Accepted Article Title Page

Title of the article:

ARE TEMPOROMANDIBULAR DISORDERS ASSOCIATED WITH FACIAL

ASYMMETRY? A SYSTEMATIC REVIEW AND META-ANALYSIS

Full names of the authors, academic degrees and institutional affiliations and
positions:
1. Fernanda Blaudt Carvalho Marques, DDS and MS and PhD Student from the
Department of Orthodontics and Pediatric Dentistry of Universidade Federal do
Rio de Janeiro, Rio de Janeiro, Brazil. First author, initial conception of the study,
study design, provision of needed resources, collection of data, analysis and
interpretation of data, manuscript writing.

2. Lílian Siqueira de Lima, DDS and MS and PhD Student from the Department of
Orthodontics and Pediatric Dentistry of Universidade Federal do Rio de Janeiro,
Rio de Janeiro, Brazil. Provision of needed resources, collection of data, analysis
and interpretation of data.

3. Pedro Lima Emmerich Oliveira, DDS and MS and PhD Student from the
Department of Orthodontics and Pediatric Dentistry of Universidade Federal do
Rio de Janeiro, Rio de Janeiro, Brazil. Provision of needed resources, collection of
data, analysis and interpretation of data.

4. Marcela Baraúna Magno, DDS and MS and PhD Student from the Department of
Orthodontics and Pediatric Dentistry of Universidade Federal do Rio de Janeiro,
Rio de Janeiro, Brazil. Analysis and interpretation of data.

5. Daniele Masterson Tavares P. Ferreira, librarian of Central Library of the Health

Science Center, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/ocr.12404
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Accepted Article Initial conception of the study, study design, provision of needed resources,
collection of data

6. Amanda Cunha Regal de Castro, DDS, MS, PhD and Professor in the Department
of Orthodontics and Pediatric Dentistry of Universidade Federal do Rio de Janeiro,
Rio de Janeiro, Brazil. Study design, provision of needed resources, analysis and
interpretation of data.

7. Jose Vinicius Bolognesi Maciel, DDS, MS, PhD and Associate Professor in the
Department of Orthodontics and Pediatric Dentistry of Universidade Federal do
Rio de Janeiro, Rio de Janeiro, Brazil. Study design, provision of needed
resources, analysis and interpretation of data.
8. Antonio Carlos de Oliveira Ruellas, DDS, MS, PhD and Associate Professor in the
Department of Orthodontics and Pediatric Dentistry of Universidade Federal do
Rio de Janeiro, Rio de Janeiro, Brazil. Study design, provision of needed
resources, analysis and interpretation of data.

9. Lucianne Copple Maia, DDS, MS, PhD and Associate Professor in the Department
of Orthodontics and Pediatric Dentistry of Universidade Federal do Rio de Janeiro,
Rio de Janeiro, Brazil. Corresponding author and advisor, initial conception of the
study, study design, provision of needed resources, analysis and interpretation of
data.

Corresponding author: Lucianne Cople Maia

Address: Department of Orthodontics and Pediatric Dentistry of Universidade Federal do
Rio de Janeiro, Avenida Professor Rodolpho Paulo Rocco, 325, Ilha do Fundão, Zip code
21941-617, Rio de Janeiro, RJ, Brazil.
Telephone: +55 21 39382098
E-mail address: rorefa@terra.com.br

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 KEY WORDS: Facial asymmetry; temporomandibular joint disorders
Accepted Article
ACKNOWLEDGMENTS

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de

Nível Superior – Brasil (CAPES) Finance Code 001.

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 ARE TEMPOROMANDIBULAR JOINT DISORDERS ASSOCIATED WITH
Accepted Article
FACIAL ASYMMETRY? A SYSTEMATIC REVIEW AND META-ANALYSIS

ABSTRACT

Objective: To assess scientific evidence of the association between temporomandibular joint

(TMJ) disorders and facial asymmetry (FA).

Methods: A systematic review was performed in accordance with the PRISMA checklist. A
search strategy was developed in electronic databases including MEDLINE, Scopus, Web of
Science, Virtual Health Library and Cochrane Library until January 2020. Eligibility criteria
included observational studies that investigated the occurrence of FA among patients with
and without signs and symptoms of TMJ disorders. Risk of bias of individual studies was
analyzed after study selection and data collection processes according to Fowkes and Fulton
guidelines. Four meta-analyses (MA) were performed to evaluate the association between
TMJ disorders and linear/angular menton deviation, subgrouping the studies into unilateral
and bilateral cases. The evidence was certainty-tested using the GRADE approach.

Results: The search retrieved 2371 studies, 31 of which were eligible for full text reading.
Seven cross-sectional clinical studies met the eligibility criteria and were included in the
qualitative synthesis, comprising a total of 621 subjects (345 with TMJ disease and 276 in
control group), four of which, were classified as being methodologically sound. Five studies
were eligible for quantitative synthesis. Linear and angular menton deviation were greater in
individuals with unilateral TMJ disorders than controls (MD = 2.41 [0.33, 4.50] p=0.02;
I2=86% and MD = 2.68 [0.99, 4.38] p=0.002; I2=0%, respectively).

Conclusions: Despite the low certainty in evidence, the present study indicated that unilateral
TMJ disorders are associated to FA. However, longitudinal studies with greater certainty of
evidence should be conducted to achieve a stronger estimate of this association.

