{"paper_id":"417d50c6-d317-4b01-8971-5abdc2d40467","body_text":"FGFR2 gene Related Apert and Crouzon Syndrome Patients with Different Craniofacial Dysmorphisms: A Systematic Review and Meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review FGFR2 gene Related Apert and Crouzon Syndrome Patients with Different Craniofacial Dysmorphisms: A Systematic Review and Meta-analysis Shalini Dhiman, Inusha Panigrahi, Bijaya Kumar Padhi, Shifali Gupta, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4443370/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background This study aimed to compare the prevalence of craniofacial dysmorphisms, such as maxillary, mandibular, and dental arch dimensions, and cranial suture fusion in Apert and Crouzon syndrome patients from publicly available scientific information and to provide insights to improve the findings of further studies. Over a large-scale interval from January 2000 to January 2023, a comprehensive search was performed on different database platforms: PubMed, Google Scholar, Cochrane, Web of Science, and the Wiley online library. The preferred reporting item for Systematic Review and Meta-Analyses (PRISMA) guidelines were followed to conduct this systematic review. The protocol was submitted to the International Prospective Register of Systematic Reviews (CRC42023395454; https://www.crd.york.ac.uk/prospero/record_email.php) on 11 February 2023. We collected the data from different databases and ranked the publications based on their adherence to the Newcastle‒Ottawa Quality Assessment Scale. The meta-analysis was carried out by calculating the random effects model and pooled mean proportions with 95% confidence intervals (CIs). Results A total of 53 studies were considered worthy, but 39 were excluded due to unusable data formats. The meta-analysis was carried out by calculating the random effects model and pooled mean proportions with 95% confidence intervals (CIs). Patients with Apert syndrome were noted as having AS, and Crouzon syndrome was noted as having CS; different studies were included in the systematic review. A total of seven studies reported outcomes. The I2 index provides a better way of assessing effect size heterogeneity. Forest plots were generated to visualize the heterogeneity of the individual outcomes. Subgroup analyses were performed for each outcome to assess the potential differences in effect sizes. The effect size and heterogeneity of the dental arch were greater in the CS group (I2: 58%, 95% CI=0.01, 0.29; P=0.12) than in the AS group (I2: 52%, 95% CI=0.01, 0.27; P=0.15). Effect size and heterogeneity of the maxilla of AS patients (I2: 91%, 95% CI 0.09; 0.47, P<0.01) and CS patients (I2: 94%, 95% CI 0.07; 0.64, P<0.01). We observed significant heterogeneity in AS and CS patients. Conclusion This review demonstrated the large variation in cephalometric measurements between CS and AS patients. The CS patient had a smaller skull and mandible volume than the AS patient. The CS procedure did not change the maxillary intercanine width or intermolar width, but the maxillary intercanine width increased in patients with AS. With the growth period of the children, the maxillary and mandibular intercanine indices increased in the CS, whereas no change in mandibular or maxillary intercanine indices during the growth period was predicted in the AS. The anterior maxillary region is more affected in AS patients than in HCs but less affected in CS patients. ASs had an anterior crossbite (p<0.001), and CSs had an edge-to-edge bite (p<0.011). CSs tend to have short and flat cranial bases, smaller orbital volumes, and cleft palates. Apert Cranium Crouzon Craniosynostosis Dental Arches FGFR2. Maxillary Mandibular Proptosis. Figures Figure 1 Figure 2 Figure 3 1. Introduction The main manifestation of Apert syndrome (AS) and Crouzon syndrome (CS) is craniosynostosis. Craniosynostosis is a condition of early fusion of the skull bones (Bhoj & Zackai, 2021; Lu et al., 2020). Early sutural fusion impairs skull growth and gives rise to craniofacial dysmorphism in the AS and CS (Das & Munshi, 2018; Lu et al., 2021). AS is a complex syndrome that causes craniosynostosis and hand and foot fusions. It was first described by Eugene Apert in 1842. It is also known as acrocephalosyndactyly (Junaid et al., 2023; Ko, 2016; Sawh-Martinez & Steinbacher, 2019). In addition to craniosynostosis, craniofacial dysmorphism, visual