Genetics in Orthodontics

Presented by,
Dr. Akash A M
First year MDS
Department of Orthodontics
and Dentofacial
Orthopaedics
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 Contents
1. Introduction 11. Conclus
2. Genetics in orthodontics ion
12.References
3. Why study genetics?
4. Terminology
5. Mode of inheritance
6. Mode of transition of malocclusion
7. Method of studying role of genes
8. Role of homeobox genes
9. Clinical considerations
10. Syndromes

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 Genetics
Genetics is the science concerned with structure & function of all genes in
different organisms. In simple words, it is a field of biological science which deals with
genes, mechanisms of heredity and genetic variations among individuals.

Genetics - Greek word - ‘genetikos’ meaning "generative“ or “origin”

Study of genetics helps to understand about the pattern of inheritance from parents
to offspring and the variation and change in populations.

Genetics explain how every individual is distinguished between each other.

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Joseph Adams is known as the founder of human

genetics Gregor Mendel is know as the Father of modern

genetics.

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 Genetics in orthodontics
Malocclusion is a manifestation of genetic and environmental interaction on
the development of the orofacial region. It is important to consider genetic factors to
understand the cause of existing problems, which has influence on the outcome of
treatment.

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 Why should a student of orthodontics be interested in
genetics?

1. To know exactly why or how malocclusion occurs.

2. To what extent does it express in the next generation.

3. To know prevalence

4. To know its reaction to treatment plan.

5. To segregate inherited malocclusions from

environment malocclusions.
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 Terminologies
Chromosomes : thread like structures in the nucleus made up of DNA

Gene: Basic unit of inheritance by determining the make up and structure of

particular characteristic in an organism.

Transcription: process by which information is transmitted from the DNA to the

mRNA. Translation: process by which the genetic information is actually converted to

protein.

Genotype : genetic constitution of an individual .

Phenotype: specified character or to all the observable characteristics of individual .

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 Modes of inheritance:

1. Autosomal dominant

2. Autosomal recessive

3. X linked

4. Multifactorial

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 Autosomal dominant
(one allele is sufficient for expression of trait)

1. The trait occurs in successive generations; it shows vertical inheritance

2. 50% of offspring will have the trait.

3. Male and female have equal predilection.

4. Parents who do not have the trait have offspring who do not have the trait

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 Autosomal recessive
(Both alleles on a homologous pair of autosomes are required for the production of
the trait)

• Parents of a child with the AR trait are heterozygous (carriers) and most often are
diagnosed as normal

• The following three gene pairs are found:

1. AA—homozygous, not showing the trait being a carrier for the trait

2. Aa—heterozygous, not showing the trait but being a carrier of the trait

3. aa—homozygous, showing the trait.

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• The recurrence risk for an affected child in this case is 25%.

• Note that transmission of the phenotype in a pedigree is horizontal (typically

present only in siblings) and not vertical, as with a dominant trait.

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 X linked
Males- XY Female- XX

The characteristics are:

• As with any X-linked trait, the disease is never passed from father to son.

• Males are much more likely to be affected than females.

• All affected males in a family are related through their mothers.

• Trait or disease is typically passed from an affected grandfather, through his

carrier daughters, to half of his grandsons.

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 Multifactorial inheritance:
If the genetic variation of a particular phenotypic trait is dependent on the
simultaneous segregation of many genes and affected by environment.

E.g. Congenital heart defects, neural tube defects, cleft lip and palate.

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 Mode of transition of malocclusion:
1. Repetitive trials: the recurrence of a single dentofacial deviation within the
immediate family and in the progenitors. The same trait is seen generation
after generation.

2. Discontinuous traits: it is recurrence of a malocclusion that reappears within

the family over several generations but not continually.

3. Variable traits: the occurrence of different but related types of malocclusions

with in several generation eg: missing teeth – same teeth may not be missing
in different generations.