KEY WORDS: Facial asymmetry; temporomandibular joint disorders

1. INTRODUCTION

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 1.1 Background
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Temporomandibular disorders (TMDs) are characterized as musculoskeletal and
neuromuscular illnesses. Clinical signs and symptoms including the masticatory muscles,
temporomandibular joint (TMJ), and associated structures may be presented1. Pain or
tenderness located on pre-auricular area, TMJ or masticatory muscles; limitation or deviation
of mandibular motion and articular sounds, as clicking or crepitus during mandibular function
are common features of TMDs2.
TMDs affect approximately 5% to 12% of the population3, are highly prevalent in
females4,5, and are associated to considerable morbidity3. Frequency and severity of signs and
symptoms increase with age6, particularly from the second through the fourth decade of life7.
The incidence rate of the first TMD onset was nearly 4% per year in an United State
community-based cohort study8.
The etiology of TMDs has not been totally elucidated, particularly regarding the
interaction between physical and psychological factors9 since they may result from an
interaction of causes, including multiple genetic and environmental domains10. In
consideration of the complex etiopathogenesis and multiplicity of symptoms, many efforts
have been made to build up a standardized diagnostic system. The Research Diagnostic
Criteria for Temporomandibular Disorders (RDC/TMD) was introduced for that purpose in
199211, and have been extensively applied. As further studies improved its validity and
clinical use, a new Diagnostic Criteria for Temporomandibular Disorders (DC/TMD)12 was
published in 2014. Since then, it is considered the standard reference for TMDs classification
and diagnosis. It provides a taxonomic classification of TMDs, basically, into four categories:
(I) temporomandibular joint disorders; (II) masticatory muscle disorders; (III) headache, and
(IV) associated structures12. The diagnostic criteria is based on Axis I and Axis II protocols.
The first one consists of a physical assessment, while the second one aim to evaluate pain
intensity, psychological status and psychosocial functioning. Magnetic resonance imaging
(MRI) and computed tomography (CT) may be required for confirmation of disc
displacement and degenerative joint disease, respectively. Therefore, imaging exams
indication is based on whether the information gained will change patient’s treatment plan or
prognosis12,13.
Facial asymmetry (FA) might arise from some pathological conditions that affect
TMJ, such as congenital disorders14, internal derangements15, rheumatoid arthritis16, and
osteoarthritis17. For this reason, the relation between TMJ disorders and craniofacial

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 morphology has been extensively studied18-23. FA refers to a state of lack of equity between
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the right and left side structures, divided by the median sagittal plane24, which may impact
facial esthetic and attractiveness. It is known that the mandible is involved in most facial
asymmetries, particularly the lateral displacement of the chin in relation to the midsagittal
plane25,26. The prevalence of FA varies between 11% and 37% in the reported literature26,27,
without gender-associated differences observed28.
The assessment of TMJ in subjects with FA is a clinically relevant topic. Therefore,
particular attention should be given to the clinical exploration of TMJ in asymmetrical
patients, even in the absence of signs and symptoms of TMJ disorders. Despite the
importance of this topic, there is still no scientific evidence of the association between TMJ
disorders and FA. Clear consensus about this association might contribute to the existing
knowledge regarding diagnose and treatment strategies of these alterations.

1.2 Aim
The aim of this systematic review and meta-analysis was to critically assess evidence
from cross sectional studies to check the null hypothesis that facial asymmetry occurrence is
similar in patients with and without TMDs.

2 MATERIALS AND METHODS

2.1 Protocol and Registration

The study protocol was registered in the PROSPERO database under protocol
CRD42018061067, which is available at
http://www.crd.york.ac.uk/prospero/display_record.php?RecordID=61067. It was performed
in accordance with the PRISMA statement29.

2.2 Eligibility criteria

The PECOS question was used to determine the selection criteria. Population (P):
male or female gender at any age, in any socioeconomic or ethnic group. Exposure (E):
patients with confirmed diagnosis of TMJ disorders; Comparisons (C): patients without TMJ
disorders; Outcome (O): occurrence of FA diagnosed through posteroanterior cephalometric
radiography or computed tomography; Study design (S): observational studies were eligible.

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 Inclusion criteria comprised primary studies that evaluated patients at any age and
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gender with confirmed diagnosis of TMJ disorders and assessment of facial symmetry,
compared to a control group. Papers written in any language or of any publication date were
considered.

Studies comprised of subjects with rheumatoid disease, any injury to the TMJ,
congenital syndrome or any other significant pathology were excluded. Animal and
laboratory studies, technical and case reports, opinion and review articles were also excluded.

2.3 Information sources, search strategy, and study selection

A systematic search of the literature was conducted in the following electronic

databases up to January 2020: PubMed (MEDLINE), Scopus, Cochrane Library, Web of
Science and Virtual Health Library (VHL). The grey literature was searched via the System
for Information on Grey Literature in Europe (SIGLE) through OpenGrey. In order to find
additional studies, a hand search was carried out in the reference lists of retrieved studies.
Search alerts were activated as a self-updating tool.
The search strategy was outlined with controlled vocabulary (MeSH terms) and free
keywords (Table 1) to detect studies based on the elements of the PECOS question. The
search strategy included appropriate changes in the keywords and followed the syntax rules
of each database. Mesh terms, keywords, and other free terms related to
“Temporomandibular joint disorders, facial asymmetry, asymmetry jaw, maxilla asymmetry,
mentum asymmetry, asymmetry Condyle and Craniofacial asymmetry” were used with
Boolean operators (OR, AND) to combine searches.

2.4 Study selection

All titles and abstracts compiled from database searches were evaluated independently
by two investigators (F.B.C.M. and L.S.L.) who excluded irrelevant records. The entire text
was screened when there was lack of information in the abstract. Qualified articles were
attached to a reference management system (EndNote Web Software; Thomson Reuters, New
York, NY, USA). Duplicate records were removed.