impairments, cleft palate, and hearing loss are found in AS. Bilateral coronal synostosis is most frequently found in the AS (Alsaeed et al., 2023; Kumari et al., 2023; Massimi et al., 2019). Other metopic, lambdoid, and sagittal suture fusions are also rarely found in AS patients. Early closure of cranial sutures is known to occur in patients with AS via genetic factors (Choudhary et al., 2023; Faasse & Mathijssen, 2023; Koca, 2016; Tan & Mankad, 2018; Timberlake et al., 2023). In 1912, Octave Crouzon first identified Crouzon syndrome (CS) (Al-Namnam et al., 2019; Balyen et al., 2017). This condition has complete penetrance and variable expressivity. CS is an autosomal dominant disorder with common features, such as a long face, a proptosis prominent jaw, hypertelorism, exophthalmos, maxillary hypoplasia, hearing loss, and a beaked nose, as well as synostosis of coronal, sagittal, and lambdoid sutures (Motch Perrine et al., 2017; Rostamzad et al., 2022; Shlobin et al., 2022; Taylor & Bartlett, 2017; Tønne et al., 2020). The prevalence rate of AS has been estimated to be between 1/65,000 new-borns, and that of CS is estimated to be 1/25000 new-borns, without prediction by sex (Munarriz et al., 2020; Munib et al., 2023). AS and CS are associated with advanced paternal age, maternal infections, maternal drug consumption, and cranial inflammatory processes (Fernandes et al., 2016; Kyprianou & Chatzigianni, 2018; Lu et al., 2019; Sakamoto et al., 2021). Fibroblast growth factor (FGFR2) gene-specific missense pathogenic mutations at chromosomal region 10q25-10q26 cause more than 98% of AS and CS patients (Azoury et al., 2017; Morice et al., 2020). FGFR belongs to the family of mitogenic signaling molecules that play important roles in the control of cell proliferation and survival (Luong et al., 2019; Ma et al., 2023). In AS and CS patients, fibroblasts cannot produce the essential fibrous material in several craniofacial tissues, including bone sutures and cartilage, or during odontoblast formation and regeneration (Di Rocco et al., 2023; Elarjani et al., 2021; Hoshino et al., 2023). Most of the variations are missense variations in FGFR2 leading to craniofacial dysmorphism and hand and foot malformations. Several syndromes are associated with the FGFR2 gene. These phenotypes also include Antley Bixler syndrome, Beare Stevenson syndrome with cutis gyrata, Pfeiffer syndrome, Jackson Weiss syndrome, and Saethre Chotzen syndrome clinically classified as additional digital anomalies, skin furrows and skeletal bowing and synostoses (Kiziltug et al., 2023; Pinto et al., 2023; Stanton et al., 2022). In AS and CS patients, the most commonly explored features are asymmetry in mandibular width, height and length; dental arch dimensions; and cranial suture fusion. In this review, we discuss FGFR2 gene-related craniofacial dysmorphism in rare syndromes, which include AS and CS. This is the first systematic review focused on craniofacial dysmorphism in two syndromes associated with one FGFR2 gene. This meta-analysis aimed to better understand craniofacial dysmorphism in AS and CS patients by exploring the previously published scientific literature. 2. Materials and Methods This systematic review was carried out according to the preferred reporting methods for systematic reviews and meta-analysis (PRISMA 2020) guidelines [Table S1] (Page et al., 2021). The protocol was submitted to the International Prospective Register of Systematic Reviews CRD42023395454 ( https://www.crd.york.ac.uk/prospero/record_email.php ) accessed 11 February 2023. 1.1 Search Eligibility The search included peer-reviewed journals and publications in which full-text articles on AS and CS were discussed. Among the different types of research that have been ruled out are animal mouse studies, clinical case reports, pilot studies, bibliographic reviews, book chapters, and systematic reviews. The four main steps included in selecting the article were identification, screening, eligibility, and inclusion. Case‒control, cross-sectional, cohort studies have compared cephalometric CT scans and radiographs of patients with AS, patients with CS, and nonsyndromic patients. Most related studies have evaluated different conditions, such as maxillary and mandibular dysmorphism, dental arch asymmetry, and cranial vault dysmorphism. All the research papers that met the inclusion criteria were included. The researchers worked independently and reviewed the title and abstract of all the records to select all the relevant studies, and any discrepancies in the results were resolved. 