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 Method of studying role of genes
1. Twin studies
2. Pedigree studies
3. Inbreeding

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 Twin studies
• Are the studies carried out in twins.
• Pioneer – Sir Francis Galton (1822-1911).
• He argued that Heredity (nature) plays a stronger role than Environment
(nurture) in determining characteristics of TWINS.
• There are two different types of
twins Monozygotic (MZ)
Dizygotic (DZ)

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 Monozygotic twins have identical genotype

Dizygotic twins are only as alike as siblings.

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 Twin studies
• Done to evaluate the role of genetics played in various traits.

• If both the individuals of monozyotic twins (they have identical make up) express a
trait that is seen in the parent, it is strong evidence for a very significant role of
genetics in that particular trait.

• In case only one of the monozygotic twins express the trait and the other is absolutely
normal , then we come to the conclusion that although there is a genetic component in
the disease, there are some other factors which control the disease. Ig multifactorial
traits.

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• Depending up on the presence or absence of a particular trait twins can be classified in
to concordant and discordant twins.

• If a particular character is seen in both the members then they are said to be
concordant.

• If only one member of the pair express the trait then they are said to be discordant

• Cleft studies suggest that the concordance rate in monozygotic twins for cleft lip was
35% and that for cleft palate was 26%.

• In Dizygotic twins the concordance rate for cleft lip was 5% and that for cleft palate
was 6%.

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Twin studies reveals that:

• Genetic variation has a major effect on arch width and length.

• Identical twins were not occlusally identical.

• Greater genetic basis for tooth size and shape.

• Known dimensions were largely under genetic control.

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Pedigree studies- most common

Definite trait of an individual is studied along his family tree so as

to find any hereditary influence.

Inbreeding- the mode of transmission of certain traits can be studied

and their dominant and recessive characteristics are determined by
analysing certain communities were practices like polygamy and
marriages within the family still exist.

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 Role of Homeobox genes
A homeobox is a DNA sequence found within genes which are involved in the regulation
of development (morphogenesis) of animals, fungi and plants.

Genes that have a homeobox are called homeobox genes and form the homeobox gene
family.

Homeobox genes are highly conserved throughout the evolution of diverse organisms and
are now known to play a role in patterning the embryonic development.

These can also be regarded as the master genes of the head and face controlling patterning,
induction, programmed cell death, and epithelial mesenchymal interaction during the
development of the craniofacial complex.
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• These genes were first discovered in the fruit fly Drosophila melanogaster.

• These genes, also known as HOX genes, form hox codes, which specify the
position a cell should occupy, and the structure that cell should develop into.

• Four homeobox gene clusters (HOXA, HOXB, HOXC, and HOXD) that comprise
a total of 39 genes have been identified in humans.

• HOX genes control the patterning of pharyngeal arches (except 1st arch).

• The vehicles through which HOMEOBOX genes express their

information include FGF, IGF, TGF and BMPs.

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 Growth factors
The term growth factors denominates a group of polypeptides which are
involved in cellular proliferation, differentiation and morphogenesis of tissues
and organs during embryogenesis, postnatal growth and adulthood.

• Transforming Growth Factor (TGF)

• Fibroblast Growth Factors (FGF)

• Insulin-like Growth Factors (IGFs)

• Bone Morphogenetic Proteins (BMPs)

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1. Transforming Growth factor (TGF)
2 classes of polypeptide growth factors:

• TGF alpha

• TGF beta

Alpha : produced in macrophages, brain cells and keratinocytes, and induces

epithelial development.

Beta: exist as TGFbeta1, TGF beta 2, TGF beta 3 in humans

Play crucial role in tissue regeneration, cell differentiation, embryonic development

and regulation of immune system.
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2. Fibroblast Growth Factor (FGF)
• Involved in angiogenesis, wound healing and embryonic development.

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3. Insulin like growth factor (IGF)

Play roles in promotion of cell proliferation and inhibition of cell death (apoptosis)

• IFG1 and IGF 2

• IGF1 – secreted by liver; regulates normal physiology and a no. of pathological

state like cancer.

• IGF2 – requires for early development and function of organs such as brain , liver
and Kidney.

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4. Bone morphogenetic proteins(BMPs)
• Induces formation of bone and cartilages

• Total of 20 BMPs are there.