After selecting suitable studies, the two authors independently reviewed the full texts
with regard to the eligibility criteria. When disagreement could not be solved, a third

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 researcher (L.C.M.) was consulted. Authors were contacted when necessary to obtain details
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on study design and data clarification.

2.5 Data items extraction and collection

Relevant items of information were extracted from selected studies (F.B.C.M) as

follows: (1) author, year of publication and geographical location; (2) study design; (3)
sample size; (4) control and study groups; (5) age range; (6) gender; (7) TMJ examination
criteria; (8) facial asymmetry examination criteria; and (9) outcome evaluation criteria; and
checked by a second reviewer (L.S.L.).

2.6 Quality assessment and risk of bias analysis

The appraisal of quality and bias control were performed independently by two
researchers (F.B.C.M. and L.S.L.). The critical assessment of medical articles, developed by
Fowkes and Fulton30, which consists of a scale for methodologic quality broadly applied in
dental articles31-33, was used to determine the risk of bias in the included studies. This
protocol enabled identification of the important elements of the methodologic design of
studies. Study design, study sample, characteristics of the control group, quality of
measurements and outcomes were analyzed by a guideline checklist. When checking each
criteria, the terms minor (+) or major (++) were assigned to each problem, in terms of their
expected effect on the results. No problem was assigned as (0). The abbreviation NA was
inserted when the question was not applicable.
The evaluation of each question on the checklist was standardized by the examiners,
as follows. In the item “Sample Size”, a sample calculation was performed to estimate the
adequateness of the population sample size. The calculation was performed with mean and
standard deviation of the measurement of the horizontal distance from vertical reference line
to menton, obtained from the study of Choi et al., 201121. Applying the formula proposed by
Pandis34, with a test power of 80% (α = 0.05), the need for at least 40 patients in each study
group was detected. Therefore, "minor" problem (+) was assigned when the number of
participants per group was 30 and < 40; “major” problem (++) was assigned when the
number was <30 and no problem when it was 40. For “Definition of Controls”, control
patients must have been diagnosed without signs and symptoms of TMD after clinical
examination and magnetic resonance imaging (MRI). If only one method was used (clinical
examination or MRI), a “minor” problem (+) was assigned. Absence of evaluation

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 description was classified as “major” problem (++). For “Comparable characteristics”, a
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similar distribution of groups according to age, gender and skeletal pattern was considered.
Then, no problem was assigned if at least two of these variables were comparable in the
study, a “minor” problem (+) was assigned if the study presented at least one of comparable
characteristics (age or gender or skeletal pattern); and a “major” problem (++), if the study
variables could not be compared.
In the item “Validity”, it was considered a “major” problem (++) if the study did not
use previously validated criteria for both TMD and asymmetry diagnosis, and a “minor”
problem, if just one of TMD and asymmetry diagnosis criteria was not validated. The
RDC/TMD was considered the gold standard for clinical classification of TMDs since 199211
and was replaced by DC/TMD in 201412. Magnetic resonance (MRI) is considered the
reference standard for confirmation TMJ-related diagnosis12,13. Posterior anterior
cephalogram contains diagnostic information for symmetry analysis35 and TC has have been
used to evaluate skeletal asymmetries, since anatomic form can be visualized in 3
dimensions36.
For “Quality control”, problems were assigned when clinical examination, computed
tomography, radiographic and magnetic resonance were not performed considering the
recommendations of the methods. A “major” problem was ascribed when the parameters of
the applied methods were not mentioned, and if the applied methods differed from the gold
standard parameters12,37-39, a “minor” problem was attributed.
For the item “Confounding Factors”, problems were assigned when genders, skeletal
patterns and ages were not considered by authors. A “minor” problem (+) was assigned when
one or two of these characteristics were present and a “major” problem (++) if none factor
was considered.

On concluding assessment of the methods and results, the studies were analyzed to
determine potential “biased results,” “serious confounders,” and the “occurrence of chance
results”30. Lastly, three questions were raised in order to determine the value of the study:
“Are the results erroneously biased in a certain direction?”; “Are there any serious
confounding or other distorting influences?”; and “Is it likely that the results occurred by
chance?” If these 3 summary questions were answered with “no,” the study was considered
methodologically sound. If one of these three summary questions was answered with ‘YES’,
there was a high probability that the research presented a high risk of bias.

2.7 Quantitative synthesis

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 Data were analyzed using RevMan (Review Manager v. 5.3, The Cochrane
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Collaboration; Copenhagen, Denmark) and Comprehensive Meta-analysis software (version
3.2; Biostat) to assess the relationship between TMJ disorders and facial asymmetry. Due to
different evaluation parameters used in the studies, unilateral/bilateral TMJ disorders and
linear/angular facial asymmetry records were considered as a subgroup analysis. Then, four
meta-analyses (MA) were performed: two of them evaluating the association between linear
menton deviation with the presence of TMJ disorders (1st MA), and with unilateral or
bilateral TMJ disorders (2nd MA). The association between angular menton deviation with the
presence of TMJ disorders (3rd MA), and with unilateral or bilateral TMJ disorders (4th MA)
were also evaluated.
A preliminary analysis was performed when the study presented two or more case
groups. The pooled mean and standard deviation of these groups were calculated using
Comprehensive Meta-analysis software. In this context, as all of the groups were provided
from a single study, the population included in the analysis was considered functionally
identical, thus a fixed effect model was applied40. This process was performed to obtain a
single mean and representative standard deviation for each case group, in attempt to not to
exclude samples from the studies and avoid duplication of the control group.
As the studies reported the outcome using the same method, the mean difference, with
95% confidence interval (CI), was calculated 41 using the random effect model. The I2 index
was used to check the heterogeneity.