2.2 PICO search strategy The following electronic databases were used for the search: PubMed, Cochrane Library, Medline, and Web of Science. The articles were published from January 2000 to January 2023 [Table S3]. The main search terms used were craniofacial OR craniosynostosis (Apert syndrome) OR (craniofacial dysmorphism) AND (Crouzon syndrome) OR (craniofacial dysmorphism) AND (((Craniosynostosis [Title/Abstract])) OR (Cranium [Title/Abstract])) OR (FGFR2[Title/Abstract]). 2.3 Inclusion/exclusion criteria The systematic review and meta-analysis inclusion criteria for patients were as follows: studies on humans; papers written in English; children with descriptive studies such as case reports, case series, and randomized controlled trials; cohort studies; and case‒control studies of Apert syndrome and Crouzon syndrome with craniofacial dysmorphism. This meta-analysis was not performed on an ethnicity or sex basis. The exclusion criteria for patients were as follows: cross-sectional studies; editorials; systematic reviews; and meta-analyses. Patients who had pathological fractures were excluded. The search strategy for eligibility of studies and variables of interest were prespecified in the protocol. The variables of interest were chosen, and the subsequently anticipated heterogeneity in managing and reporting the variables was also noted [Table S2]. 2.4 Data Extraction The researchers (SD, KD, MG) recaptured the information from different articles as authors with, year, country, and sample and used methodology in the studies, independently screening the retrieved studies for inclusion on the basis of the titles and abstracts. The papers revealed craniofacial dysmorphism in AS and CS based on clinical cephalometric CT scans and radiographs. The program Endnote X20 software was used for reference. 2.5 Quality assessment The Newcastle Ottawa Scale was used for qualitative evaluation of the studies included in the meta-analysis. The risk of bias was assessed based on three criteria, selection, comparability, and outcome, as mentioned in Table S4. The following domains were assessed: confirmed cases, representativeness of the cases, selection of control/comparator, definitions of control/comparator, case, control/comparator, assessment of outcome, the same methodology used for cases for AS, CS, and NS, and nonresponse rate. Each of the domains was assessed as yes, no, or unclear. If the study met the criteria, points were given as (*) in that domain, which was defined as a low risk of bias. If the study did not meet the criteria or was unclear, (-) points were given. The points for each item were summed, resulting in a total quality score. Studies with scores ranging from 7–9 were considered high quality, 4–6 were considered high risk, and 0–3 were considered to have a very high risk of bias. The Newcastle–Ottawa Scale contains 9 items within 3 domains, and the total maximum score is 9. 2.6 Statistical analysis Descriptive statistics were used for the different craniofacial dysmorphisms in AS and CS patients. These meta-analysis proportions were calculated using the random effects model for the different anomalies, and pooled mean proportions with 95% CIs were calculated. A p value of the small sample sizes and possibly extreme proportions was defined as statistically significant. Heterogeneity was evaluated by the I2 statistic. The software program R version 4.1.2 for Windows was used for the meta-analysis and forest plots (Balshem et al., 2011; Higgins & Thompson, 2002; Viechtbauer & Cheung, 2010; Wang, 2018). 3. Results The PEPO population, exposure, comparator, and outcome criteria were used to determine craniofacial dysmorphism in AS and CS patients. The PEPO criteria were used in the following ways: people with AS and CS were referred to the research article search, and screening was performed according to the PRISMA 2020 chart. 3.1 Study selection Our initial search strategy yielded 8685 papers from databases such as PubMed, Web of Science, Cochrane Library, and Science Direct. After the authors eliminated 6598 papers in the detection phase, the remaining 1198 papers were further screened (review, summary documents, nonhuman, editorials, case reports, commentaries, letters, and duplicate studies). A total of 53 studies were considered worthy, but 39 were excluded due to unusable data formats. Thus, based on the research objectives and inclusion and exclusion criteria, 14 studies were eventually included in this study, and the full texts of all included studies were retrieved [Fig. 1 ]. 