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BRIEF CLINICAL STUDIES
Genetic Factors Involved in
Mandibular Prognathism
Anna Doraczynska-Kowalik, MD,
Kamil H. Nelke, DMD, PhD,y Wojciech Pawlak, DMD, PhD,y
Maria M. Sasiadek, MD, PhD,
and Hanna Gerber, DMD, PhDy
Abstract: Mandibular prognathism is defined as an abnormal
forward projection of the mandible beyond the standard relation
to the cranial base and it is usually categorized as both a skeletal
Class III pattern and Angle Class III malocclusion. The etiology of
mandibular prognathism is still uncertain, with various genetic,
epigenetic, and environmental factors possibly involved. However,
many reports on its coexistence in both twins and segregation in
families suggest the importance of genetic influences. A multi-
factorial and polygenic background with a threshold for expression
or an autosomal dominant mode with incomplete penetrance and
variable expressivity are the most probable inheritance patterns.
Linkage analyses have, thus far, shown the statistical significance of
such loci as 1p22.1, 1p22.3, 1p32.2, 1p36, 3q26.2, 4p16.1, 6q25,
11q22, 12pter-p12.3, 12q13.13, 12q23, 12q24.11, 14q24.3 to 31.2,
and 19p13.2. The following appear among candidate genes:
MATN1, EPB41, growth hormone receptor, COL2A1, COL1A1,
MYO1H, DUSP6, ARHGAP21, ADAMTS1, FGF23, FGFR2,
TBX5, ALPL, HSPG2, EVC, EVC2, the HoxC gene cluster,
insulin-like growth factor 1, PLXNA2, SSX2IP, TGFB3, LTBP2,
MMP13/CLG3, KRT7, and FBN3. On the other hand, MYH1,
MYH2, MYH3, MYH7, MYH8, FOXO3, NFATC1, PTGS2,
KAT6B, HDAC4, and RUNX2 expression is suspected to be
involved in the epigenetic regulations behind the mandibular
prognathism phenotype.
Key Words: Candidate gene, class III malocclusion, familial
segregation, genetic predisposition, mandibular prognathism
M andibular prognathism is an abnormal relationship between
the mandible and the cranial base, characterized by an
excessively anterior projection of the mandibular bone. The defect
can be easily diagnosed by facial profile and soft tissue relation-
ships. The lower facial region is enlarged due to a protruded
mandible. In some patients, extreme long face syndrome can occur.
Mandibular prognathism is also related to improper lip contact or
even to a lack of contact. In many patients lip closure and oral seal
closure are not performable as the trait is often associated with
anterior cross-bite or even with open occlusion in anterior or lateral
occlusal sites.1–3 The paranasal area, cheek line, and nasolabial
folds are flat. Moreover, mandibular protrusion leads to a concave
From the Department of Genetics; and yDepartment of Maxillo-Facial
Surgery, Wroclaw Medical University, Wroclaw, Poland.
Received November 9, 2016.
Accepted for publication December 21, 2016.
Address correspondence and reprint requests to Anna Doraczynska-Kowalik,
MD, Department of Genetics, Wroclaw Medical University,
ul. K. Marcinkowskiego 1, 50-368 Wroclaw, Poland;
E-mail: anna.doraczynska-kowalik@umed.wroc.pl
The authors report no conflicts of interest.
Copyright # 2017 by Mutaz B. Habal, MD
ISSN: 1049-2275
DOI: 10.1097/SCS.0000000000003627
The Journal of Craniofacial Surgery  Volume 00, Number 00, Month 2017
Copyright © 2017 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
facial profile and everted lower lip. In most patients, it is not only
facial esthetics that are negatively affected but also the ability to
speak, chew, and pronounce.
Most patients with mandibular prognathism present both an
occlusal and a skeletal Class III pattern. However, occlusal Class III
depends on the placement of teeth and their presence in the
dental arch.
According to Angle occlusal classification, malocclusions are
divided into 3 classes. The Class III occlusal phenotype is a state
where the upper first molars are located posteriorly to the mesio-
buccal grooves of the lower first molars. As for Angle Class I and
Class II malocclusions, it has been proven that the etiology is
mainly environmental, without any significant genetic background.
On the other hand, Class III is the least common but also the most
hereditary malocclusion.
In 3-dimensional bone relationships, mandibular prognathism is
described as an increased mandibular bone growth in 3 planes. It is
classified as a Class III skeletal pattern whose main features can be
easily seen on a lateral cephalometric radiograph. The radiograph
presented as Figure 1 is a preoperative picture taken on an extremely
affected patient—a man in his early twenties showing both mandib-
ular prognathism and maxillary hypoplasia. Preoperative phenotype
of the patient included a protruded mandible, long face syndrome,
improper lip contact, a concave facial profile, and severe speech
difficulties. The radiograph shown in Figure 2 was taken on the
patient after the operative procedure that consisted of LeFort I
maxillary osteotomy, mandibular bilateral sagittal split osteotomies,
and geniplasty. A great variety of postoperative changes can be seen
in soft tissues as well as skeletal relationships. Beside the lateral
cephalomeric radiograph, to fully depict the Class III skeletal phe-
notype, a detailed cephalometric analysis should also be performed
(Table 1). The presented table shows pre- and postoperative values of
chosen cephalometric landmarks in our patient, as well as their norm
values for the Caucasian population. The direct relationship between
the mandible and the maxilla can be measured by various approaches.
However, A point-nasion–B point angle (ANB) is a crucial parameter
showing whether the malocclusion has Class I, Class II, or Class III
skeletal pattern. Before the operation, the ANB value in our patient
was highly negative, indicating a severe Class III skeletal phenotype.
On the other hand, sella-nasion-B point angle and sella-nasion-
pogonion angle are the most important measurements for an assess-
ment of mandible size. Preoperative sella-nasion-B point angle and
sella-nasion-pogonion angle values in our patient were above the
norm, which means that mandible prognathism was a significant part
of his Class III skeletal pattern. Moreover, the preoperative sella-
nasion-A point angle value in our patient was below the norm, which
shows that his Class III skeletal phenotype was complex, including
the involvement of maxillary hypoplasia.