2.8 Certainty of evidence

The certainty of the evidence (certainty in the estimate of effect) was defined by using
the Grading of Recommendations Assessment, Development and Evaluation (GRADE)
approach42. In this system, the quality of the body of evidence is determined from study
design. When only observational studies are included, the certainty of the evidence begins at
a low level. The quality of evidence may be reduced or increased in accordance with risk of
bias, inconsistency, indirectness, imprecision and publication bias. In this way, the quality of
the evidence can vary from very low to high.

3 RESULTS

3.1 Study selection and characteristics

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 A flow diagram of the search and selection procedures, according to the PRISMA
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guidelines29, is outlined in Fig.1. A total of 2371 titles and abstracts were identified and
retrieved, 930 of which were duplicated and eliminated, remaining 1441 studies. All titles
and abstracts of these studies were analyzed according to the study criteria, and 1410 records
were excluded. The full texts of the remaining 31 studies were assessed for eligibility and 24
studies were thereafter excluded (Supplementary file). A total of 7 articles were included in
the qualitative analysis15,18,20,21,43-45 and 5 of them were included in quantitative synthesis
(meta-analysis)15,20,21,43,45.

Table 2 exhibits an elaborate description of the studies included in this systematic

review. All of the studies presented a cross-sectional design and were conducted in
universities settings. Studies were published between 1999 and 2015 and were performed in 6
different countries: South Korea, Japan, Canada, China, Romania and Spain. The sample size
ranged from 41 to 321. Two studies investigated the amount of craniofacial asymmetry in
adolescents, one between the ages of 10 and 17 years15 and another between 10-20 years45,
while the other studies recruited patients over 17 years of age. Three studies included only
women participants15,18,20. TMJ diagnostic method varied as follows: 5 studies performed
magnetic resonance imaging (MRI)15,18,20,21,45 and 2 studies used clinical examination43,44. For
the FA diagnosis, posteroanterior cephalogram radiograph was used in 6 studies and only one
used reconstructed computed tomography44.

Two studies did not specify which TMJ disorder was studied43,44. Five studies
evaluated subjects with TMJ disc displacement (DD)15,18,20,21,45. Anh et al, 200520 and Choi et
al, 201121 subdivided sample into groups with DD with reduction and group without
reduction.

3.2 Risk of Bias within studies

Table 3 shows the risk of bias in the 7 included articles, rated according to the Fowkes
and Fulton30 quality assessment.

Six studies omitted the sampling method15,18,20,43-45 and only one article had an
adequate sampling size45. In relation to ‘acceptance’ of the control group, most of the studies
presented major problems in ‘matching’ due to the absence of, or not evaluating, or not
describing case and control group pairing. Blinding of assessors was mentioned in only two
reports43,44.

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 Though some minor and major problems were listed, the majority of the studies were
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evaluated as being methodologically sound15,20,21,45. One study18 was considered to have
‘results that were erroneously biased in a certain direction’, and two43,44 were considered to
have some ‘serious confounding or other distorting influences’. Therefore, considering the
summary questions, these three studies were classified as not being methodologically sound.

3.3 Results of individual studies and data synthesis

Inui et al. 199918 was not included in meta-analysis due did not present suficient data
even after autors contact. Yanez-Vico et al. 201344 was not included because it has a different
methodological approach compared with the others studies (3D reconstruction). Five studies
were eligible for meta-analysis15,20,21,43,45. Four of them subdivided the sample into groups:
bilateral normal TMJ, bilateral and unilateral TMJ disease15,20,21,43. One study45 has focus
only on unilateral TMJ disease. Therefore, the meta-analysis results (FIGURE 2) were
presented as the following subgroups:

TMJ disorders and linear menton deviation (general). Four studies were included in this
analysis. The results showed that the linear mean of menton deviation was greater in
individuals with TMJ disorders (n=310) than controls (n=250) MD = 1.42 [0.31, 2.53]
p=0.01; I2=62% with very low certainty of evidence (Table 4).

Unilateral/Bilateral TMJ disorders and linear menton deviation. Four studies were
included in this analysis. Linear mean of menton deviation was similar between individuals
with bilateral (n=66) and without TMJ disorders (n=94) MD = 0.56 [-0.41, 1.53] p=0.26;
I2=0%. However, linear mean of menton deviation was greater in individuals with unilateral
TMD (n=244) than controls (n=250) MD = 2.41 [0.33, 4.50] p=0.02; I2=86%. Both analysis
were classified with very low certainty of evidence (Table 4).

TMJ disorders and angular menton deviation (general). Two studies were selected for this
analysis and their pooled results showed that in general, angular mean of menton deviation
was similar between individuals with and without TMJ disorders, n=84 and n=39,
respectively. MD = 0.37 [-0.34, 1.07] p=0.31; I2=0%, with very low certainty of evidence
(Table 4).

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 Unilateral/Bilateral TMJ disorders and angular menton deviation. Two studies were
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included in this analysis. The angular mean of menton deviation was similar between
individuals with bilateral (n=57) and without (n=39) MD = 0.14 [-0.60, 0.88] p=0.72; I2=0%,
with low certainty of evidence (Table 4). The results showed that angular mean of menton
deviation was greater in individuals with unilateral TMJ disorders (n=27) than controls
(n=39) MD = 2.68 [0.99, 4.38] p=0.002; I2=0%, with very low certainty of evidence (Table
4).