3.2 Study characteristics All of the studies included were published in peer-reviewed journals. The main components of the included studies are summarized in Table 1 . The studies used here were all published in high-quality academic publications. These research articles had cohort, observational, retrospective, and case‒control study designs. In this meta-analysis, three studies were included from different places: one from the Netherlands, one from Brazil, one each from France, the United States, Italy, Japan, and China. The most common gold standard method used in these studies was cephalometric radiographic measurements. Fourteen studies were included that mentioned both AS and CS patients. We included most of the studies that focused on comparing ASs, CSs, and nonsyndromic/healthy controls based on craniosynostosis, dental and maxillary dimensions, and craniofacial manifestations. Craniosynostosis manifestation studies were from Sweden, Brazil, Italy, France, and Brazil. Kahnberg et al., in 2010 (n = 31), and Lu et al., in 2020 (n = 32), evaluated the highest number of cases of AS with craniosynostosis manifestations. Bouaound et al. (2020) evaluated the highest number of cases (n = 25) of CS with craniosynostosis. The dental and maxillary manifestations studied were from the Netherlands, Japan, and China. The highest number of cases (n = 40) of AS were studied by Reitsma et al., 2014, and CS (n = 40) were studied by Reitsma et al., 2013. Studies of craniofacial dysmorphism were performed in the United States, the Netherlands, and Brazil. The highest number of cases of AS (n = 18) and CS (n = 16) were studied by Pinto et al., 2023. Table 1 Characteristics of the studies on Apert and Crouzon syndrome included in this analysis [FFMBA: front-facial monobloc advancement; STL: stereolithography; SNA: sella, nasion, A point) indicating whether the maxilla is normal, prognathic, or retrognathic; SNB: sella, nasion, B point) indicating whether the mandible is normal, prognathic, or retrognathic or the PP palatal plane] S.No. Country Study type Apert Syndrome AS Crouzon Syndrome CS Non Syndromic NS Age, years, mean (SD)/ Median Method used Major findings in AS/CS Craniosynostosis manifestation: Kahnberg et al., (2010) Sweden Retrospe-ctive study 31 12 19 7-8Y Orthognathic surgical techniques Patients who had sagittal split of the mandible, disturbances of sensitivity in a range of 10–15% developed, as in all other orthognathic patients. Lu et al., (2020) Brazil Case- Control 25 11 36 2D-16 Y CT scan and Cephalometric measurements This study attempts to clarify the individual influences of isolated bicoronal synostosis, Apert(AS) and Crouzon (CS) on skull base morphology. Meazzini et al., (2020) Italy Case control 13 20 38 1–12 Y CT Scan The syndromic group showed a significant earlier ossification of all sutures compared to the nonsyndromic group Bouaoud et al., (2020) France Retrospective Study 10 25 25 - CT Scan analysis The study aimed at assessing the variations in thickness of the supra-orbital bar in CS and AS before and after FFMBA using CT-scan data. Lu et al., (2020) Brazil Prospective Observatinal 32 0 50 - CT Scan analysis Malformation of the middle cranial fossa is an early, perhaps the initial, pivotal cranial morphologic change in Apert syndrome. Dental and maxillary manifestation: Reitsma et al., (2014) Netherlands Case -Control (Population based) 28 40 451 3.9–15.1 Y AS, others 2.9-17.9Y Pnoramic radiographs analysis Girls with AS had a statistically signifcant less mature dental maturity compared with controls Reitsma et al., (2013) Netherlands Case- Control (Population based) 40 28 457 4–14 Y CT scan with Cephalometric analysis Maxillary intercanine width for patients with AS were increased, while other arch width variables showed no change Kobayashi et al., (2020) Japan Cohort 7 12 0 Mean age, 12.3 ± 5.0 years),Mean age, 10.8 ± 2.9 years) Orthopantomographic images and Cephalometric analysis Cephalometric analysis revealed that AS patients had significantly more severe maxillary hypoplasia in two dimensions and increased clockwise mandibular rotation. Lu