Class III malocclusion is mainly caused by mandibular prog-
nathism.4,5 However, many authors report a large share of maxillary
retrusion in its etiology6,7 just like we observed in the presented
patient. In the standard approach, Class III malocclusion phenotype
refers to a few clinical presentations: pure mandibular prognathism
(due to a large and/or protruded mandible), a coexistence of
mandibular prognathism and maxillary hypoplasia, and pure maxil-
lary hypoplasia. However, the latest research in this field suggests
that Class III malocclusion should be considered as a compilation of
5 distinct subphenotypes. This conclusion was presented by Bui
et al8 who analyzed 67 cephalometric variables in 309 subjects with
a Class III skeletal pattern. Moreover, in each of the 5 Class III
subphenotypes, the common variables are anteroposterior, vertical,
and angular cephalometric measurements rather than the overall
size, position, or shape of the mandibular or maxillary bone.
It is also important to note that the skeletal origin observed in
Class III malocclusion differs slightly depending on the subject’s
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FIGURE 1. Preoperative lateral cephalogram of a patient with mandibular
prognathism.
FIGURE 2. Postoperative lateral cephalogram of a patient with mandibular
prognathism.
age, sex, and ethnicity. Cranial proportions in both sexes are
similar but male Class III mandibles are larger.4 A difference
between men and women is visible in linear but not angular
cephalometric parameters.9 Sexual dimorphism of Class III mal-
occlusion is marked mainly in linear sizes of mandible, maxilla,
and anterior facial heights, which are smaller in women than in
men.10,11 These differences are especially significant during cir-
cum-pubertal and postpubertal periods.10 Many researchers
emphasize ethnic differences in Class III malocclusion. Overall,
the skeletal origin is more severe in the Chinese, Korean, and
Japanese population than that observed in Caucasians.9,12,13
Furthermore, in Asians, mandibular prognathism is a more com-
mon cause of Class III malocclusion than it is in Caucasians.14
However, faced with the high incidence of mandibular prognath-
ism in the Asian population, the variability in the mandible size in
patients without pronunciation, mastication, or severe esthetic
problems should be reconsidered a normal phenotype variation.
Moreover, many authors describe the skeletal phenotype of Class
III malocclusion in Middle-East Asians as quite different from that
in Far-East Asians.11,15,16
The prevalence of Class III malocclusion also depends on
ethnicity. The highest frequency is noticed among Far-East Asians
and oscillates between 13% and 19%. In Middle-East Asians, Class
III malocclusion occurs in 5.1% to 10%.16 The lowest prevalence is
described in Caucasians and ranges from 0.48% to 4%.17
The cause of mandibular prognathism is still uncertain. The
defect has been associated with various environmental factors like
enlarged tonsils, nasal breathing difficulties, posture, habitual head
position, endocrine disturbances (such as acromegaly), trauma, and
instrumental deliveries.18,19 Nevertheless, much of the evidence
indicates that mandibular prognathism tends to occur in both twins
and to generally segregate in families, meaning genetic factors play
an important role in its etiology. Many studies have been carried out
to describe this problem. However, a genetic background of this
malocclusion has yet to be fully uncovered.
Twin Studies
The basic method to prove a genetic background of a feature is a
twin study. Numerous reports have been published describing
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TABLE 1. A Comparison of Presurgical and Postsurgical Cephalometric
Measurements in a Mandibular Prognathism Affected Patient
Norm Values
for the Caucasian Presurgical Postsurgical
Cephalometric Measurements Population Values Values
ANB (A point-nasion-B point angle) 2.02.0 10.2 1.7
SNB (sella-nasion-B point angle) 80.03.0 88.5 83.1
SNPg (sella-nasion-pogonion angle) 81.0  3.0 91.1 85.5
SNA (sella-nasion-A point angle) 82  3.0 78.2 81.4
Wits appraisal (mm) 0.0  2.0 21.9 9.4
cephalometric similarities seen in twins, suggesting that some
craniofacial dimensions are highly inheritable. Lobb20 analyzed
cephalograms of 60 pairs of twins—30 monozygotic and 30
dizygotic—and found that in monozygotic pairs the assessments
of craniofacial bones shape are similar in 92%, while the
proportion is 71% in dizygotic pairs. Dudas and Sassouni21
measured 15 craniofacial parameters in twins—12 monozygotic
and 10 dizygotic pairs—over a 10-year period and showed that 4
cephalometric parameters (N-S-Go, N-S-Gn, lower anterior
facial height, and total anterior facial height) seem to be strongly
gene-related while 2 parameters (S-N-Pog and Ar-Pog) are
suspected of being susceptible to environmental factors. These
results are similar to those reported earlier by Horowitz et al22
whose analysis of cephalograms performed on same-sex adult
twins—35 monozygotic and 21 dizygotic pairs—revealed that
some craniofacial features (anterior cranial base, mandibular
body length, total face height, and lower face height) have an
evident genetic background.
Twin studies have also shown that vertical cephalometric
parameters are more hereditary than horizontal ones. In addition,
anterior vertical parameters seem to be more genetically dependent
than posterior vertical parameters.23 Features of the lower third of
the face are apparently strongly gene-related22,23 but mandible
shape is more hereditary than its size.23
As for specific twin studies for mandibular prognathism, the
reports of its coexistence in pairs of monozygotic twins demonstrate
an obvious genetic background of the feature.18,24 However, Jena
et al18 have highlighted the importance of variable expressivity by
presenting the case of monozygotic female twins affected where 1
girl shows a more severe phenotype than the other.
Familial Segregation
Numerous cases show that mandibular prognathism has a
tendency to segregate in families. Strong genetic influence has
been proven by examinations of both past and present day
families.
