GENETICS IN ORTHODONTICS

Presented byJasbir meher Jr-1

CONTENTS
Introduction
History of Genetics Mendelian Genetics Beyond Mendel

Basic terminologies in Genetics

Mode of inheritance Homeobox genes Genetic basis of malocclusion Family study Twins study Class-I malocclusion

Class-II div-I malocclusion

class-II div-II malocclusion Class-III malocclusion

 Genetic influence on tooth no,size,morphology,position and eruption Disorders of tooth development Molecular genetics in craniofacial dysmorphology

Butlers field theory

Practical and clinical implications Conclusion References

INTRODUCTION

The relative contribution of genes and the environment to the etiology of malocclusion has been a matter of controversy throughout the 20th century. Genetic mechanisms are clearly predominant during craniofacial morphogenesis but environment is also thought to influence dentofacial morphology postnatally.

WHY SHOULD A STUDENT OF ORTHODONTICS BE INTERESTED IN GENETICS????

The key to the determination of the etiology of malocclusion lies in the ability to differentiate the effect of genes on the craniofacial skeleton in a particular individual. Genes effect growth and development and function of oral and facial structures which is important for an orthodontics. Orthodontists may be interested in genetics to help understand why a patient has a particular malocclusion and if the problem is genetic they may be limited in what they can do.

HISTORY
Farmers since Babylonian times, about 6000 years ago, have always understood many issues of animal and plant pedigree, recognizing that the characteristics of the parents in sexual reproduction are something of a guarantee of certain characteristics in the offspring.

The ancient Egyptians practiced cross pollination in order to improve the quality and quantity of a crop.

 William Bateson was a British geneticist. He was the first person to use the term genetics to describe the study of heredity and biological inheritance.

He was the first to suggest the word "genetics" (from the Greek genno, i.e. to give birth) to describe the study of inheritance and the science of variation

He first used the term "genetics" publicly at the Third International Conference on Plant Hybridization in London in 1906.

 Pythagoras (550 BC) in a doctrine which lasted at least until the Renaissance, held that the male semen was created from fluid collected from the entire body.
The male parent played the dominant role in determining the form Of the child. The mother served as the receptacle for the embryo formed entirely from male material.

 Aristotle, postulated that semen was purified blood. Both parents contributed purified blood to the embryo, but the male semen was more purified than the female menstrual fluid.

Thus, the male semen was the source of life and form; the female material was the matter, or building material.

 In the 17th and 18th centuries separate studies by William Harvey (1578-1657) and Anton van Leeuwenhoek (16321723 led to the discovery of the production of eggs in female animals. And of the union of the egg and the sperm as the creative act forming an embryo, which then went through a series of developmental stages.

 The Dutch scientist Jan Swammerdam (1637-1680) proposed that each sperm contained, in miniature, a complete human being (tiny babies were contained in the heads of each of the sperm).

This theory suggested that the mother provided only the location and nourishment for the growth of the embryo, since the male sperm contributed everything else

 Pierre Louis Maupertuis (1698-1759) proposed that the reproductive material contained small particles which had the power to organize the body parts and that in the combination of these particles. The contribution of one parent might exert a stronger influence than the contribution of another (an early anticipation, although without experimental evidence, of the idea of dominant and recessive particles).

 Charles Robert Darwin (1809 -1882 was an English naturalist. After becoming eminent among scientists for his field work and inquiries into geology. He proposed and provided scientific evidence that all species of life have evolved over time from one or a few common ancestors through the process of natural selection.

Gregor Johann Mendel (1822-1884) was an Augustinian priest and scientist, and is often called the father of genetics for his study of the inheritance of traits in pea plants. Mendel showed that the inheritance of traits follows particular laws, which were later named after him. Studied segregation of traits in the garden pea (Pisum sativum) beginning in 1854. Presented his paper on Experiments with Plant Hybridization in 1866.