et al., (2019) China Case‒control 36 36 54 0-62y CT scan and Cephalometric measurements The narrowed angle between the mandible and the posterior cranial base in Apert skulls is consistent with the more limited nasopharyngeal and oropharyngeal airway space. Craniofacial dysmorphism Lu et al., (2021) USA case –control 57 0 59 0.64–9.64 mean age CT Scan Apert syndrome, suggest that the associated cranial vault suture synostosis indeed does influence the development of the orbital bony structure. Reitsma et al., (2013) Netherlands Case- Control (Population based) 7 6 486 8-19Y CT Scan The SNA, ANB, and SN/PP angles were signifcantly smaller in the syndromic patients, and the LFH ratio was signifcantly larger than control values. Forte et al., (2014) Brazil Case‒control 10 9 17 6-13Y CT Scan Midface retrusion in the Crouzon/Apert group is associated with altered sphenoid morphology (widened and retruded pterygoid plates), with a flatter and wider maxilla, suggesting diminished growth inferiorly and anteriorly Pinto et al., (2023) Brazil retrospective longitudinal case‒control study 18 16 34 AS mean age 14.4 years, CS was 13.4 years Digitizing the sample models and obtaining the STL fles Digital models were obtained from the archive of a public tertiary care hospital. 3.3 Meta-analysis The analysis was carried out using the log risk ratio as the outcome measure. A random-effects model was fitted to the data. The amount of heterogeneity (i.e., τ2) was estimated using the restricted maximum-likelihood estimator. In addition to the estimate of τ2, the Q test for heterogeneity and the I2 statistic are reported. When heterogeneity was detected (i.e., τ^2 > 0^2 > 0, regardless of the results of the Q test), a prediction interval for the true outcomes was also calculated. Studentized residuals and Cook’s distances are used to examine whether studies may be outliers and/or influential in the context of the model. Studies with a studentized residual larger than the 100×(1 − 0.05/(2×k))100×(1 − 0.05/(2×k)th percentile of a standard normal distribution were considered potential outliers (i.e., using a Bonferroni correction with two-sided α = 0.05 for k studies included in the meta-analysis). Studies with a Cook’s distance larger than the median plus six times the interquartile range of the Cook’s distances were considered to be influential. The analysis was carried out using R (version 4.2.2) and the meta package (version 3.8.1) (Pollock et al., 2016). Only craniofacial and axial skeleton measurements were included in the analysis. For interpretation of the meta-analysis results, caution should be exercised. Due to the large variation in cephalometric measures, only a few were added to the meta-analysis forest plots. This analysis revealed the difference between AS patients and CS patients. The CS patient had a smaller skull and mandible volume than the AS patient. In patients who had a sagittal split of the mandible, disturbances of sensitivity in a range of 10–15% developed, as in all other orthognathic patients (Raposo-Amaral et al., 2014; Reitsma et al., 2014; Reitsma et al., 2013). Bicoronal synostosis in the cranium was found mostly in the AS and CS groups on the basis of skull base morphology. The frontal bones were not thick in AS patients, but children with CS had significantly thicker frontal bones. Cephalometric analysis revealed that AS patients had significantly more severe maxillary hypoplasia in two dimensions and increased clockwise mandibular rotation. The CS patients were predicted to have no change in maxillary intercanine width or intermolar width, but the AS patients had increased maxillary intercanine width (Elmi et al., 2015; Kobayashi et al., 2021; Nur et al., 2014). With the growth phase of children, the maxillary and mandibular intercanine thicknesses increase in the CS, whereas no change in mandibular or maxillary intercanine density is predicted in the AS (Forte et al., 2014; Khonsari et al., 2016). The anterior maxillary region is more affected in AS patients than in HCs but less affected in CS patients. ASs had an anterior crossbite (p < 0.001), and CSs had an edge-to-edge bite (p < 0.001) (Pinto et al., 2023). CSs tend to have shorter and flatter cranial bases, smaller orbital volumes, and cleft palates. The dental development of both AS and CS children was delayed, as was that of normal children (Spruijt et al., 2016). There was a statistically