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Genetic basis of mandibular prognathism
AgataTomaszewska *1 ,2, Przemysław Kopczyński 1 , Rafał Flieger1
ABSTRACT
Mandibular prognathism is one of the craniofacial bone defects, characterised by excessive forward
growth of the mandible often accompanied by maxillary undergrowth, causing occlusion disorders.
Detailed understanding and accurate etiological analysis of that defect are essential in the further
treatment process. Long-standing observations indicate that mandibular prognathism is genetically
determined. This paper aims to outline the information about the genetic basis of that defect and analyses
the most recent findings concerning the impact of the identified mutations and polymorphisms in various
genes involved in the incidence and development of mandibular prognathism.
Key Words: Craniofacial Growth; Genetics; Mutation; Malocclusion; Orthodontic Treatment.
INTRODUCTION
Mandibular prognathism, also known as progenism, is a developmental disorder of the craniofacial
area. It is characterised by irregularities of the
shape, size and positional relationship of individual
bones. The defect is characterised by excessive
forward growth of the mandible often accompanied
by maxillary undergrowth, causing occlusion disorders. They manifest as full mesial occlusion with
a distinctive reverse overjet of the incisors and
two-sided buccal occlusion. Mandibular prognathism is also characterised by extended corpus
mandibulae and excessively obtuse angle of the
mandible, reflected in the facial features by smoothing of the mentolabial fold and chin protrusion
Correspondence: * [email protected]
1 The Centre for Orthodontic Mini-implants of the Chair and Clinic
of Maxillofacial Orthopaedics and Orthodontics, Poznań
University of Medical Sciences, Bukowska 70, str., 60-81 2
Poznań, Poland
2 The Chair and Department of Biochemistry and Molecular
Biology, Poznań University of Medical Sciences, Poland
beyond the coronal plane [1 , 2]. The defect occurs
in ca. 0.5-4% of the Caucasian population, whereas
the frequency in the Asian race is much higher,
i.e. 5-1 0%.
Etiopathogenesis of mandibular prognathism is
quite complex. Developmental disorders are caused
primarily by genetic and environmental factors. The
environmental factors comprise, first of all, external
determinants present especially during the first 3
months of the pregnancy, i.e. both hypoxia, ionizing
radiation, nutrition deficiency and metabolic and
hormonal disorders of the mother [3, 4].
The purpose of the work is to analyse the most
recent scientific findings concerning the genetic basis of mandibular prognathism.
MATERIALS AND METHODS
The analysed material comprised publications
from the last 20 years found in the library resources.
The search criterion were the following phrases:
mandibular prognathism, malocclusion, mutations,
Received: November 04, 201 3; Accepted: November 1 5, 201 3; Published: November 1 8, 201 3
Copyright: © 201 3 Author(s). Archives of Biomedical Sciences © 201 3 T.M.Karpiński. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
Archives of Biomedical Sciences 201 3, Volume 1 , Issue 2, pp. 1 6-1 9
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Tomaszewska et al. Genetic basis of mandibular prognathism
polymorphisms, orthodontic treatment. Finally, 20
publications were chosen for analysis.
REVIEW
It has been observed that mandibular prognathism may be an isolated defect or a complication
related to the co-occurring morphological and functional disorders. It is believed that the defect is
autosomal dominant with incomplete penetration
or autosomal recessive and the heritability ratio
has been estimated at h 2=0.31 6. It is also postulated that the mutations and polymorphisms responsible for mandibular prognathism may occur.
Given the above, a hypothesis about polygenic
inheritance of that defect has been put forward.
Studies conducted on twins indicated that in the
case of monozygotic twins the morphological
mandibular prognathism occurs in both children six
times as often as in dizygotic twins [5, 6].
Genetic causes of mandibular prognathism have
not been fully analysed yet. Nevertheless, high
interest and will to discover the etiology of that
defect allowed to select a dozen or so chromosomal
regions and to analyse genetic markers related to
the development of the defect.
The main candidate chromosomal regions associated with mandibular prognathism comprise the
loci located on the following chromosomes:
- 1 (1 p22.1 , 1 p22.2, 1 p36),
- 3 (3q26.2),
- 4 (4p1 6)
- 5 (5p1 3-p1 2),
- 6 (6q25),
- 11 (11 q22.2-q22.3),
- 1 2 (1 2q23, 1 2q1 3.1 3),
- 1 4 (1 4q24-q31 )
- 1 9 (1 9p1 3.2).