4. DISCUSSION

4.1 Summary of evidence

A number of studies have attempted to associate TMJ disorders and FA, which
substantiated the development of this systematic review to determine whether the level of
scientific evidence available was enough to support this association, or not. The present study
provided both qualitative and quantitative evidence regarding this topic. Data provided by the
studies15,20,21,43,45 included in the MA showed that linear and angular mean of menton
deviation were greater in individuals with unilateral TMJ disorders than controls. To our
knowledge, the present study is the first systematic review and meta-analysis to collect and
synthesize evidence on this topic.
TMDs are common problems faced by dentists who treat patients with asymmetry. A
high prevalence of articular disc displacement, the characteristic of TMJ internal
derangement that causes most concern, has been reported in patients with asymmetry15.
Function and shape of TMJs may be influenced by FA, especially mandibular asymmetry46.
Differences in bilateral TMJ morphology in patients with mandibular asymmetry may
represent anatomic disorders that predispose these patients to TMJ problems47. Vertical
dental and facial skeletal asymmetries, such as canting of occlusal planes, particularly those
related to a difference in the height of both mandibular rami have been considered important
contributors to disturbance in TMJ loading48. On the other hand, if disc displacement become
progressive, osseous changes in condylar articular surface may be developed49. Changes in
the mandibular condyles, specially decreased condylar height, may induce shortening of the
disc displacement side, leading to facial asymmetry50. Therefore, it is difficult to describe a
clear cause end effect relation between FA and TMDs.

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 Primary studies retrieved from the present systematic review presented different
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sample selection approaches. Sample was entirely constituted by female gender in three
studies15,18,20. Skeletal pattern was considered a selection criteria in two studies20,21, as Anh et
al, 200520 evaluated subjects with SNB angle less than 78, whereas Choi et al, 201121
analyzed adult patients with skeletal Class III malocclusion. Despite previously investigated
in a few studies5,50,51, the relationship between TMJ disc displacement and facial morphology
was not consistently addressed in the literature.
Only two from the seven eligible studies recruited in this systematic review were
conducted on growing patients15,45. Trpkova et al15 found that growing females (from 10 to
16.6 years old) with bilateral TMJ internal derangement presented greater amount of
asymmetry than individuals with unilateral TMJ or normal TMJ. On the other hand, Xie et al,
201545 assessed patients between 10 and 17 years old with only unilateral disc displacement,
concluding that the more the disc was displaced and deformed, the more the mandible was
deviated, in accordance with previous reports in the literature17,21. The hypothesis that TMJ
disc displacement was one of the causative factors of FA in growing subjects was confirmed
in a longitudinal study of Flores-Mir et al, 200648, which suggested that disc displacements
disrupt the normal downward and forward growth of the mandible. The study of Xie et al,
201652 also suggested that FA was secondary to unilateral TMJ disc displacement in growing
patients, especially due to alteration in condylar height, which was much shorter on the
ipsilateral side.
A meta-analysis is a type of systematic review that applies statistical methods to
outline the results of distinct primary studies53. This study null hypothesis was that facial
asymmetry occurrence was similar in patients with and without TMDs. Nevertheless, it was
rejected by the meta-analysis results, as linear e angular menton deviation were greater in
patients with unilateral TMJ disorders. These results may be interpreted with caution
considering the reduced number of studies retrieved in the present meta-analyses. In addition,
only observational studies with small sample size were included. Another important
parameter to be considered in a meta-analysis is heterogeneity, represented by I2. Higgins and
Green, 201141 suggest that I2 value close to 0% indicates non-heterogeneity between studies.
A very high heterogeneity implies that the studies are completely different, and therefore, the
validity of pooled effects are questionable. In the present study, four from the six meta-
analysis performed revealed I2 of 0%. However, as there were a few studies selected with a
small sample size, heterogeneity index must also be interpreted carefully.

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 In addition, the level of evidence assessment through GRADE guidelines42 indicated a
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low certainty of evidence regarding bilateral TMJ disorders and angular menton deviation
and a very low certainty for the remaining analyses, suggesting that further studies are needed
to increase the consistency of evidences regarding TMD and FA.
The small sample size of some primary studies included in this systematic review was
compensated by the meta-analyses pooling of samples, totaling 621 subjects evaluated (345
with TMJ disease and 276 in control group). The pooling was 560 subjects (310 with TMJ
disease and x 250) on MA that analyzed linear menton deviation and TMJ (general).
This study was based on cross-sectional investigations. Therefore, follow-up
investigations are required to establish the long-term relationship between TMJ disorders and
FA. The degree of this association, and how these factors interact with each other, are still
unclear. Variables such as the age of individuals at the time they are affected by the disorder
and/or asymmetry are underlying factors that are difficult to assess statistically. Therefore,
longitudinal studies are needed for further investigations.

4.2 Strenghts and limitations

This systematic review and meta-analysis has a priori registered protocol in

international prospective register of systematic reviews (PROSPERO)55, an extensive
literature search, application of the GRADE approach42 and a clear report of data retrieved. It
is the first systematic review to evaluate the association between TMJ disorders and
asymmetry.
Only cross-sectional studies were included in this study. It is known that association
analyses in cross-sectional studies are evidently subject to different selection, information
and confusion biases56. Prospective studies are preferable to control the time variable, and
determine the appropriate association of the impact of TMJ disorders with facial asymmetry.
However, to date, prospective studies are not available in the literature.

5 Conclusions

Evidence from the present systematic review and meta-analysis indicates that
unilateral TMJ disorders are associated to FA. However, considering the quality and very low
certainty of evidence provided by the primary studies retrieved, the present study results

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 should be limited to a preliminary evidence level. Therefore, longitudinal studies are
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necessary to corroborate with these findings.