Historical portraits of some noble European lineages show faces
that suggest mandibular prognathism. The best-known royal family
affected were the Habsburgs and this bloodline has even given its
name to the ‘‘Habsburg jaw.’’ Wolff et al25 examined the lineages of
13 noble families related to the Habsburgs, counting 409 members
over 23 generations. The analysis showed that, in these royal
bloodlines, the feature was most probably determined by a single
autosomal-dominant gene of high (equaling about 95%) penetrance
and wide variation in expression. Moreover, the examination has
led the authors to conclude that the main facial feature of the
Habsburgs was caused by mandibular prognathism. However, the
latest reports draw other conclusions, as the findings of recent
studies are not so explicit. Lippi et al26 who performed postmortem
cephalograms and panoramic radiographs using the skull of Joanna
of Austria, as well as Peacock et al27 who reexamined the most
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TABLE 2. Statistically Significant Loci
Loci Author
1p36, 6q25, 19p13.2y Yamaguchi et al34
1p22.1, 3q26.2, 11q22z, 12q13.13§, 12q23jj Frazier-Bowers et al35
4p16.1 Li et al36
14q24.3-31.2 Li et al37
12q24.11 Tassopoulou-Fishell et al38
1p22.3, 1p32.2 Ikuno et al39
12pter-p12.3 Chen et al40

Not confirmed with the D1S234 in the study performed by Cruz et al.41
y
Confirmed with the rs12327845 in the study performed by Tassopoulou-Fishell et al.38
z
Confirmed with the rs571407 in the study performed by Tassopoulou-Fishell et al.38
§
Not confirmed with the rs7300317 in the study performed by Tassopoulou-Fishell et al.38
jj
Not confirmed with the rs11113231 in the study performed by Tassopoulou-Fishell et al.38
illustrative portraits of the Spanish Habsburgs for the presence of 18
anatomic features (11 for maxillary deficiency and 7 for mandibular
prognathism), reported that maxillary deficiency had a large share
in the skeletal etiology of the ‘‘Habsburg jaw.’’
The segregation of mandibular prognathism is also observed in
present-day families. Suzuki28 analyzed the lineages of 243 Japa-
nese families, totaling 1362 members, and found that when a
proband has mandibular prognathism, the incidence of this feature
in his family is higher (34.3%) than in the family of a proband with
normal occlusion (7.5%). Nakasima et al29 measured 19 cephalo-
metric features in 104 Asian probands with Class III malocclusion
and their parents, and performed an offspring–parent comparison
that showed high correlation values. Watanabe et al19 studied 3-
generation family histories taken from 105 adult Japanese patients
severely affected by mandibular prognathism. The analysis
revealed that 68.6% of the probands had at least 1 relative with
the same defect. The affected ratio was estimated as 17.5% in first-
degree relatives (25% in siblings and 12.4% in parents) and 7.6% in
second-degree relatives (7.4% in grandparents and 7.7% in aunts/
uncles). Litton et al30 examined families of 51 American patients
affected with Class III malocclusion and found that it was present in
13% of the probands’ siblings. Cruz et al31 examined the cephalo-
grams of 55 Brazilian mandibular prognathism affected probands
and their family members, reporting that 95% of probands had at
least 1 relative who displayed the same phenotype. The results
obtained revealed that prevalence of the trait was 32.9% in male
siblings, 27.6% in female siblings, 48.2% in parents, and about 46%
in grandparents.
Possible Inheritance Mode
The inheritance pattern of mandibular prognathism is still
unclear. Large-group examinations suggest a multifactorial and
polygenic background with a threshold for expression or a single
autosomal-dominant gene with incomplete penetrance and variable
expressivity as the most probable inheritance mode.
Litton et al30 analyzed the lineages of 51 affected families and
revealed that Class III malocclusion may have a polygenic origin
with a threshold for expression, or its inheritance pattern differs
depending on the population or even family affected. On the
other hand, El-Gheriani et al32 studied the lineages of 37 Libyan
# 2017 Mutaz B. Habal, MD
Copyright © 2017 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
Brief Clinical Studies
Method
Linkage analysis performed on 42 Korean and Japanese families including 90 mandibular
prognathism-affected sibling pairs
Linkage analysis performed on 4 Colombian families, totaling 57 members, 28 of whom are
class III malocclusion affected
Linkage analysis performed on 2 Chinese families, totaling 42 members, 18 of whom are
mandibular prognathism affected
Linkage analysis performed on 1 Chinese family, totaling 21 members, 11 of whom are
mandibular prognathism affected
Comparison of the frequency of 33 SNPs in 44 subjects with mandibular prognathism and in 35
class I subjects
Microsatellite genome-wide association study (GWAS) performed in 240 Japanese subjects
with mandibular prognathism and 360 controls, using 23,465 microsatellite markers
Linkage analysis performed on 1 Chinese family, totaling 19 members, 8 of whom are
mandibular prognathism affected
probands displaying a mandibular prognathism phenotype and
reported that the most probable inheritance mode of this trait is
autosomal dominant. Moreover, Cruz et al31 looked into the
pedigree patterns of 55 affected Brazilian families and concluded
that the coexistence of a major autosomal-dominant gene, along
with the influence of other genes and environmental factors, is a
highly possible explanation for familial patients. A similar
conclusion was presented by Ko et al33 who examined 3-gener-
ation lineages of 100 Korean patients affected by mandibular
prognathism. The segregation analysis showed that familial
patients of mandibular prognathism are probably caused by
the additional influences of minor effect genes and environmen-
tal factors.
Linkage Analysis
Faced with evidence of a genetic background of mandibular
prognathism, there is now a need to indicate major candidate genes.
The best method for finding loci of phenotype-related genes is
linkage analysis, a statistical analysis of the segregation of traits and
SNPs in affected families. Thanks to the linkage analyses some
chromosome locations suspected of being associated with Class III
malocclusion have been indicated.34–40 Statistically significant loci
reported thus far are presented in Table 2.
However, Cruz et al41 performed linkage analysis on 10
Brazilian families, with 42 members affected with Class III
malocclusion, using 6 microsatellite markers (D1S234,
D4S3038, D6S1689, D7S503, D10S1483, and D19S566) located
near formerly reported suspected loci, and did not obtain any
significant result.
Moreover, the question of linkage analysis in mandibular
prognathism seems to be even more complicated in light of a
theory presented by Bailey42,43 who performed animal studies.