• Have an important role during the early embryonic development on the embryonic
patterning and early skeletal formation.

• Disruption in BMP signalling can affect the body plan for the developing embryo.

• Mutation in BMP are associated with no. of human disorders which affects
the skeleton.

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 Subfamilies of Hox genes
Which are of particular interest in craniofacial patterning and
morphogenesis includes:
• Muscle segment (MSX) • Paired- related (PRX, SHOT)
• Distal less (DLX) • LIM homeobox

• Orthodenticle(OTX) • Indian hedgehog(IHH)

• Sonic hedgehog (SHH)
• Goosecoid(GSC)

• Bar class(BARX)

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• 3 MSX (muscle segment genes ) in mammals.

• MSX 1 defect causes clefting, deficiency in alveolar bone, aberration in

tooth development and missing teeth.

• MSX 2 defect cause multiple inductive failures and early death.

• Combined defect of MSX 1 and 2 cause deficiency in calvarium, teeth

and alveolar bone.

• SHH and FGFR expressed in early palatal epithelium. Their disruption

causes failure of growth of palatal processes.

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• DLX (distal less genes) are involved in neural crest derived skeletal elements of
1st and 2nd branchial arches.

• Goosecoid (GSC) is involved in organization of complete body axis of embryo

and is also essential for inductive tissue interactions during formation of head.

• SHH (sonic hedge hog genes) are involved in left-right asymmetry,

determination of polarity in CNS, somites and limbs and in organisation and
formation of skeleton.

• Loss of SHH causes defective patterning of neural plate (holoprosencephaly),

failure of cleavage in midline of brain and cyclopia.

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 Odontogenic homeobox code
Various odontogenic HOX genes are:

• PAX GENE (paired box homeotic genes)- mutations cause hypodontia and transposition.

• BARX GENE (bar class homeobox genes)- localized around developing molars(DLX-2).

• MSX GENE (muscle segment homeobox genes)- expressed in migrating neural crest cells and
in mesenchymal cells of dental papilla and dental follicle

• DLX GENES- restricted to areas of future molar teeth.

• SHH GENES- is essential for initiation of tooth development, epithelial signalling and
cuspal morphogenesis.
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Clinical considerations

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Genetic basis of various types of malocclusions:

CLASS II DIV. 1

• Harris (1963, 1975) noted that in Class II patient, the mandible is smaller and
overall mandibular length is reduced. They found that a higher correlation
between the patient and his immediate family than data from random pairing
of unrelated siblings thus supporting the concept of polygenic inheritance for
Class II Div 1 malocclusion

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 Class II div 2 malocclusion

• Class II division 2 malocclusion comprises the 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.

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• Markovic 1992 carried out a clinical and cephalometric study of 114 Class II
Division 2 malocclusion, 48 twin pairs and six sets of triplets. Intra-and inter
pair comparison were made to determine concordance/discordance rates for
monozygotic and dizygotic twins. Of the monozygotic twin pairs, 100 percent
demonstrated concordance for the Class II division 2 malocclusion, while
almost 90 percent of the dizygotic twin pairs were discordant. This is strong
evidence for genetics as the main aetiological factor in the development of Class II
Div 2 malocclusion.

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 CLASS III
• Strohmayer (1937) concluded from his detailed pedigree analysis of the Hapsburg
family line that the mandibular prognathism was transmitted as an autosomal dominant
trait.

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• Suzuki (1961) studies Japanese families and noted that while index cases had
mandibular prognathism, there was a significantly higher incidence of this trait in
other family members in comparison to families of individuals with normal
occlusion.

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• Schulze and Weise (1965) studies mandibular prognathism in monozygotic and
dizygotic twins and reported a 6 times higher concordance rate in monozygotic twins
than dizygotic twins.

• Both these studies support a polygenic hypothesis as the primary cause for mandibular
prognathism.

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 Maxillary Midline diastema:

• Maxillary midline diastema is also found to be of genetic in origin.

• Gass et al studied the genetic basis of midline diastema in 15 black, 14 white and 1
mixed race.