Mendels laws
Law of Uniformity A unit of genetic information is transmissible unchanged from generation to generation. Law of Segregation Alternate forms of the gene must segregate during gamete formation and recombine independently in the offspring to provide ratio of 1:2:1. Law of Independent assortment Independent assortment occurs only when genes affecting different characters are on different chromosomes. In other words genes that are not alleles are distributed to gametes independently to each other.

BEYOND MENDEL
In 1900 paper quoted by 3 European botanists Hugo De Vries, Carl Correns & Von Tschermark resurfaced the work of Mendel and this marked the real beginning of medical genetics.

Evidence for DNA as genetic material. In 1928 E.Griffith in his experiments with S.pneumoniae found that there is transforming factors which converted non lethal strains to lethal ones.

 In 1952 Hershey & Chase published a research that supported the notion that DNA is the genetic material using bacteriophages.

BASIC TERMINOLOGIES
Genetics
The branch of biology which deals primarily with the principles of heredity & variation & secondarily with the role of environmental factors as they interact with genes in the development of an individual.

Chromosome
A threadlike linear strand of DNA and associated proteins in the nucleus of eukaryotic cells that carries the genes and functions in the transmission of hereditary information.

Chromatid
it is the name given to the material of which chromosomes are made.

Gene
A segment of a DNA molecule that contains all the information required for synthesis of a protein. It is the biological unit of heredity transmitted from parent to progeny.

Locus:
The position that a given gene occupies on a chromosome.

Alleles:
Different forms of genes at the same locus or position on the chromosome.

Homozygous:
If both copies of genes are identical.

Heterozygous:
If the two copies of genes differ.

Autosome
It is any chromosome other than the sex chromosome.

Genotype
Genetic constitution of an individual.

Phenotype
It is the final product or all the observable characteristics of an individual.

Depends on genotype and environmental factors.

DNA:
The molecule that encodes genetic information in the nucleus of cells. It determines the structure, function and behaviour of the cell .

RNA:
A polymeric constituent of all living cells and many viruses, consisting of a long, usually single-stranded chain of alternating phosphate and ribose units with the bases adenine, guanine, cytosine, and uracil bonded to the ribose. The structure and base sequence of RNA are determinants of protein synthesis and the transmission of genetic information.

Mitosis
The process by which a cell divides and produces two daughter cells identical to parent cell.

Meiosis
The process of cell division in sexually reproducing organisms that reduces the number of chromosomes in reproductive cells from diploid to haploid, leading to the production of gametes in animals and spores in plants.

GENETIC DISORDERS
Genetic disorders in a general aspect can be considered to be of twotypes: Numerical disorder. Structural disorders. Numerical disorders:-

These are those in which there is a change in the number of chromosomes with in the cell.
Eg:-Polyploidy Monosomy Trisomy

Turners syndrome.
Klinefelters syndrome. Structural disorders:Those in which there is change in basic composition & structure of chromosomes.

Eg:-Translocation
Deletions Ring chromosomes.

MODE OF INHERITANCE
Trait:
It is a particular aspect or characteristic of the phenotype,
E.g. no of teeth, arch length and width. Depending on the genetic influence on traits ,it is of 3 typesi)monogenic, ii)polygenic, iii)multifactorial

Monogenic traits These develop because of influence of single gene locus. They can also be described as discrete or qualitative. The traits in peas that Mendel described in his inheritance studies happened to be monogenic. Hence monogenic traits are sometimes called Mendelian traits. It can be expressed by any of the following mode of inheritanceAutosomal Dominant

If a trait or disease manifests itself when the affected person carries only one copy of the gene responsible along with one normal allele, the mode of inheritance of the trait is dominant.

Autosomal recessive-

If two copies of the defective gene are required for expression of the trait.
X linked recessive Full expression of rare X linked recessive phenotypes is almost completely restricted to males. The genes must be present at same locus in females to express themselves fully.

Polygenic/ Multifactorial traits Refers to the genetic differences caused by the segregation of many genes and the concerned genes are called polygenes. Many gene loci collectively assert their influence on the trait. Along with genes the trait are also affected by the environment.