The recent years have seen enormous development in the genetic methods employing modern
technologies and allowing for a concurrent analysis
of hundreds of thousands genetic polymorphisms
located across the genome (the so-called GWAS –
genome-wide association studies). The objective
of GWAS is to verify the relations between the
selected candidate genes and their impact on the
studied trait. The studies allow to identify the genetic risk factors of commonly occurring diseases.
As a result of the clinical observation conducted
on the Japanese and Korean populations by the
Yamaguchi team, the decision was taken to study
the entire genome (Genome-wide Linkage Analysis). Segregation analysis allowed to identify the
most probable chromosomal loci associated with
the incidence of mandibular prognathism. As a
result, the following regions were selected: 1 p35-36,
5p1 3, 6q25 and 1 9p1 3 [7].
In the case of the research conducted on the
Chinese Han population, regions 1 p36, 4p1 6 and
1 4q24-31 were selected [8, 9]. The studies on
the Hispanic cohort conducted by the FrazierBowers team indicated regions 1 p22, 3q26, 11 q22,
1 2q1 3 and 1 2q23 [1 0]. Some of the genes in those
loci have been put forward as potential genetic
markers (perlecan, cartilage matrix protein 1 , alkaline phosphatase, erythrocyte membrane protein
band 4.1 , growth hormone receptor, transforming
growth factor beta 3, latent transforming growth
factor beta binding protein 2, Ellis-van Creveld
syndrome protein (EVC), EVC2, insulin-like growth
factor 1 , homeobox genes, and collagen type II
alpha 1 ) [11 ].
It is suspected that mutations or polymorphisms
occurring in such genes may have a considerable
effect on the incidence of mandibular prognathism.
To-date the several mutations and polymorphisms
have been confirmed in the genes encoding specific
growth factors and other signalling molecules involved in the bone and cartilage morphogenesis of the
craniofacial area.
Growth factors and cytokines belong to local
released mediators, affecting the target cells
through specific receptors, stimulating the cells to
proliferate, differentiate and increase the gene
expression as well as to further secrete biologicallyimportant substances. As it was shown in the tests
conducted by the Rabie et al. research team
[1 2, 1 3], excessive forward mandibular growth is
related to the increased expression of Ihh and
PTHrP, promoting differentiation of mesenchymal
stem cells into specialised bone and cartilage cells
as well as their further proliferation; such proteins,
as mediators of mechanotransduction, promote increased cartilage growth.
The growth factor VEGF and transcription factors SOX9 and RUNX2 hold an essential role in
the differentiation of chondrocytes, therefore they
are potential markers in searching for the genetic
causes of mandibular prognathism. The most recent
findings indicate presumably important role of
HSPG2, MATN1 and ALPL in development of irregularities in the growth of the cartilage and bone
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Tomaszewska et al. Genetic basis of mandibular prognathism
tissues of the craniofacial area [1 4, 1 5].
Another genetic factor taken into account when
looking for the reasons behind mandibular prognathism is the receptor of the growth hormone,
having the key role in the development of the
bone structures and morphogenesis of the craniofacial area. Studies carried out on the Japanese
population confirm strong correlation between variant Pro561 Thr in the growth hormone receptor
(GHR) and incidence of mandibular prognathism
[1 6].
The research conducted by the Nikopensius et
al [1 7] allowed to identify the missense mutation
c.545C>T (p.Ser1 82Phe) in gene DUSP6. A variant
of that gene co-segregates with the incidence of
the disease with autosomal dominant inheritance
with incomplete penetration.
Another highly interesting research carried out
on the Korean population suggests a significant role
of the identified polymorphisms of the SNP type in
gene MATN1 [1 8]. On the other hand, TassopoulouFishell et al direct attention to fairly important
variants of the gene encoding myosin 1 H
(MYO1H), associated with the development of
mandibular prognathism [1 9].
Also the reports on identified SNP polymorphisms in gene erythrocyte membrane protein band
4.1 (EPB41) show a strong relation between 4
variants of that gene and progenism [20].
CONCLUSION
To sum up, the results of many studies have
shown that both genetic and environmental factors
contribute to incidence of mandibular prognathism.
Detailed understanding and accurate analysis of the
genetic causes of that defect is of key importance
for further treatment and stability of the effects of
the applied multi-disciplinary treatment. The above
findings confirm the polygenetic basis of mandibular
prognathism, therefore the studies focused on
identification of factors involved in its incidence
constitute a crucial element.
TRANSPARENCY DECLARATION
The authors declare no conflicts of interest.
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