ACKNOWLEDGMENTS

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal

de Nível Superior – Brasil (CAPES) Finance Code 001.

CONFLICT OF INTEREST

None. All authors declare that there are no conflicts f interest.

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Accepted Article
TABLES
Table 1. Electronic database and search strategy (January, 22nd, 2020).
Pubmed
(((Temporomandibular joint[mh] OR
Temporomandibular joint*[tiab] OR
TMJ[tiab] or Temporomandibular
joint disorders[mh]))) = 27677
Scopus
( TITLE-ABS-
KEY ( ( temporomandibular AND joi
nt* ) ) ) OR
( TITLE-ABS-KEY ( ( tmj ) ) )=
32233
Web of Science
((temporomandibular joint*)
OR ( tmj ) ) = 16545
BVS
(“temporomandibular joint” OR
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((Facial asymmetry[mh] OR Facial
asymmetr*[tiab] OR Facial deformit*[tiab] or
asymmetry jaw [tiab] OR maxilla
asymmetry[tiab] OR mentum asymmetry
[tiab] OR asymmetry Condyle [tiab] OR
Craniofacial asymmetry[tiab] ))= 6858
( TITLE-ABS-
KEY ( ( facial AND asymmetr* ) ) ) OR ( TI
TLE-ABS-
KEY ( ( facial AND deformit* ) ) ) OR ( TI
TLE-ABS-KEY ( ( "asymmetry
jaw" ) ) ) OR ( TITLE-ABS-
KEY ( ( "maxilla
asymmetry" ) ) ) OR ( TITLE-ABS-
KEY ( ( "mentum
asymmetry" ) ) ) OR ( TITLE-ABS-
KEY ( ( "asymmetry
Condyle" ) ) ) OR ( TITLE-ABS-
KEY ( ( "Craniofacial asymmetry" ) ) ) =
15657
(( facial AND asymmetr* ) OR ( facial AN
D deformit* )
OR ( "asymmetry jaw" ) OR ( "maxilla
asymmetry" ) OR
( "mentum asymmetry" ) OR ( "asymmetry
Condyle" ) OR
( "Craniofacial asymmetry" ) ) = 8737
(mh:"facial asymmetry" or "assimetria facial"
(((Temporomandibular joint[mh] OR
Temporomandibular joint*[tiab] OR
TMJ[tiab] or Temporomandibular joint
disorders[mh]))) AND ((Facial
asymmetry[mh] OR Facial asymmetr*[tiab]
OR Facial deformit*[tiab] or asymmetry jaw
[tiab] OR maxilla asymmetry[tiab] OR
mentum asymmetry [tiab] OR asymmetry
Condyle [tiab] or Craniofacial
asymmetry[tiab] ))= 784
( ( TITLE-ABS-
KEY ( ( facial AND asymmetr* ) ) ) OR ( T
ITLE-ABS-
KEY ( ( facial AND deformit* ) ) ) OR ( TI
TLE-ABS-KEY ( ( "asymmetry
jaw" ) ) ) OR ( TITLE-ABS-
KEY ( ( "maxilla
asymmetry" ) ) ) OR ( TITLE-ABS-
KEY ( ( "mentum
asymmetry" ) ) ) OR ( TITLE-ABS-
KEY ( ( "asymmetry
Condyle" ) ) ) OR ( TITLE-ABS-
KEY ( ( "Craniofacial
asymmetry" ) ) ) ) AND ( ( TITLE-ABS-
KEY ( ( temporomandibular AND joint* ) ) )
OR ( TITLE-ABS-KEY ( ( tmj ) ) ) ) = 978
(#2 AND #1) AND Tipos de
documento: (Article) = 481
(#2 AND #1) AND Tipos de
documento: (Review) = 26
(tw:((“temporomandibular joint” OR
 “temporomandibular joint” OR tmj
Accepted Article
OR mh: “temporomandibular joint
disorders” OR “transtornos da
articulação temporomandibular”)
= 2943
Cochrane Library
#1 [Temporomandibular Joint]
explode all trees =18
#2 Temporomandibular joint*= 1406
#3 TMJ = 708
#4 [Temporomandibular Joint
Disorders] explode all trees = 863
#5 #1 or #2 or #3 or #4 = 1692
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or “facial asymmetry” OR “facial deformities” “temporomandibular joint” OR tmj OR mh:
OR “ asymmetry jaw” OR “maxilla
asymmetry” OR “mentum asymmetry” OR “
“temporomandibular joint disorders” OR
“transtornos da articulação
asymmetry condyle” OR “craniofacial temporomandibular))) AND (tw:(("facial
asymmetry”)= 1344 assymetry" or "assimetria facial" or “facial
asymmetry” OR “facial deformities” OR “
asymmetry jaw” OR “maxilla asymmetry”
OR “mentum asymmetry” OR “ asymmetry
condyle” OR “craniofacial asymmetry”)))= 63
#6 Mesh descriptor: [Facial Asymmetry]
explode all trees = 91
#7 Facial asymmetry* = 364
#8 Facial deformit* = 162
#9 #6 or #7 or #8 = 497
#10 Craniofaial asymmetry = 54
#11 asymmetry jaw = 99
#12 maxila asymmetry = 39
#13 mentum asymmetry = 0
#14 asymmetry Condyle = 16
#15 #11 or # 12 or #13 or #14 = 127
#16 #9 or #10 or #15 = 585
#5 and #16 = 37
Accepted Article
Table 2. Data extracted from the studies included in the review
OBJECTIVES PARTICIPANTS
AUTHOR(S)/ ASYMMETRY MAINLY
OF THE AGE RANGE TMJ EXAMINATION MAINLY RESULTS
COUNTRY/YEAR SAMPLE SIZE GENDER EXAMINATION OUTCOME
STUDY (MEAN  SD)
Clinical examination and
disc displacement in one
or both TMJs revealed The angle
To examine
by MRI examination and between the Angular relationship ():
the Control: 23.4 to
49 the disturbance or the mid-facial ID group: 4.12
Inui et al., 199918 prevalence of 28.2 (25.8) PA,3 angular
Control group: 15 female limitation in the sagittal plane and the Control group: 0.7
Japan* FA in the ID group: 17.4 measurements.
TMJ ID group: 34 and the horizontal line running (p<0.001)
patients with to 37.1 (23.6)
tracings of condylar through ANS
TMJ ID
movement recorded by and Me
axiograph findings