MODE OF TRANSMITION OF MALOCCLUSION

1.REPETITIVE TRAITS:- Recurrence of single dentofacial deviation with in the immediate family and in the progenitors.

Seen generation after generation.

2.DISCONTINUES TRAITS:- Recurrence of a tendency for a malocclusal trait to reappear in the family background over several generations.

Seen in family but not in all generations.

VARIABLE TRAITS: O ccurrence of different but related type of malocclusion within several generation of same family.

Traits seen with variable expression . E.g, missingteeth, which are commonly seen feature in some families, but the same teeth may not be missing in different generations or with in the same generation.

HOMEOBOX GENES
These are regarded as master genes of head & face ,having prominent control over craniofacial development. These genes were first discovered by W.Gehring & colleagues in fruit fly Drosophila melanogaster, in which a group of genes called homeotic genes which specify the general body plan of the fly. A gene containing a short DNA sequence of about 180 base pairs referred to as a homeobox. The nucleotides of the homeobox are translated into a peptide region of 60 amino acids called Homeo domain. In a landmark survey done using DNA of different species it was confirmed that homeobox were not only found in insects but also in vertebrates.

 The degree of sequence similarity between Drosophila and human homeobox confirmed that the genetic control of development is universal.
These vertebrate genes are called Hox genes and they are 39 in no. arranged in 4 clusters as HOX A, HOX B, HOX C, HOX D, on 4 different chromosomes. 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 (TGF, TGF) Bone Morphogenetic Proteins (BMPs) .

GENETIC BASIS OF MALOCCLUSION

There is dental anthropological evidence that population groups are generically homogenous tend to have normal occlusion. However in heterogeneous population, the incidence of malocclusion is significantly high. METHODS OF STUDYING HERITABILITY OF MALOCCLUSION The bulk in the evidence for the heritability of various types of malocclusion comes from familial and twin studies. The methods to estimate heritability are based on correlation and measurements of the traits between various kind of pairs of individuals in families.

Family studies
As early as 1921 family studies were conducted. The report of Wingate Todd in 1930 , brought to orthodontics the value of the study of family line. Korkhaus 1931 & Andersons 1944 family line studies concluded that mandibular protrusion showed a definite inheritance pattern.

 Bell 1939 concluded that the restoration of masticatory function and facial symmetry may be accomplished up to the limit of inherited tendency. Downs in 1928 reported on the inheritability of class II type of malocclusion Rubbrecht in 1939 presented family pedigrees of several cases including the nine generation Hapsburg family . The Hapsburg jaw the prognathic mandible of German royal family is a strong indication for genetic control over craniofacial growth. Family study techniques realy largely on screening large populations.

 A comparison of parents and children permits one to identify the structures that present strong similarities. In the absence of any cause the logical hypothesis is to attribute it to similarity between parents /children.

A number of researchers have established that resemblance of facial structures exist in varying degrees( Brown 1961, Curtner 1953,Decoster 1951,Grosser 1961 , Sassouni 1955,62, Wasson 1962).
In 1975 James E Harris et al , conducted a study to establish the importance of familial information in orthodontic diagnosis and treatment planning. they studied the mode of transmission of cl II div 2 malocclusion. 77 families were studied with each family having a child treated for cl II div2 malocclusion.

 Stein 1956 , studied resemblance between adult brothers /sisters and their parents and found strong resemblance in premaxilla position relative to cranial base and slope of lower border of mandible. Brown 1963 , concluded that when parents are prognathic the incidence of mandibular prognathism was twice as frequent.

From these family line studies it may be concluded that cranial base, antero - posterior position of premaxilla and mandible show a strong genetic component of variability.
Overall the evidence suggests that there is polygenic model for inheritance of class II div I malocclusion and family provides the clinician with valuable information in orthodontic diagnosis case assessment and treatment planning.

 Family studies were done mainly using roentgenographic cephalometry.

