  Suzuki (1961) studied 243 Japanese families and noted that there was a significantly higher incidence of the trait in family members of cases who had mandibular prognathism.  Schulze and Weise (1965) reported that concordance for mandibular prognathism in monozygotic twins was six times higher than among dizygotic twins.  Both of the above studies report a polygenic hypothesis as the primary cause for mandibular prognathism.
    •  A Class III malocclusion may result from deficiency in maxillary growth, excessive mandibular growth, or a combination of both. Influence of a distinctive cranial base morphology with a more acute cranial base angle and shortened posterior cranial base resulting in a more anterior position of the glenoid fossa, thus contributing to the mandibular prognathism (Ellis and McNamara, 1984; Singh et al., 1997) Environmental factors e.g.enlarged tonsils, nasal blockage, congenital anatomic defects, hormonal disturbances, endocrine imbalances, posture, trauma/disease, including premature loss of the first permanent molars.
    •  Litton et al. (1970) proposed a polygenic model with a threshold for expression to explain familial distribution, and the prevalence within the general population and in siblings of affected persons.  They also made the suggestion that different modes of transmission might be operating in different families or different populations.  Soft tissues do not generally play a part in the etiology of Class III malocclusion, and may in fact have a compensatory effect. 
    • Hypodontia and microdontia.  Studies of different populations indicate a wide variability in the incidence of hypodontia.  Some authors have reported the permanent maxillary lateral incisor as most commonly missing, while others have reported the mandibular 2nd premolar as being so.  Agenesis of teeth is generally related to an overall reduction in tooth size. Hence, hypodontia and microdontia tend to occur in the same children.
    •  Hypodontia is, to a great degree, genetically determined, and transmitted by an autosomal dominant inheritance with incomplete penentrance and variable expression.  Environmental factors may also play a role. A mutation in the homeobox gene MSX1 has been implicated as a factor in familial selective agenesis of second premolars and third molars.  The increased incidence of hypodontia in children with clefts suggests that the same etiologic factors might be responsible for both the anomalies in affected
    • Maxillary Canine Impaction  Buccal impaction of the maxillary canine is usually due to inadequate arch space and it eventually results in eruption in most cases.  In contrast, palatal displacement of the maxillary canine is a positional anomaly that generally occurs despite adequate arch space.  Peck, Peck and Kataja (Angle Orthod 1994) support a genetic etiology for the palatally displaced canine (PDC) on the basis of five evidential categories: 
    • 1. Occurrence of other dental anomalies concomitant with PDC 2. Bilateral occurrence of PDC 3. Sex differences in PDC occurrence. 4. Familial occurrence of PDC. 5. Population differences in PDC occurrence. From analysis of available evidence, the PDC positional anomaly appears to be a product of polygenic, multifactorial inheritance.
    • Tooth Transpositions. Def: Positional interchange of two adjacent teeth – particularly of the roots – or the development or eruption of a tooth in a position occupied normally by a nonadjacent tooth. The Maxillary Canine-1st premolar transposition has been the most frequently reported type of transposition, with a low prevalence rate ranging from 0.03% (Sweden) to 0.25% (Scotland). Peck, Peck and Attia (Angle Orthod 1993) gathered data from 43 cases with this anomaly. They found a number of factors to be associated with it.
    • Increased frequency of associated dental anomalies (tooth agenesis, 37%, and peg-shaped maxillary lateral incisors, 16%). Bilateral occurrence in a high percentage of cases (23%). Familial occurrence (one pair of identical twins). Different pattern of occurrence in males and females (females predominate, 34 to 9). Different frequency of occurrence likely in different populations (40 whites and 3 blacks). It appears that the Mx.C.P1 transposition anomaly is polygenic in origin, fitting into the broader pattern of multifactorial inheritance.
    • Midline diastema.     Maxillary midline diastema (MMD) is a relatively common dental malocclusion characterized by a space between the maxillary central incisors, with functional and esthetic consequences. The literature strongly supports racial differences in the distribution of the trait, with blacks demonstrating consistently higher prevalence values than Whites, Asians, or Hispanics. Nainar and Gnanasunderam( Angle Orthod 1999) mention that familial incidence was 1 of 3 significant factors associated with the prevalence of MMD. Shashua and Artun ( Angle Orthod 1999) reported that a family history of diastema was 1 of 2 significant factors for diastema relapse after orthodontic correction.
    •  Gass, Valiathan, Tiwari, Hans and Elston (AJODO 2003) reported that MMD is more heritable in Whites than in Blacks.  Environmental influences such as periodontal drift, unreported habits, inaccurately reported missing teeth, or excessive incisor proclination might be responsible for higher prevalence rate in Blacks.  The data from their study also suggested an autosomal dominant mode of inheritance of maxillary midline diastema.