Linear relationship
(mm):
63 Group 1: 1.864.34
Group 1 (bilateral normal Group 2: 6.596.30
disc position): 13;
Group 3: 0.853.83
Group 2 (unilateral normal Vertical
Group 4: 3.082.79
To analyze TMJ and contralateral reference line
Bilateral MRI in the Group 5: 0.234.52
20
the DDR): 8 PA, 14 to Me (mm)
Ahn et al., 2005 Over 17 sagittal (opened and (p<0.05)
relationship Group 3 (bilateral DDR): female cephalometric and
South Korea* (23.94.6) closed) and coronal Angular relationship ():
between FA 14; variables vertical
(closed) planes Group 1: 1.123.01
and TMJ DD Group 4: (unilateral DDR reference line
Group 2: 4.953.98
and contralateral DDNR): to ANS-Me ()
Group 3: 0.432.55
8;
Group 5 (bilateral DDNR): Group 4: 1.992.59

19 Group 5: 0.272.56
(p<0.01)

Choi et al., To investigate 97 Female MRIs, closed mouth and PA and lateral Men-Mid: Linear relationship
21
---- (22.13.5)
2011 the Group 1 (bilateral normal (60) and open mouth cephalogram horizontal (mm):

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Accepted Article
South Korea* relationships disc position): 39; male (37) (11 linear, 7 distance from Group 1: 3.52.5
between TMJ Group 2 (bilateral DDR or angular and 3 vertical Group 2: 4.12.2
DD and FA in bilateral DDNR):10 proportional reference line Group 3: 8.04.0
skeletal Class Group 3 (DD was more measurements) to Me (mm) Group 4: 8.34.8
III patients advanced on the R): 25; (p<0.001)
Group 4 (DD was more
advanced on the L): 23

80
Cluster groups formed by
combining TMJ ID scores:
Group 1(bilateral normal
TMJ): 42 Linear relationship
To explore Group 2 (unilateral TMJ ID (mm):
whether TMJ R) 13 Group 1: 2.094
ID is Group 2 (Unilateral TMJ ID Group 2: 2.446
PA and lateral
Trpkova et al., associated L): 10 Perpendicular Group 3: 2.908
10.01 to 16.64 Bilateral MRI, closed cephalogram
200039 with CFA in a Group 3 (Bilateral TMJ ID): female distance from (p=0.400)
(13.201.70) mouth Total: 14
Canada* sample of 15 Me-FM Group IV:2.060
measurements
growing Cluster groups based on Group V: 2.211
female TMJ ID scores and TMJ ID Group VI: 1.410
patients side dominance (p=0.749)
Group IV (no side
dominance): 52
Group V (R dominant): 16
Group VI( L dominant): 12

Group I
To quantify unilateral TMD: Angular relationship():
61
Almasan et al, the changes 24.87 PA. 14 linear Group I: 3.45  4.31
43
Group I unilateral TMD: 19 Female:47 ANS-ME to
2013 in PA in Group II Axis I of RDC/TMD and angular Group II: 1.47  1.33
Group II bilateral TMD: 16 Male:14 vertical plane
Romania* subjects with bilateral TMD: measurement Group III: 1.21  1.26
Group III no TMD: 26
TMDs 25.7 P value= 0.02 (ANOVA)
Group III no

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Accepted Article
TMD: 22.88

To study the
symmetry of
the
craniofacial
structure
using
Mandibular
reconstructed
rotation: the
3D CT 41 Patients were screened Linear relationship
TMJ sound: distance
Yanez-Vico et al, imaging and Presence of unilateral joint for the presence of TMJ Reconstructed (mm):
36.704.51 Female:18 between Me
201344 the influence sounds: 20 sounds by means of an 3D CT. 12 Control group: 1.34
Control group: Male:23 and the
Spain* of asymmetry Absence of unilateral joint interview and clinical measurements TMJ sound group: 2.25
37.144.05 midsagittal
on unilateral sounds: 21 examination
reference
TMJ sounds
plane
in patients
with and
without
unilateral TMJ
sounds

To investigate
the
prevalence
and severity
of MA within Linear relationship
321
Xie et al, the unilateral 10 to 20 Horizontal (mm):
Control: 156 Female PA. 1
201545 TMJ DD Control: 16.21 MRI distance from ADD group: 5.62
ADD group: 165 and male measurement
China* patients and ADD: 16.74 Me to midline Control: 4.19
analyze the (p<0.01)
TMJ influence
factors on the
severity of MA

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Accepted Article
*cross-sectional design; ANS: anterior nasal spine; ADD: anterior disc displacement; CT: computed tomography; DD: disc displacement; DDR: disc displacement with
reduction; DDNR: disc displacement without reduction; FA: facial asymmetry; MA: mandibular asymmetry; Me: menton; Me-FM: menton to the facial midline; MRI:
magnetic resonance imaging; PA: posteroanterior cephalogram; TMJ: temporomandibular joint; TMJ ID: temporomandibular joint internal derangement; R: right; L: left;
RDC/TMD: Research Diagnostic Criteria for Temporomandibular Joint Disorders.