So useful is cephalometry in genetic studies that Porok in 1963 & Hunter in 1965 suggested the use of cephalometric measurements to determine zygosity. One of the most important and difficult problems in orthodontics is to predict the amount and direction of growth of jaws, since besides modifying the face as a whole ,lack of coordination in this growth may create a malocclusion or worsen an existing one. Examination of patient alone does not make a prediction possible. The study of the hereditary background might permit a more accurate prediction of facial growth.

Twin studies
Twin studies are useful in study of population genetics. To determine the role of genetic and environmental factors. Twins can be dizygotic or monozygotic.

Monozygotic /identical twins

They arise from a single fertilized ovum Identical genetic makeup Same sex Resemble each other

Dizygotic /fraternal twins They develop from two different embryos. Genetically alike like any other siblings. Can be of different sex. Resemblance only like siblings.

Concordant twins:
If both show a trait.

Discordant twins:

If only one shows the trait. If a condition has no genetic component concordance rate would be expected to be same in both type of twins. For a single gene or chromosomal disorder the monozygotic concordance will be 100% whereas the dizygotics rate will be less than this and equal to rate in siblings.

 Goldber in 1929 studied biometrics in 15 pairs of identical twins and concluded that environment did not play a major role. One of the pioneering studies was by Kraus et al 1959,where 6 sets of triplets were tested for genetic determination on 17 skeletal traits. From the study Kraus concluded that morphology of all bones of craniofacial complex was under genetic forces but the variability in craniofacial outline may be due to the environment. In cleft studies , the monozygotic twin concordance rate for CL(p) and for CP is 35 & 26 %, respectively and for dizygotic twins is 5 & 6 %.(Connor & Ferguson smith, 1993)

In studies by Riguelmex green 1970, l.shapiro 1967 on twins for influence of genetic and environmental factors on the palatal dimensions showed the effect of both genetic and environmental factors.

Class II div I malocclusion

The cephalometric studies done on heretability of Class II malocclusion showed that in these patients mandibular body length is small as compared to ClassI patients.

He showed that this type of malocclusion has polygenic inheritance.( Harris DCNA 1975)

A large role is played by environmental factors such as habits like thumb sucking.

Class II div II malocclusion

Class II Div 2 with its distinct & more consistent collection of definable morphological features can be called more of a syndrome rather than malocclusion. 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. Markovic (EJO1992)carried out cephalometric study on 114 Class II Div 2: 48 twin pairs & 6 sets of triplets. Result showed that 100% monozygotic twins were concordant & 90% dizygotic twins were discordant. Mutations of genes such as Treacle that lead to less pronounce changes in protein function or expression may be responsible for the milder cases of mandibular retrognathia commonly seen in orthodontic practice.

Class III malocclusion

A Class III malocclusion may result from deficiency in maxillary growth, excessive mandibular growth, or a combination of both. The relative contribution of genetic and environmental factors to class III has been the subject of many studies. Familial studies of mandibular prognathism are suggestive of hereditary in the etiology of this condition. It is apparent that certain types of malocclusion run in families.

 The Hapsburg jaw, the prognathic mandible of the German royal family, is the best known example, but dentists see repeated instances of similar malocclusion in parents and their offspring.

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.

Genetic influence on tooth number, size,morphology, position and eruption.

Clinical evidence suggests that congenital absence of teeth &reduction in tooth size are associated.
A study of children with missing teeth found up to half of their siblings or parents also had missing teeth .

Supernumerary teeth.
The prevalence of supernumerary teeth in British schoolchildren is 2.1 pc with a male female ratio of 2:1. The most common supernumerary teeth the mesiodens shows inheritance but does not follow a simple Mendalian pattern.

Abnormal tooth shape.

There is substantial evidence that missing and malformed lateral incisors may be a result of a common gene defect.

Variations range from peg shaped to microdont to missing teeth, all of which have familial trends, female preponderance, association with other dental anomalies suggesting a polygenic etiology.