• This suggest a possible genetic basis for maxillary midline diastema and a greater role
of environmental factors in the black sample than in the white sample.

• It was found to be autosomal dominant mode of inheritance.

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 Occlusion and arch width
Harris and Smith in 1980 studied on the occlusion and arch width of 1200
samples from 14 villages. On average, only about 10 percent of the variation in
overjet, overbite, crowding, tooth rotations, and molar relationships results from non-
environmental causes. In contrast, about 60 percent of the variation in measurements
of arch size and shape is attributable to heredity.

Vertical malocclusion

Vertical malocclusion like deep bite and open bite of skeletal origin are of heredity in
origin.

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 Genetic influence on teeth morphology

• Two common morphologic traits are the Cusp of Carabelli and shovel-shaped incisors
- polygenic origin with a discontinuous varitions.

• Asian populations show the greatest expression of shoveling,

• Cusp of Carabelli - more common in Caucasian groups.

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 Abnormal tooth shape

Alvesalo and Portin (1969) stated that missing and malformed lateral incisors might be
the result of a common gene defect. Abnormalities in the lateral incisor region range 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 canines and transpositions, suggesting a polygenic etiology.

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 GENETIC INFLUENCE ON TOOTH NUMBER

• Grahnen (1956 ) concluded that if either parent had one or more congenitally missing
teeth, there was an increased likelihood that their children also would be affected.

• Niswander and Sugaker (1963) observed that the supernumerary teeth most
frequently seen is a pre maxillary conical midline tooth (mesiodens) with a male sex
prediction and appears to be genetically determined.

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• Mackovic (1982) found a high rate of concordance for hypodontia in
monozygotic twins while dizygous twins were discordant. So, the mode of
transmission could be explained by a single autosomal dominant gene with
incomplete penetrance.

• Vastardis (1996) stated that mutation in MSX gene, located on chromosome 4p,
caused familial tooth agenesis.

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• Solitary median maxillary central incisor syndrome - Mutation in the sonic
hedgehog (SHH) gene

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 Genetic influence on tooth size
• Twin studies by Osborne et al (1958) have shown that tooth crown dimensions are strongly
determined by heredity.

• Richardson’s (1975) studies have shown that the size of permanent dentition is larger in
Negros than Caucasians.

• Shrestha R (2005) Mean tooth width in the Nepalese populations was smaller than in the
White Northern European and North American Caucasian.

• Hypodontia and hypoplasia of maxillary lateral incisors are frequently present simultaneously.
Spence (1974) showed that hypodontia and reduction in tooth size are in fact controlled by the
same or related gene loci and fit the polygenic multifactorial threshold model of inheritance.
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 Genetic influence on tooth position
Ectopic maxillary canines

Peck et al (1994) have concluded that palatally ectopic canines are an inherited trait
being one of the anomalies in a complex of genetically related dental disturbances,
often occurring in combination with missing teeth, tooth size reduction, supernumerary
teeth and other ectopically positioned teeth.

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Submerged primary molars
Primary molar submergence occurs most often in the mandibular arch with a
prevalence of less than 10%. The siblings of affected children are more likely to be
affected and in monozygotic twins there is a high rate of concordance, indicating
a significant genetic component in the etiology

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 Syndromes
• Crouzon’s syndrome

• Apert’s syndrome

• Treacher Collins syndrome

• Pfeiffer syndrome

• DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomalies

face syndrome

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 Crouzon’s Syndrome
A form of craniofacial dysostosis,
Autosomal dominance inheritance
pattern Characteristic-
• Brachycephalic shape to the skull,
• Midface hypoplasia with an Angle's class III malocclusion,
• Hypoplastic orbits with a proptosis,
• Parrot beak nose and short anterior cranial base.

Genetic etiology: It is caused by multiple mutations in the

fibroblast growth factor receptor 2 gene (FGFR2).

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 Apert’s syndrome
Autosomal dominant inheritance pattern.

• Synostosis and skull defect : bicoronal ,irregular ossification defect.

• Facial defect : hypertelorism ,downslanting palpebral fissures ,cleft palate.

• Fused hands and feet , mental retardation, cardiac defect.