He analyzed the shape of the mandible in a congenic mouse
strain, as well as the distances between 12 mandibular landmarks
in a recombinant inbred mouse strain. The results obtained
suggested that during murine mandible development the pheno-
typic effects of genes expression are highly localized to the small
regions of the mandible. The conclusion is that every specific
gene variation in mice seems to regulate the size of the
specific part of its mandible rather than the general size or
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shape of the whole mandibular bone. Considering this thesis,
there is most likely a multitude of statistically significant loci for
mandibular prognathism.
Candidate Genes
Knowledge of the human genome map allows candidate genes to
be found by suspected loci derived from the linkage analysis.
1p36 is a location for genes such as MATN1 encoding matrilin 1,
EPB41 encoding erythrocyte membrane protein band 4.1, HSPG2
encoding heparan sulfate proteoglycan 2, and ALPL encoding
alkaline phosphatase.17
Matrilin 1 is a cartilage extracellular matrix protein playing an
up-regulating role in the chondrogenesis process. The nature of
matrilin 1 and matrilin 3 was the subject of detailed investigation
by Pei et al44 whose in vitro experiment proved that both proteins
play a significant role in enhancing and maintaining chondro-
genesis but only if the process is first stimulated by TGFb1. The
influence of MATN1 polymorphisms on the mandibular prog-
nathism phenotype was of interest to Jang et al45 who analyzed
the frequencies of 3 MATN1 polymorphisms (158 T>C, 7987
G>A, 8572 C>T) in 164 Korean patients affected with man-
dibular prognathism and in a control group totaling 132 people
with normal occlusion. The results revealed that 8572 C>T
polymorphism is connected with increased mandibular prognath-
ism risk, whereas the 7987 G>A polymorphism has a protective
role.
Furthermore, detailed analysis of 1p36 SNP markers and their
connection with mandibular prognathism in the Chinese population
was performed by Xue et al.46 The results showed that 6 SNPs
within the EPB41 gene are significantly associated with this trait
(rs2762686, rs2788888, rs4654388, rs502393, rs11581096, and
rs488113). The G-allele of SNP, assigned as rs4654388, showed
the strongest link with an increased risk of mandibular prognathism.
Further analysis revealed the mandibular prognathism-associated
haplotype as GTTCAGGT.
The next candidate gene, located in 1p36, is HSPG2, a gene
for heparan sulfate proteoglycan 2 (also called perlecan), which
is a large molecule containing a multidomain protein core.
Perlecan interacts with many growth factors, as well as extra-
cellular and cell-surface components like laminin, entactin,
fibulin, fibronectin, collagen type IV, fibroblast growth factors
(FGFs), platelet-derived growth factor (PDGF), and growth
factor-binding proteins. The protein is involved in the stabiliz-
ation and organization of matrix structure, the modulation of
growth factor signaling cell proliferation and differentiation, and
the promotion of the mitogenesis and angiogenesis processes.47
Mutations in this gene are responsible for the allelic skeletal
dysplasias Schwartz–Jampel syndrome type 1 (SJS1; OMIM:
255800) and the Silverman–Handmaker type of dyssegmental
dysplasia (DDSH; OMIM: 224410), both of which are autosomal
recessive. It is important to note that, besides short stature,
skeletal anomalies, myotonia, and blepharophimosis,
Schwartz–Jampel syndrome type 1 is also characterized by
orodental disorders such as microstomia, pursed lips, cross-bite,
cleft palate, mandibular hypoplasia, the risk of dentigerous cysts,
and impacted teeth.48
The last—but certainly not the least—candidate gene located in
1p36 is ALPL. This gene encodes tissue nonspecific alkaline
phosphatase that is a membrane-bound enzyme present in the
liver, bones, and kidneys, and is involved in extracellular matrix
mineralization and vitamin B6 metabolism. Mutations in ALPL
which reduce enzyme activity are responsible for hypophospha-
tasia (OMIM: 146300, 241510, 241500), a rare disorder charac-
terized by defective bone and teeth mineralization and early
tooth loss.
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 Volume 00, Number 00, Month 2017
Other candidate genes are EVC and EVC2 located in 4p16.1,
directly alongside one another.36 Mutations in both these genes are
known to be a cause of 2 allelic dyspalsias: Ellis–van Creveld
syndrome (chondroectodermal dysplasia, EvC; OMIM: 225500)
and Weyers acrofacial dysostosis (WAD, Curry–Hall syndrome;
OMIM: 193530). Ellis–van Creveld syndrome is an autosomal-
recessive disorder whose phenotype includes short limbs, postaxial
polydactyly, malformation of the wrist bones, nail hypoplasia, and
congenital heart defects. As to orodental manifestations, the follow-
ing, among others, have been described: partial anodontia, enamel
hypoplasia, delayed eruption of teeth, neonatal teeth, conical and
microdontic teeth, peg-shaped laterals, the absence of a mucobuccal
fold, light serrations of the alveolar ridge, multiple small alveolar
notches, a partial cleft lip, and hyperplastic frenula. Moreover,
malocclusions are also a common feature observed in Ellis–van
Creveld syndrome including hypoplastic anterior maxilla, mandible
prognathism, and increased height of the lower third of the face.49
On the other hand, Weyers acrofacial dysostosis is inherited in an
autosomal-dominant mode. Its phenotype is milder than that seen
in Ellis–van Creveld syndrome but also includes dental anomalies
such as an abnormal shape and number of mandibular and
maxillar incisors.
Other candidates, the HoxC gene cluster and COL2A1 gene, are
located in 12q13.13.35
HoxC (Hox3) is one of the homeobox regions encoding con-
servative transcription factors involved in embryonic morphogen-
esis. As Vieille-Grosjean et al50 proved, Hox genes are expressed in
the human embryonic hindbrain and the branchial arches and play a
critical role in human craniofacial development.
Conversely, COL2A1 encodes the alpha 1 chain of type II
collagen, which is present in cartilage and in the vitreous humor.