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Accepted Article
Table 3. Risk of bias assessed according to Fowkes and Fulton guidelines.

Guideline Checklist Inui et al, Trpkova Ahn et al, Choi et al, Almasan Yáñez-Vico Xie et al,
1999 et al, 2005 2011 et al, et al, 2013 2015
2000 2013
(1) Study design Objective Common design
appropriate to Prevalence Cross sectional 0 0 0 0 0 0
objectives? Prognosis Cohort
Treatment Controlled trial
Cause Cohort, case-control, cross sectional 0
(2) Study sample Source of sample 0 0 0 0 0 0 0
representative? Sampling method ++ ++ ++ + ++ 0 ++
Sample size ++ ++ ++ ++ ++ ++ 0
Entry criteria/exclusions + + 0 0 + + 0
Non-respondents NA NA NA NA NA NA NA
(3) Control Definition of controls + 0 + + + + 0
group Source of controls 0 0 0 0 0 0 0
acceptable? Matching/Randomization ++ ++ ++ ++ ++ ++ ++
Comparable characteristics + + 0 + ++ ++ +
(4) Quality of Validity + 0 0 0 0 + 0
measurements Reproducibility ++ + + ++ + 0 ++
and outcomes? Blindness ++ ++ ++ ++ 0 0 ++
Quality control ++ 0 0 + 0 + +
(5) Compliance NA NA NA NA NA NA NA
Completeness? Drop outs NA NA NA NA NA NA NA
Deaths NA NA NA NA NA NA NA
Missing data 0 0 0 0 0 0 0
(6) Distorting Extraneous treatments NA NA NA NA NA NA NA
influences? Contamination NA NA NA NA NA NA NA
Changes over time NA NA NA NA NA NA NA
Confounding factors + + 0 + ++ ++ +
Distortion reduced by analysis ++ 0 ++ ++ ++ ++ ++
(7) Summary Bias - Are the results erroneously biased in a certain direction? YES NO NO NO NO NO NO

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Accepted Article
questions
Confounding - Are there any serious confounding or other NO NO NO NO YES YES NO
distorting influences?
Chance - Is it likely that the results occurred by chance? NO NO NO NO NO NO NO

(+) minor problem; (++) major problem; (0) no problem; NA (not applicable).

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Accepted Article
Table 4. Evidence profile: Association between linear and angular menton deviation and TMJ disorders.

Certainty assessment Summary of findings

Study event
№ of participants Overall Anticipated absolute effects
Risk of Other rates (%)
(studies) Inconsistency Indirectness Imprecision certainty of
bias considerations With With Risk difference with
Follow-up evidence Risk with control
control DTM DTM

TMJ disorders and linear menton deviation

560 not serious a not serious serious b none ⨁◯◯◯ 250 310 The mean linear menton deviation MD 1.42 higher
(4 observational serious VERY LOW and TMJ disorders was 0 (0.31 higher to 2.53
studies) higher)

Bilateral TMJ disorders and linear menton deviation

160 not not serious not serious very serious none ⨁◯◯◯ 94 66 The mean linear menton deviation MD 0.56 higher
b,c
(3 observational serious VERY LOW and bilateral TMJ dosorders was (0.41 lower to 1.53
studies) 0 higher)

Unilateral TMJ disorders and linear menton deviation

494 not serious a not serious serious b strong ⨁◯◯◯ 250 244 The mean linear menton deviation MD 2.41 higher
(4 observational serious association VERY LOW and unilateral TMJ disorders was (0.33 higher to 4.5
studies) 0 higher)

TMJ disorders and angular menton deviation

123 not not serious not serious very serious strong ⨁◯◯◯ 39 84 The mean angular menton MD 0.37 higher
b,c
(2 observational serious association VERY LOW deviation and TMj disorders was 0 (0.34 lower to 1.07
studies) higher)

Bilateral TMJ disorders and angular menton deviation

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Accepted Article
Table 4. Evidence profile: Association between linear and angular menton deviation and TMJ disorders.

Certainty assessment Summary of findings

96 not not serious not serious very serious very strong ⨁⨁◯◯ 39 57 The mean angular menton MD 0.14 higher
b,c
(2 observational serious association LOW deviation and bilateral TMj (0.6 lower to 0.88
studies) disorders was 0 higher)

Unilateral TMJ disorders and angular menton deviation

66 not not serious not serious very serious strong ⨁◯◯◯ 39 27 The mean angular menton MD 2.68 higher
b,c
(2 observational serious association VERY LOW deviation and unilateral TMj (0.99 higher to 4.38
studies) disorders was 0 higher)

CI: Confidence interval; MD: Mean difference; a. Substantial heterogeneity; b. Upper or lower confidence limit crosses the effect size of 0.5 in either direction; c. Total number of participants is less than 400.

FIGURE LEGENDS
Figure 1. Flowchart diagram of literature search (January, 2020) according to Preferred Reporting Items for Systematic Review and Meta-
Analysis (PRISMA) guidelines.

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Accepted Article
Figure 2 FOREST PLOT 1.Relationship between TMD and linear menton deviation. Relationship between (a) general; (b) bilateral and (c)
unilateral TMD and linear menton deviation. 2. Relationship between TMD and angular menton deviation. Relationship between (a) general; (b)
bilateral and (c) unilateral TMD and angular menton deviation.

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Accepted Article

ocr_12404_f1.tiff

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