Aspects of tooth morphology such as the Carrabelle trait also seem to be strongly influenced by genes as evidenced by an Australian twin study.

Ectopic Maxillary canines

Various studies in the past have indicated a genetic tendency for ectopic maxillary canines. Peck et al concluded that palatally ectopic canines were an inherited trait, being one of the anomalies in a complex of genetically related dental disturbances. Previous studies have also shown an association between ectopic maxillary canines and Class II divII malocclusion, a genetically inherited trait.

Submerged primarymolars
It occurs most commonly in mandibular arch. There is a high rate of concordance between the monozygotic twins. Number of studies provide evidence for genetically determined primary failure of eruption

Maxillary midline diastema

Numerous etiologies have been proposed toothsize arch length discrepancy ,aberrant labial frenum attachment ,parafunctional habits, tooth loss , periodontal disease, deep bite ,maxillary midline pathology ,broadbent phenomenon .

Gardinger stated that parents &offsprings appear to share dental phenotype ,a few authors found heredity to play a greater role in MMD.

DISORDERS OF TOOTH DEVELOPMENT

Amelogenesis imperfecta
It is a group of genetically inherited disorders affecting enamel formation,it is basically of 4 types(Witkop 1988) Hypoplastic Hypomaturation Hypocalcified

Hypomaturation-hypoplastic with taurodauntism

It is genetically heterogenous with families exhibiting autosomal dominant, autosomal recessive and X-linked inheritance. Genes involved: Amelogenin (AMELX & AMELY) Ameloblastin located in chromosome 21

Dentinogenesis imperfecta
It is autosomal dominant disorder. Type I: DI associated with osteogenesis imperfecta Type II:DI not associated with OI Type III:Maryland/Brandywine type

Mutations in the DSPP (dentin sialophosphoprotein) gene have been identified in people with type II and type III dentinogenesis imperfecta. Type I occurs as part of osteogenesis imperfecta, which is caused by mutations in one of several other genes. The DSPP gene provides instructions for making three proteins that are essential for normal tooth development. Mutations in the DSPP gene may affect the proteins made by the gene, leading to the production of abnormally soft dentin.

Hypodontia
Msx 1 is strongly expressed in dental mesenchyme throughout the bud ,cap &bell stages of odontogenesis . Vastardis et al (1996) demonstrated that a mutation in Msx 1 caused familial tooth agenesis & genetic linkage analysis of a family with autosomal dominant agenesis of 2nd premolar & 3rd molar identified a locus on chromosome 4p as the site of the Msx 1 gene. Genetic factors are believed to play a major role in most of the cases of hypodontia with autosomal dominant, autosomal recessive, X-linked, and multifactorial inheritance reported. A couple of genes (MSXl and PAX9) involved in dentition patterning have been found to be involved in some families with nonsyndromic autosomal dominant hypodontia although there are many other candidate genes, including KROX26.

Solitary median maxillary central incisor syndrome

The presence of a single primary and permanent maxillary incisor which is in the midline and symmetric with normal crown and root shape and size, can be an isolated finding or can be part of the solitary median maxillary central incisor syndrome.

This heterogeneous condition may include other midline developmental abnormalities of the brain and other structures that can be due to mutation in the sonic hedgehog (SHH) gene, SIX3 gene.

MOLECULAR GENETICS IN CRANIOFACIAL DYSMORPHOLOGY

Crouzon Syndrome
In 1912, Crouzon described the hereditary syndrome of craniofacial dysostosis in a mother and son. He described the triad of calvarial deformities, facial anomalies, and exophthalmos. Crouzon syndrome is inherited as an autosomal dominant trait. Mutations in the FGFR2 & FGFR3 genes appear to cause increased proliferation of the osteoprogenitor cells within the sutural mesenchyme. This eventually leads to craniosynostosis.

Treacher Collins Syndrome

In 1900, Treacher Collins described the essential traits of the syndrome that bears his name. Treacher Collins syndrome is also known as Franceschetti-Zwahlen-Klein syndrome or mandibulofacial dysostosis.