In vitro observation also showed that the presence of collagen—
either type I or II—promotes matrix production and turnover.51
Moreover, mutations in COL2A1 are associated with many skeletal
disorders such as type II achondrogenesis (ACG2; OMIM: 200610)
or type I Stickler syndrome (STL1; OMIM: 108300). Important
findings were reported by Garofalo et al52 who created transgenic
mice carrying a point mutation in the COL2A1 gene. The offspring
of different founders showed a phenotype of lethal chondrodyspla-
sia including not only short stature and a small thorax but also
craniofacial deformities and a cleft palate. The link between
COL2A1 and insulin-like growth factor 1 (IGF1) polymorphisms
and mandibular prognathism in the Chinese population was inves-
tigated by Xue et al.53 This analysis of 11 COL2A1 SNPs and
5 IGF1 SNPs in 221 cases and 224 controls revealed that the
presence of the A allele of rs1793953 SNP, located in COL2A1,
decreases the risk of mandibular prognathism. However, the results
did not confirm the suggested link between IGF1 polymorphisms
and mandibular prognathism.
As regards IGF1, this is the most probable candidate gene
located in the suspected 12q23 loci35 and it encodes an insulin-
like growth factor 1. The protein stimulates the production of
proteoglycans, promotes chondrocyte survival, and inhibits cata-
bolic activities of cytokines.54 Visnapuu et al55 analyzed the
localization of receptors for the growth hormone (GH) and IGF1
in the rat’s temporomandibular joint. Insulin-like growth factor 1
receptors were mainly found in the fibrous articular surface and in
the superior and posterosuperior cartilage regions of the condyle.
Growth hormone receptors were detected in various components of
the joint, but not in the above-mentioned locations that are critical to
condylar growth. These results suggest that the postnatal growth
and development of the condylar cartilage in the mandible seem to
be more directly IGF1 than GH dependent. It is also significant that
the quantitative trait locus analysis, performed in an SMXA
recombinant inbred strain of mice, revealed that mandible length
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related loci are placed in the murine chromosomes 10 and 11.56
These regions correspond to the human 12q21 (located near sus-
pected 12q23) and 2p13 bands.35
The growth hormone receptor (GHR) gene is another candi-
date believed to be involved in the regulation of mandible
growth. Its locus is 5p12-p13. Zhou et al57 used the quantitative
trait locus method to evaluate the association between 4 SNP
markers for the GHR gene and craniofacial linear measurements
in a healthy Chinese population. The analysis revealed that the
genotype CC of polymorphism I526L is related to a longer
mandibular ramus (greater condylion-gonion/articulare-gonion
dimension) in comparison with the genotype AC or AA. Further-
more, Tomoyasu et al58 genotyped 5 SNPs located in exon 10 of
the GHR gene in 167 healthy Japanese subjects to evaluate the
relationship between GHR polymorphisms and linear craniofa-
cial measurements. The results showed that in the Japanese
population the CC genotype of polymorphism P561T and the
GG genotype of polymorphism C422F are associated with greater
mandibular height than the CA and GT genotypes, respectively.
Moreover, the correlation between the P561T polymorphism and
the effective mandibular length (condylion-gnathion), as well as
lower face height (anterior nasal spina-menton), was reported by
Bayram et al59 who compared the frequencies of P561T and
C422F variants in 99 subjects with severe mandibular prognath-
ism with their frequencies in 99 Class I subjects. Besides the
polymorphisms I526L, P561T, and C422F, a common GHR gene
isoform that lacks the exon 3 (d3-GHR) was also believed to be
involved in mandibular growth, as this is associated with an
increased responsiveness to the growth hormone pharmacother-
apy.60 Nevertheless, Kang et al61 examined the association
between GHR polymorphisms and 5 craniofacial linear measure-
ments in 159 Korean subjects (87 Class I, 44 Class II and 28
Class III) and found a statistically significant correlation between
the mandibular ramus height and earlier reported P561T and
C422F polymorphisms, but not the d3-GHR isoform or I526L
polymorphism.
Furthermore, Tassopoulou-Fishell et al38 compared the inci-
dence of 33 SNPs, situated near all the formerly reported candidate
loci, in 44 subjects affected by mandibular prognathism with their
incidence in 35 Class I subjects. In both groups, the ethnicity of the
subjects was heterogeneous, with a dominance of Caucasian and
African-American. The analysis showed a statistically significant
mandibular prognathism association with the G allele of SNP
signed as rs10850110. This marker is located in 12q24.11 and
flanks the 50 end of the MYO1H (class I subclass H myosin) gene. It
is interesting that class I myosins play a different role than con-
ventional class II myosins as they are monomer proteins involved
in intracellular movements, vesicle transport, organelle transport,
and phagocytosis.
Interesting findings in this field were reported by Ikuno et al39
who performed a microsatellite genome-wide association study
(GWAS) in 240 Japanese subjects with mandibular prognathism,
as well as 360 controls, using 23,465 microsatellite markers. The
multistep analysis revealed that the trait is significantly associated
with 2 loci: 1p32.2 that is a novel locus and 1p22.3 that is located
near the previously reported 1p22.1 locus. Moreover, the authors
suggested 2 candidate genes: PLXNA2 for 1p32.2 locus and
SSX2IP for 1p22.3 locus. PLXNA2 encodes plexin A2 which is
one of the proteins known to be coreceptors for semaphorin 3A and
3C. Semaphorin 3A acts as an osteoprotective factor as its effects
lead to the suppression of osteoclastic bone resorption and the
increase of osteoblastic bone formation. SSX2IP, on the other
hand, encodes a protein that bonds to the antigen named synovial
sarcoma X breakpoint 2 protein, and regulates its function in
malignant cells.
# 2017 Mutaz B. Habal, MD
Copyright © 2017 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
Brief Clinical Studies
Moreover, a large phenotype-genotype association study was
performed recently by Da Fontoura et al62 who genotyped 269
individuals with skeletal Classes I, II, and III malocclusion for 198
SNPs in 71 potentially causal genes. The results revealed that
rs2249492 variant in COL1A1 as well as rs2162540 and
rs11200014 variants in FGFR2 are correlated with an increased
risk of Class III malocclusion, while rs1248046 variant in TBX5 is
associated with reduced risk of this trait.