Genetic etiology: At the molecular level, one of the two fibroblast growth factors 2
gene (FGFR2) mutations involving amino acids (ser 252 trp and pro 253 Arg) are
found to cause Apert’s syndrome.

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 Treacher Collins syndrome
Mandibulofacial dysostosis
Autosomal dominant
Characterized by bilaterally symmetrical abnormalities
of the structures within the first and second branchial
arches.
It is characterized by malar hypoplasia, mandibular
hypoplasia, downward palpebral fissures and coloboma
of lower eye lid and malformed external ears.

Genetic etiology: The gene for Treacher Collins

syndrome has been mapped to chromosome 5q31.3-
q33.3.

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 Pfeiffer Syndrome
Autosomal dominance inheritance pattern.

Craniostenosis, orbital dystopia, midface hypoplasia,

broad and medial deviated thumbs and great toes and
partial soft tissue syndactyly of the hands and feet.

Genetic etiology: It is heterogeneous because it is

caused by a single recurring mutation of the FGFR1
gene and by several different mutations affecting the
FGFR2 gene.

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 DiGeorge syndrome
DiGeorge syndrome, velocardiofacial syndrome and
conotruncal anomalies face syndromes come under disorders in
CATCH 22 spectrum. CATCH 22 is due to the deletion of long
arm of chromosome 22 (more specifically, foci 22q11).

Cardiac defects, abnormal facies, thymic hypoplasia, cleft palate

and hypocalcemia are the clinical features.

The origin of defects is caused by abnormal development of

neural crest cells which contribute to the formation of all the
affected structures.

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 Future of molecular research in craniofacial
growth
• In case of craniosynostosis, significant advances have been made in
understanding how various tissues and factors interact to regulate suture patency.
In vitro culture of fetal rat and mouse calvaria have shown that both TGF-3 and
neutralizing antibodies to TGF-2 can be used to rescue coronal sutures from
obliteration. Once the biology of the suture response to growth factor is better
understood, it will be possible to apply these factors to human subjects with
premature suture obliteration.

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• The growth factors and related molecules present in the mandibular condylar
cartilage (MCC) are being accessed. Some genes, like IHH, have been shown to
be upregulated when active condylar growth ensues. Improved understanding of
the molecular and biochemical processes in the condylar cartilage open the
possibility of "growing the mandible".

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• Adult stem cells play an important role in the remodeling and the repair of
tissues throughout the life of an organism. Recent research shows that adult
stem cells are capable of giving rise to multiple cell types produced from
different germ layers. Adult stem cells have been identified from dental
pulp, periodontal ligament, jaw bones, etc. Complete discovery of the
molecular mechanisms that regulate stem cell behavior might simplify the
treatment of dento-facial anomalies. Stem cells can be cultured to replace
cells or tissues lost by trauma or disease.

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 Gene therapy
• In gene therapy, a "corrected" gene is inserted into the genome to replace an
"abnormal," disease-causing gene.

• A carrier called a vector must be used to deliver the therapeutic gene to the
patient's target cells. Currently, the most common type of vectors are viruses

• Scientists have tried to harness this ability by manipulating the viral genome to
remove disease causing genes and insert therapeutic ones.

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• Target cells such as the patient's liver or lung cells are infected with the vector.
The vector then unloads its genetic material containing the therapeutic human
gene into the target cell. The generation of a functional protein product from the
therapeutic gene restores the target cell to a normal state.

Gene therapy is still in infancy but is full of promise.

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 Conclusion
• A permanent interaction between genetic and environmental factors, both of a
continually altering nature, determine the dentofacial morphology .

• We know the underlying biology of an individual may be just as important as the

malocclusion in the development of a treatment plan.

• The influences of genetic factors on treatment outcomes must be studied and

understood in quantitative terms.

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 Reference
1. Textbook of craniofacial growth : Sridhar Premkumar

2. Orthodontics Current Principal and Techniques :Graber , Vanarsdall, Vig

3. Orthodontics: Diagnosis and management of malocclusion and dentofacial

deformities: O.P. Karbanda

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