significant difference in maxillary and dental arch outcomes between patients with AS and those with CS. A total of seven studies reported outcomes. The I2 index provides a better way of assessing effect size heterogeneity. Forest plots were generated to visualize the heterogeneity of the individual outcomes. Subgroup analyses were performed for each outcome to assess the potential differences in effect sizes. The effect size and heterogeneity of the dental arch were greater in the CS group (I2: 58%, 95% CI = 0.01, 0.29; P = 0.12) than in the AS group (I2: 52%, 95% CI = 0.01, 0.27; P = 0.15). Effect size and heterogeneity of the maxilla of AS patients (I2: 91%, 95% CI 0.09; 0.47, P < 0.01) and CS patients (I2: 94%, 95% CI 0.07; 0.64, P < 0.01). Significant heterogeneity in AS and CS patients was observed [Figure 2 ]. 3.4 Risk of bias A funnel and bubble plot was generated to visualize the risk of bias among the studies. The bubble plot shows the relationship between study-specific effect size and the size of each bubble, which is proportional to the precision of each study. AS and CS funnel plots showed no obvious risk of bias (Fig. 1 ). Asymmetry in the funnel plot indicates a lack of homogeneity and bias. This asymmetry can be attributed to differences in methodological designs and sample sizes. In addition to language bias, only English was used, and citation bias may also affect the asymmetry [Figure 3 ]. 4. Discussion The present meta-analysis was performed to compare the craniofacial manifestations of AS and CS patients. The most common FGFR2 gene on chromosome 10 (10q25-10q26) was found to be the pathogenic cause of AS and CS. Fibroblast growth factors are unable to produce essential fibrous material in craniofacial tissues, such as bone sutures and cartilage, or odontoblast formation (Luong et al., 2019; Morice et al., 2020; Timberlake et al., 2023). This protein is one of the four FGFRs responsible for the formation of blood vessels, wound healing, embryonic evolution, and the regulation of cellular division, growth, and maturation (Munib et al., 2023; Sawh-Martinez & Steinbacher, 2019; Shlobin et al., 2022). Gain of function due to the FGFR2 pathogenic variant has an impact on dental abnormalities, early fusion of sutures, which functions in the fusion process of skull bones, facial asymmetry, a prominent forehead, abnormal eyelid closing, and limb bone fusion. Due to early closure of the sutures, other health issues, such as intellectual development and increased intracranial pressure, can occur (Munarriz et al., 2020; Tønne et al., 2020). Patients with CS tend to have shorter skull bases, v-shaped maxillary arches, wider dental spacing, cleft palate, edge-to-edge bites, and minor limb malformations. This review demonstrated the large variation in cephalometric measurements between AS and CS patients. The maxillary intercanine width in patients with AS increased, whereas that in patients with CS did not. With the growth period of the children, the maxillary and mandibular intercanine indices increased in the CS, whereas no change in mandibular or maxillary intercanine indices during the growth period was predicted in the AS. The anterior maxillary region is more affected in AS patients than in HCs but less affected in CS patients. ASs had an anterior crossbite (p < 0.001), and CSs had an edge-to-edge bite (p < 0.011) (Pinto et al., 2023). Compared with CS patients, AS patients were found to have clinical features of limb malformations. Increased mandibular asymmetry, increased lower facial height ratios, decreased transverse dimensions, an increased inclination of the palatal plane, and a more protruding mandible were observed in the AS patients. The maxillary and mandibular volume are reduced in CS patients, but these changes are mostly age related (Andersson et al., 2010; Khonsari et al., 2016; Kreiborg & Cohen Jr, 2010). Orbital sphere expansion is limited in CS patients compared to AS patients. Only a few studies were found to be significant for this meta-analysis. As an outcome of this study, we found some minor differences between the AS and CS patients. More craniofacial measurements from different regions are needed to clarify the estimate of the maxillary and mandibular vertical and anteroposterior positions for a definitive conclusion. In this meta-analysis, we conducted a literature search of English language articles published between January 2000 and 2023 January. Only the relevant information was taken from the previous literature. A literature search was performed to determine the measurements and comparisons of AS and CS with healthy control NS patients. 