Scientific progress means that the latest fast and efficient
molecular techniques, such as new generation sequencing
(NGS), are now in common usage. New-generation sequencing
allows the whole exome, or even the whole genome, of a subject to
be sequenced in a relatively short time. Some recently published
reports about candidate genes in familial mandibular prognathism
are therefore based on the results of whole exome sequencing
(WES) and whole genome sequencing.
Nikopensius et al63 performed WES on 5 Estonian siblings
affected by Class III malocclusion and reported heterozygous
missense mutation, c.545C>T (p.Ser182Phe), in the DUSP6
gene as a potentially causative variant in this family. Analysis
of the segregation of the suspected variant and Class III phe-
notype in the family revealed that the variant cosegregated with
the defect following an autosomal-dominant mode of inheritance
with incomplete penetrance. The DUSP6 gene is localized in the
previously reported 12q23 chromosomal region. Its product, dual
specificity phosphatase 6, is known to down-regulate mitogen-
activated protein kinases, which are involved in proliferation and
differentiation processes. Moreover, DUSP6 expression is
regulated by FGF/FGFR and mitogen-activated protein
kinases/ERK signaling during the early stages of skeletal devel-
opment.
The new-generation sequencing technique was also used by
Perillo et al64 who performed WES on 5 members of an Italian
family affected by mandibular prognathism, whose defect was
confirmed by cephalometric validation. The results of whole
genome sequencing revealed 5 suspected gene variants whose
segregation in the family and its coexistence with the mandib-
ular phenotype was analyzed afterward. The Gly1121Ser var-
iant in the ARHGAP21 gene was then indicated as the most
probable causative variant in this family. The missense
mutation presented is a rare variant for the Caucasian popu-
lation and is predicted to be potentially important for the
structure and the function of the encoded product, Rho GTPase
activating protein 21.
Moreover, Guan et al65 performed WGS in a large Chinese
family affected by mandibular prognathism, and then a validation
for the chosen SNPs in 230 unrelated patients and 196 unrelated
controls. The results obtained revealed rs2738 an rs229038 SNPs of
ADAMTS1 gene as possibly being associated with mandibular
prognathism. The protein encoded by the ADAMTS1 gene plays
an antiangiogenic role and is involved in many biological processes,
including morphogenesis and growth.
Detailed research was also carried out by Chen et al40 who
performed linkage analysis using 4958 SNPs in a 4-generation
Chinese pedigree affected by mandibular prognathism and ident-
ified 12pter-p12.3 as a new statistically significant loci. Thereafter,
WES performed in 3 affected family members and genotyping for 3
possibly important variants carried out afterward in 19 family
members revealed FGF23 c.35C>A located within 12pter-p12.3
locus as potentially causal variant. During further verification the
variant was detected in 3 of the 65 sporadic mandibular prognath-
ism patients and not found in 342 healthy Chinese individuals.
In silico as well as in vitro analysis suggested that the variant
may disrupt secretion of the encoded protein, fibroblast growth
factor 23.
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Brief Clinical Studies The Journal of Craniofacial Surgery
In addition, there have been reports of other possible candidate
genes, such as TGFB3, LTBP2,37 MMP13 (CLG3),35 KRT7, and
FBN3,38 though the association between these genes and mandib-
ular prognathism has not been closely evaluated yet.
Epigenetic Factors
Many studies show that, beside the variants in the DNA
sequence, some changes in gene expression can also be involved
in the etiology of mandibular prognathism as well as in maintaining
the postoperative results. Epigenetic mechanisms, like DNA meth-
ylation and histone acetylation, regulate the transcription process
without any intervention in the nucleotide sequence. This bio-
chemical control is based on activation and deactivation of specific
genes at a certain time and in a certain situation. The change in gene
expression can be estimated by the quantification of a specific
amount of messenger RNA (mRNA) using such methods as reverse
transcription polymerase chain reaction (RT-PCR) or gene
expression microarray.
The strength of masticatory muscles is known to affect the
development of the mandible and the maxilla, and changes in the
dimensions of the craniofacial skeleton to have an impact on the
tension of masticatory muscles, and this has led to a suggestion
regarding the epigenetic mechanisms involved in this 2-way relation-
ship. According to this theory, some environmental factors, such as
forces acting upon the mandible, may have an impact on epigenetic
mechanisms that regulate the expression of genes whose products are
involved in mandible growth and remodulation. The question is at
what level the epigenetic control lies in malocclusion patients. The
complexity of interactions between tissues and cells makes it difficult
to establish whether bone, cartilage, muscle, or soft tissue matrix is a
primary determinant of craniofacial growth at a specific location.66
Gedrange et al67 used the competitive RT-PCR assay method to
examine the change in mRNA amounts for type I and II myosine
heavy chain (MyHC) in the masseter muscle samples obtained from
10 subjects divided into 2 groups (displaying a Class II or Class III
skeletoocclusal pattern) before and 6 months after orthognathic
surgery. The analysis revealed that in both groups the total amount
of mRNA for type I and II MyHC decreased by about 87%, with the
deficiency being slightly higher in patients with a mesial
mandible position.
The same question was analyzed by Harzer et al68 who com-
pared the amounts of mRNA for types I, IIa, and IId/x MyHC
(encoded by MYH7, MYH2, and MYH1, respectively) in masseter
muscle samples taken from 16 subjects with prognathic and 14
subjects with a retrognathic mandible before and 6 months after
surgery. The results showed that, in both groups, the amount of
mRNA for type I MyHC decreased from about 46% to 37%, and the
amount of mRNA for type IIa MyHC increased from about 29% to
42%; however, there was no significant alternation between the pre-
and postoperative levels of mRNA for type IId/x MyHC. Moreover,
there was no significant difference between postoperative changes
of MyHC mRNA levels in retrognathic and prognathic subjects.
These results suggest that, in retrognathic as well as prognathic
patients, surgical improvement of occlusion can cause an epigenetic
change leading to a switch from type I MyHC to type IIa.