Fishlike facial appearance

Dolichofacial pattern Hypoplastic supraorbital rims Hypoplastic zygomas Hypertelorism Down slanted palpebral fissures

 Treacher Collins syndrome is inherited as an autosomal dominant trait.

Mutation on the TCOF-1 gene which codes for the protein treacle needed for migration of neural crest cells in the branchial arches.

Mutation leads to the formation of truncated protein with no function.

Effected structures are those derived from the first and second branchial arches.

DOWNS SYNDROME
Most common chromosomal aberration Down syndrome was first accurately described in 1866 by an English physician named John Langdon Down. Chromosomal abnormalities: Trisomy 21/ extra Ch 21 1 in 600 to 1000 live births

PHYSICAL FEATURES: Head:Prominence of forehead Flattening of occiput Round flat face

Flat nasal bridge

Upward slanting palpebral fissures Limbs: Short and broad Wide space b/w first and second toe. Hypotonia of lower lip.

Cleft lip & palate

Development of the head and face comprises one of the most complex events during embryonic development. Disturbance of this tightly controlled cascade can result in a facial cleft where the facial primordia ultimately fail to meet and fuse or form the appropriate structures.

Occurrence estimates range between 1/300 and 1/2500 births for cleft lip with or without cleft palate and around 1/1500 births for cleft palate alone.
It has been reported that CLP occurs more frequently in males, while the sex bias is reversed for CP, which is more common in females.

Butlers field theory

According to this,mammalian dentition can be divided into several developmental field. The developmental fields include molar/premolar field,the canine field and the incisor field. Within each developmental field there is a key tooth. Ex-1:within molar/premolar field: According to this theory maximum variability will be seen for the 3rd molar. 3rd molar are the most common teeth to be congenitally absent and to be impacted. Variable in size-

3rd molar can be small appearing as microdonts.

They can have small roots and cusps. Variable in form They may have well-formed cusps or several small tubercles.

Some maxilary 3rd molars may not resemble any of the teeth & appear like abnormalities.

 The root can be very short,long often fused,may be separate and sometimes an extra root can be seen. Second molar can also show variation,such as microdontic tooth. When premolars are congenitally absent,the second premolars are more commonly affected than the 1st premolar. Ex-2:within incisor field : According to this theory,the maximum variability will be seen for the lateral incisor. Variability of lateral incisor includes Peg-shaped lateral incisor. Congenitally missing laterals.

Ex-3:within canine field: Canine especially in maxillary arch can be impacted or ectopically erupted.

Practical and clinical implications

In clinical orthodontics it must be appreciated that each malocclusion occupies its own distinctive slot in the genetic /environmental spectrum. The greater the genetic component to the malocclusion, the worse the prognosis for a successful outcome by means of orthodontic intervention. The difficulty, of course is that it is seldom possible to determine the precise contribution from hereditary and environment in a particular case.

For ex- In case of mouth breathing where the influence of habit and posture is very much dependant on the genetically determined craniofacial morphology on which it is superimposed, and the reason for the habit developing may well be dependant on the morphology in the first place.

 This is a classical example of the interaction of genes and environment and ultimately success of treatment will depend on the ability to ascertain the relative contribution of each. 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. Human studies to date tend to support the genetic determination of craniofacial form with a lack of evidence to show any significant long term influence on maxillary and mandibular dental bases using orthopaedic appliances.

Conclusion
We are used to describing the humans in an anatomic manner. The time has come when a number of genes will describe us. Physical characteristics (phenotype) may matter less than the set of genes one carries. (genotype) Classification of characteristics will soon be based on genetic analyses. Orthodontists may have a difficult time changing their morphologic classifications. Ex Angle`s classification. The advent of diagnostic techniques in molecular genetics would make it possible to identify relevant morphogenes and genetic markers or to influence the development of malocclusion, Ex- Eliminating crowding through the selective manipulation of homeobox gene responsible for initiation of tooth formation and patterning.

References
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