5. Conclusion Our systematic review provides updated information on the features of AS and CS craniofacial dysmorphism. The main focus is on the maxillary, dental arch dimension, and craniosynostosis. Due to the limited literature on specific craniofacial features, we included some studies focusing on selected craniofacial dysmorphisms, which cover both syndromes. In these two craniosynostosis syndromes, the phenotypes match those of patients with similar phenotypes rather than the patient’s parent’s phenotypes. In AS patients, there is midface protrusion, a decreased mandible (retrognathia), a decreased orbital volume, hypoplasia, delayed dental development, open bites, a cleft palate, and brachycephaly such as craniosynostosis. Additionally, severe limb malformations were noted. Patients with CS tend to have shorter skull bases, v-shaped maxillary arches, wider dental spacing, cleft palates, edge-to-edge bites, and minor limb malformations. This review demonstrated the large variation in cephalometric measurements between AS and CS patients. The maxillary intercanine width in patients with AS increased, whereas that in patients with CS did not. With the growth period of the children, the maxillary and mandibular intercanine indices increased in the CS, whereas no change in mandibular or maxillary intercanine indices during the growth period was predicted in the AS. The anterior maxillary region is more affected in AS patients than in HCs but less affected in CS patients. ASs had an anterior crossbite (p < 0.001), and CSs had an edge-to-edge bite (p < 0.011). In the case of craniosynostosis, AS patients experience isolated bicoronal synostosis, and CSs tend to have short and flat cranial bases and smaller orbital volumes of craniofacial morphology. Malformation of the middle cranial fossa is an early, perhaps initial, cranial morphologic change in AS patients. The CS patients had a smaller skull and mandible volume than did the AS patients. CT scans help patients pursue orthodontic and maxillofacial treatment alone or choose assisted surgery for their respective expansion. Abbreviations AS- Apert Syndrome Crouzon syndrome CT- Cephalometric Declarations Ethical approval Ethical approval was not given because we conducted a systematic review and meta-analysis in which personal information was not collected. Data statement The data that our review is based on are available in the manuscripts of the included articles. Source of funding None. Author contributions Shalini Dhiman, Inusha Panigrahi, and Ranjit Sah: Conceptualization, Study design, Data extraction, Methodology and validation, Data analysis, Interpretation of results, Writing Original Drafting the article and editing Bijaya Kumar Padhi, Shifali Gupta, Prakasini Satapathy, Mahalaqua Nazli Khatib, and Shilpa Gaidhane: Data curation, Interpretation of results, Writing-Review and Editing References Al-Namnam, N., Hariri, F., Thong, M., & Rahman, Z. (2019). Crouzon syndrome: Genetic and intervention review. Journal of Oral Biology and Craniofacial Research , 9 (1), 37-39. Alsaeed, S., Huynh, N., Wensley, D., Lee, K., Hamoda, M. M., Ayers, E., Sutherland, K., & Almeida, F. R. (2023). Orthodontic and Facial Characteristics of Craniofacial Syndromic Children with Obstructive Sleep Apnea. Diagnostics , 13 (13), 2213. Andersson, L., Kahnberg, K.-E., & Pogrel, M. A. (2010). Oral and maxillofacial surgery . John Wiley & Sons. Azoury, S. 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Balkan Journal of Dental Medicine , 22 (1), 1-6. Lu, X., Forte, A. J., Wilson, A., Steinbacher, D. M., Alperovich, M., Alonso, N., & Persing, J. A. (2020). Cranial fossa volume and morphology development in Apert syndrome. Plastic and Reconstructive Surgery , 145 (4), 790e-802e. Lu, X., Forte, A. J., Wilson, A. T., Park, K. E., Allam, O., Alperovich, M., Steinbacher, D. M., Alonso, N., & Persing, J. A. (2021). Respective roles of craniosynostosis and syndromic influences on cranial fossa development. Plastic and Reconstructive Surgery , 148 (1), 145-156. Lu, X., Sawh-Martinez, R., Forte, A. J., Wu, R., Cabrejo, R., Wilson, A., Steinbacher, D. M., Alperovich, M., Alonso, N., & Persing, J. A. (2019). Classification of subtypes of Apert syndrome, based on the type of vault suture synostosis. Plastic and Reconstructive Surgery–Global Open , 7 (3), e2158. Luong, A. L. T., Ho, T. T., Hoang, H., Nguyen, T. Q., Ho, T. C., Tran, P. D., Hoang, T. T., Nguyen, N. T., & Chu, H. H. (2019). Detection of G338R FGFR2 mutation in a Vietnamese patient with Crouzon syndrome. Biomedical reports , 10 (2), 107-112. Ma, L., Chang, Q., Pei, F., Liu, M., Zhang, W., Hong, Y.