    • Genetics and Craniofacial Syndromes. Holoprosencephaly: Malformation sequence in which impaired midline cleavage of the embryonic forebrain is the main feature. Associated facial anomalies in this syndrome include cyclopia, arhinia, median cleft lip, lateral cleft lip.
    • A number of mutations in several genes have been identified as causative, of which the best known is Sonic Hedgehog (SHH). Other gene mutations involve TGIF, SIX3, PTCH.
    •  Craniosynostosis:  Defined as the premature fusion of skull bones. It is found in association with a number of different disorders.e.g. Crouzon, Apert, Jackson-Weiss, Pfeiffer, Beare-Stevenson, and Saethre-Chortzen syndromes.  Crouzon Syndrome: Characterized by craniosynostosis of coronal sutures leading to brachycephaly.Additionally, there is a high prominent forehead, hypertelorism, strabismus, midface hypoplasia, prominent beaked nose, high arched palate, mandibular prognathism, dental malocclusion.
    • Typical picture of Crouzon Syndrome.
    •  Genetic etiology: Mutations in the Fibroblast Growth Factor Receptor (FGFR) genes with resultant gain of function, especially in FGFR2 have been identified in various craniosynostosis syndromes.  Also chromosomal alterations leading to loss of function in the TWIST gene, are implicated.
    • Treacher Collins Syndrome  Autosomal dominant disorder consisting of bilateral zygomatic hypoplasia, downslanting palpebral fissures, dysplastic ears, downturned mouth and hypoplastic mandible.
    •  Cleft  palate may also be present. Malocclusion is common, and hypoplastic teeth as well as open bite may be present.  Genetic Etiology: Mutations in the TCOF1 gene.
    • Orofacial Clefting. Much evidence supports the role of genetics in orofacial clefting. Concordance for MZ twins with cleft lip-palate(40%) is far greater than for DZ twins (4.2%). Various factors have been implicated such as major genes, minor genes, environmental factors, and developmental threshold. Two important genes implicated in clefting are MSX1 and TGFß3
    • Orthodontic Implications:      Each malocclusion occupies its own distinctive slot in the genetic/environmental spectrum. The goal of diagnosis includes determination of the relative contribution of genetics and environment. The greater the genetic component, the worse the prognosis for a successful outcome by means of orthodontic intervention. There is also, currently a lack of evidence to show that orthopedic appliances can influence the growth of skeletal bases significantly beyond their innate genetic potential. Further advances in the field of molecular genetics should contribute to a better understanding of heritability of malocclusions in the future.
    • References       Mossey P.A. The Heritability of Malocclusion: Part 1. BJO 1999;26(2): 203-213. Mossey P.A. The Heritability of Malocclusion: Part 2. BJO 1999; 26(3):195-203. Smith R.J., Bailit H. Problems and methods in Research on the genetics of Dental occlusion. Angle Orthod. 1977; 47(1): 65-81. Townsend G, Aldred M, Bartold P. Genetic aspects of dental disorders. Austr. Dent J 1998;43(4):269-286. Krishnan V. Neural Crest cells, Homeobox genes and craniofacial development. J Ind Orthod Soc 2002;35: 4250. Markovic M. At the crossroads of oral facial genetics. EJO 1992; 14: 469-481.
    •       Nainar SMH, Gnanasundaram M. Incidence and etiology of midline diastema in a population in South India. Angle Orthod 1989;59:277-82. Gass J, Valiathan M, Tiwari H, Hans M, Elston R.Familial correlations and heritability of maxillary midline diastema AJODO 2003 123 (1):35-39. Corrucini RS, Potter R.Genetic analysis of occlusal variations in twins. AJO 1980;78: 140-154. Lauweryns I. The use of twins in dentofacial genetic research. AJO-DO 1993;103:33-38. Sharma K, Corruccini R. Genetic basis of dental occlusal variations in northwest Indian twins. EJO 1986;8: 91-97. Lundstrom A, McWilliam J. A comparison of vertical and horizontal cephalometric variables with regard to heritability. EJO 1987;9:104-108.
    •      Chung C, Niswander J. Genetic and epidemiologic studies of oral characteristics in Hawaiian schoolchildren V. J Dent Res 1975;54:324-29. Shapira Y, Lubit E, Kuftinec M. Hypodontia in Children with various types of clefts. Angle Orthod 2000;70:16-21. Peck S, Peck L, Kataja M. The palatally displaced canine as a dental anomaly of genetic origin. Angle Orthod 1994;64:249-56. Peck L, Peck S, Attia Y. Maxillary canine-first premolar transposition, associated dental anomalies and genetic basis. Angle Orthod 1993;63:99-109. Rimoin D, Connor J, Pyeritz R, Korf B. Principles and Practice of Medical Genetics .2002. 4th edn. Churchill Livingstone Co.
    • Thank you Leader in continuing dental education