Additionally, Maricic et al69 took masseter muscle samples from
14 patients with prognathic mandible (ANB angle <08) and 15
patients with retrognathic mandible (ANB angle >48), preopera-
tively and 6 months after surgical correction, and analyzed the
change in the amounts of mRNA for mechano growth factor,
myostatin, and type I, IIa and IIx/d MyHC. The results showed
that in both groups there was a significant postoperative increase in
mechano growth factor mRNA levels. However, no significant
change was observed between the pre- and postoperative amounts
of myostatin mRNA. It is also important to note that, in both groups,
6 #
Copyright © 2017 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
 Volume 00, Number 00, Month 2017
the postoperative amounts of mRNA for type I MyHC were lower,
while type IIa MyHC levels were higher than those present pre-
operatively. No significant change was observed in pre- and post-
surgical levels of mRNA for type IId/x MyHC. The increase in the
level of mRNA for type IIa MyHC was higher in the prognathic than
in the retrognathic group. These results support the hypothesis
regarding a postoperative shift in MyHC types from I to IIa.
The change between pre- and postoperative levels of mRNA for
developmental types of MyHC, embryonic (type 3) and perinatal
(type 8), was a subject of interest for Oukhai et al70 who performed
masseter muscle biopsies in 24 patients, 11 affected by mandibular
prognathism (ANB angle <08) and 13 affected by a retrognathic
mandible (ANB angle >38), before and 6 months after the surgery.
The analysis of preoperative values showed that, in the prognathic
group, expression of the MYH8 gene was twice as high as that
observed in the retrognathic group, but that expression of the MYH3
gene was similar in both groups. A complete study revealed that, in
both groups, there was a postoperative increase in the amount of
MYH3 transcript with a greater growth observed in the prognathic
group. There were also some statistically insignificant changes
observed, like a postoperative increase in the amount of MTH8
transcript in the retrognathic group and its slight postoperative
decrease in the prognathic group.
A wide-spectrum study was performed by Breuel et al71 who
took masseter muscle samples from 20 patients with a retrognathic
(ANB angle >38) and 15 patients with prognathic (ANB angle <08)
mandible and analyzed the change between pre- and postsurgical
mRNA levels for genes encoding muscle stretching factors: MYH3,
MYH8, MYH1, MYH2, MYH7 (myosin heavy chain developmen-
tal types 3 and 8 as well as fast and slow types 1, 2, and 7), PTGS2
(cyclooxygenase 2), FOXO3 (forkhead box O3, transcription fac-
tor), NFATC1 (the nuclear factor of activated T cells, cytoplasmic,
calcineurin-dependent 1) and PPP3CA (calcineurin). The results
revealed that in the retrognathic group there was a statistically
significant postoperative upregulation in the expression of MYH3
and MYH7, whereas in the prognathic group there was a statistically
significant postoperative upregulation in the expression of MYH3
and downregulation in the expression of MYH8, MYH1, FOXO3,
and NFATC1. Significant differences between the prognathic and
retrognathic groups were observed in the postoperative expression
of such genes as FOXO3 (expression was downregulated in both
groups, with a larger decrease observed in the prognathic group),
MYH8, and MYH1 (expression of both was slightly upregulated in
the retrognathic and significantly downregulated in the prognathic
group). Moreover, the analysis revealed an interesting correlation
between the postoperative change in the expression of PTGS2 and
the postoperative change in the expression of the other genes for
stretching factors. The postoperative upregulation in the expression
of PTGS2 in the retrognathic group was correlated to a high
upregulation in the expression of MYH3, MYH8, MYH7, FOXO3,
NFATC1, and PPP3CA, while its downregulation in the prognathic
group was correlated to a large decrease in the expression of MYH8,
MYH1, MYH2, FOXO3, NFATC1, and PPP3CA.
Moreover, the involvement of 2 genes encoding histone mod-
ifying enzymes, K(lysine) acetyltransferase 6B (KAT6B) and
histone deacetylase 4 (HDAC4) in the etiology of skeletal mal-
occlusions was analyzed by Huh et al72 who performed the assay on
masseter muscle samples obtained from 38 subjects divided into 6
malocclusion groups depending on vertical (normal, open, or deep
bite) and sagittal (skeletal Class II or III) dimensions. The study
showed significantly higher KAT6B and HDAC4 expression in the
skeletal Class III than in the Class II group. In addition, the
expression of these 2 genes was also higher in subjects with deep
bite malocclusion than in those with open bite malocclusion.
Another assay, performed to analyze the correlation between the
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expression of KAT6B and HDAC4 and the expression of MYH1,
MYH2, MYH6, MYH7, and MYH8, revealed that HDAC4 expres-
sion correlates negatively with MYH7 expression and positively
with MYH1 expression.
The latest investigation in this field was performed by Desh
et al73 who analyzed the role of MYO1C (class I subclass C
myosin), KAT6B, and runt-related transcription factor 2 (RUNX2)
expression in the development of malocclusions. The analysis
performed on masseter muscle samples taken from 49 patients,
divided into 6 sagittal and vertical dimensions dependent malocclu-
sion groups, revealed that the amount of KAT6B mRNA was
significantly higher in the skeletal Class III than in the Class II
group. Thanks to the immunohistochemical identification of fiber
types in the muscle samples, the study of the correlation between the
percentage of occupancy of a muscle fiber type and gene expression
was performed. The results revealed a significant positive associ-
ation between hybrid type I/II fiber occupancy and MYO1C
expression in the normal vertical bite group, as well as a significant
positive association between type II fiber occupancy and RUNX2
expression in all malocclusion groups, with the highest correlation
in the sagittal Class III and the vertical open bite groups.
SUMMARY
The coexistence of mandibular prognathism in both twins, its
segregation in families and its statistically significant associations
with specific sequence variants, prove that genetic factors play an
important role in its etiology. The available findings (Table 3),
however, indicate that the etiology of mandibular prognathism is
probably elaborate and complex. The compound genetic back-
ground of this defect is thought to result from the involvement
of multifactorial and polygenic determinants in its etiology, as well
as from ethnic divergence and the vast clinical appearance of
mandibular prognathism, which causes difficulties in studying this
condition due to the lack of a clear and unambiguous definition.
In the publications presented, the authors refer to their subjects
as mandibular prognathism affected or as Class III malocclusion
affected. However, many reports quoted provide limited clinical
data and do not reveal what kind of strict criteria was used for
including subjects in a test group (whether it was Angle occlusal
classification, facial profile features, the ANB angle, or a Class III
skeletal pattern). It is also pertinent that, besides the fact that
mandibular prognathism is considered the most common cause
of Class III malocclusion, in many patients maxillary retrusion also
has a large share in its etiology. Concluding from this, Class III
malocclusion is a compilation of a few clinical conditions: pure
mandibular prognathism (due to a large and/or protruding mand-
ible), pure maxillary retrusion, or a combination of both. Moreover,
instead of being collectively described as Class III malocclusion,
each of these clinical conditions could be a different phenotype
caused by its own separate determinants, including specific genetic
factors. The matter seems to be even more complicated in light of

TABLE 3. Suspected Loci, Candidate Genes, and Their Significant Variants

Loci Candidate Genes Proteins Statistically Significant Variants

1p22.135 – – –
1p22.339 SSX2IP39 Synovial sarcoma X breakpoint 2 interacting protein –
1p32.239 PLXNA239 Plexin A2 –
1p3634 MATN117 Matrilin 1 8572 C>T45
Protective role: 7987 G>A45
EPB4117 Erythrocyte membrane protein band 4.1 G-allele of SNP rs4654388 haplotype GTTCAGGT46
HSPG217 Heparan sulfate proteoglycan 2 –
ALPL17 Alkaline phosphatase –
3q26.235 – – –
4p16.136 EVC36 EVC protein –
EVC236 EVC2 protein
5p13-p12 GHR57 Growth hormone receptor Genotype CC of I526L variant57
Genotype CC of P561T variant58,61
Genotype GG of C422F variant58,61
6q2534 – – –
10p12 ARHGAP2164 Rho GTPase activating protein 21 Gly1121Ser64
10q26 FGFR262 Fibroblast growth factor receptor 2 rs216254062
rs1120001462
11q2235 MMP13 (CLG3)35 Matrix metallopeptidase 13 (collagenase 3) –
12pter-p12.340 FGF2340 Fibroblast growth factor 23 c.35C>A40
12q13.1335 HoxC gene cluster35 Conservative transcription factors –
COL2A135 Alpha 1 chain of type II collagen Protective role: a allele of SNP rs179395353
KRT738 Keratin 7 –
12q2335 IGF135 Insulin-like growth factor 1 –
DUSP663 Dual specificity phosphatase 6 c.545C>T (p.Ser182Phe)63
12q24.1138 MYO1H38 Myosin 1H G allele of SNP rs1085011038
12q24.21 TBX562 T-Box protein 5 Protective role: rs124804662
14q24.3-31.237 TGFB337 Transforming growth factor beta 3 –
LTBP237 Latent transforming growth factor beta binding protein 2
17q21.33 COL1A162 Alpha 1 chain of type I collagen rs224949262
19p13.234 FBN338 Fibrilin 3 –
21q21.2 ADAMTS165 ADAM metallopeptidase with thrombospondin type 1 motif rs273865
rs22903865

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the latest thesis describing Class III malocclusion as a compilation
of 5 distinct subphenotypes, where common variables for each
subphenotype are saggital, vertical, and angular craniofacial dimen-
sions rather than general morphology and the position of the
mandible or the maxilla. This theory is compatible with the results
of animal studies showing that the phenotypic effects of genes
expression are rather highly localized to the small regions of the
murine mandible than scattered through the overall structure of that
bone. These findings allow one to suppose that, in Class III
malocclusion, different genes are involved in the control of separate
and specific craniofacial dimensions.
It is also important to note that there are remarkable differences
seen in the prevalence of mandibular prognathism and in its
associations with suspected loci among Far-East Asian, Middle
Eastern, and Caucasian populations. Such differences could be
explained by genetic (allelic) drift. Different populations have an
individual prevalence of a specific allele and even an individual
pool of its own unique sequence variants. This is also true for the
sequence variants associated with mandibular prognathism, as it
seems that some of the reported SNPs are specific to Class III
affected Asians and are not found in Caucasian subjects. There are
probably even some family-specific sequence variants, unique to
families affected by peculiar mandibular prognathism.
The sequence variants presented seem to play the greatest role in
the etiology of familial mandibular prognathism. In such patients,
the trait segregation suggests autosomal-dominant inheritance with
incomplete penetrance and variable expressivity. However, the
strict criteria for simple Mendelian autosomal-dominant inheritance
are mostly not fulfilled, probably due to the involvement of
epigenetic mechanisms that regulate the expression of genes.
Looking at epigenetics from a broad perspective, the role of
extrinsic and environmental factors, such as masticatory muscle
tension or diet, in the regulation of gene expression cannot be
underestimated either; however, this question goes behind the
subject of this review.
The latest genome discoveries provide a chance to discover
which sequence variations and epigenetic factors are involved in the
etiology of mandibular prognathism. This knowledge would be
important for clinical procedures, as it might allow us to predict the
growth of craniofacial bones, plan the best and the most indivi-
dualized treatment, or give advice to family members. However, the
genetic background of mandibular prognathism remains only par-
tially revealed, so it should be more closely evaluated. New,
relatively fast and efficient molecular techniques, such as NGS,
allow us to sequence a large part of the genome, even a whole
exome or whole genome, in a short time. Nowadays, great hopes are
also placed in GWAS, a broad association study in which the
prevalence of many SNPs is analyzed in large control and affected
groups. Nevertheless, NGS and GWAS provide a huge amount of
data and so a great deal of care is needed when analyzing these
results. There are often severe difficulties in determining whether a
specific sequence variant is truly associated with the trait and should
be treated as a causative mutation that is significant for the structure
and function of the encoded protein and whose effects are visible in
the phenotype, or as a nonsignificant polymorphism. However, both
NGS and GWAS could soon provide a number of important
findings in the field of the molecular background of mandibular
prognathism and further reports on this subject are expected to be
based on the results of the genomic studies and analyses that use the
newest molecular methods.
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