-K., Chai, Y., & Chen, J.-F. (2023). Skull progenitor cell-driven meningeal lymphatic restoration improves neurocognitive functions in craniosynostosis. Cell Stem Cell . Massimi, L., Bianchi, F., Frassanito, P., Calandrelli, R., Tamburrini, G., & Caldarelli, M. (2019). Imaging in craniosynostosis: when and what? Child's Nervous System , 35 , 2055-2069. Morice, A., Cornette, R., Giudice, A., Collet, C., Paternoster, G., Arnaud, É., Galliani, E., Picard, A., Legeai-Mallet, L., & Khonsari, R. (2020). Early mandibular morphological differences in patients with FGFR2 and FGFR3-related syndromic craniosynostoses: A 3D comparative study. Bone , 141 , 115600. Motch Perrine, S. M., Stecko, T., Neuberger, T., Jabs, E. W., Ryan, T. M., & Richtsmeier, J. T. (2017). Integration of brain and skull in prenatal mouse models of Apert and Crouzon syndromes. Frontiers in Human Neuroscience , 11 , 369. Munarriz, P. M., Pascual, B., Castaño-Leon, A. M., García-Recuero, I., Redondo, M., de Aragón, A. M., & Romance, A. (2020). Apert syndrome: Cranial procedures and brain malformations in a series of patients. Surgical Neurology International , 11 . Munib, N., Khan, Q. A., Rodriguez, A. R., Belay, N. F., Shah, R., & Afzal, M. (2023). Clinical Manifestations of Cruzon Syndrome. Nur, B. G., Pehlivanoğlu, S., Mıhçı, E., Çalışkan, M., Demir, D., Alper, Ö. M., Kayserili, H., & Lüleci, G. (2014). Clinicogenetic study of Turkish patients with syndromic craniosynostosis and literature review. Pediatric neurology , 50 (5), 482-490. Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., Shamseer, L., Tetzlaff, J. M., Akl, E. A., & Brennan, S. E. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj , 372 . Pinto, R. d. O., Tonello, C., Peixoto, A. P., de Jesus, A. S., Santos-Pinto, A. d., & Raveli, D. B. (2023). Three-Dimensional Evaluation of Dental Arches in Individuals with Syndromic Craniosynostosis. International Journal of Dentistry , 2023 . Pollock, A., Farmer, S. E., Brady, M. C., Langhorne, P., Mead, G. E., Mehrholz, J., van Wijck, F., & Wiffen, P. J. (2016). An algorithm was developed to assign GRADE levels of evidence to comparisons within systematic reviews. Journal of clinical epidemiology , 70 , 106-110. Raposo-Amaral, C. E., Neto, J. G. J., Denadai, R., Raposo-Amaral, C. M., & Raposo-Amaral, C. A. (2014). Patient-reported quality of life in highest-functioning Apert and Crouzon syndromes: a comparative study. Plastic and Reconstructive Surgery , 133 (2), 182e-191e. Reitsma, J. H., Balk-Leurs, I. H., Ongkosuwito, E. M., Wattel, E., & Prahl-Andersen, B. (2014). Dental maturation in children with the syndrome of crouzon and apert. The Cleft Palate-Craniofacial Journal , 51 (6), 639-644. Reitsma, J. H., Ongkosuwito, E. M., Buschang, P. H., Adrichem, L. N. V., & Prahl-Andersen, B. (2013). Craniofacial stability in patients with Crouzon or Apert syndrome after Le Fort III distraction osteogenesis. The Cleft Palate-Craniofacial Journal , 50 (5), 561-569. Rostamzad, P., Arslan, Z. F., Mathijssen, I. M., Koudstaal, M. J., Pleumeekers, M. M., Versnel, S. L., & Loudon, S. E. (2022). Prevalence of ocular anomalies in craniosynostosis: a systematic review and meta-analysis. Journal of Clinical Medicine , 11 (4), 1060. Sakamoto, Y., Takenouchi, T., Miwa, T., & Kishi, K. (2021). Assessment of long-term quality of life in patients with syndromic craniosynostosis. Journal of Plastic, Reconstructive & Aesthetic Surgery , 74 (2), 336-340. Sawh-Martinez, R., & Steinbacher, D. M. (2019). Syndromic craniosynostosis. Clinics in Plastic Surgery , 46 (2), 141-155. Shlobin, N. A., Baticulon, R. E., Ortega, C. A., Du, L., Bonfield, C. M., Wray, A., Forrest, C. R., & Dewan, M. C. (2022). Global epidemiology of craniosynostosis: a systematic review and meta-analysis. World neurosurgery , 164 , 413-423. e413. Spruijt, B., Rijken, B. F., den Ottelander, B. K., Joosten, K. F., Lequin, M. H., Loudon, S. E., van Veelen, M.-L. C., & Mathijssen, I. M. (2016). First vault expansion in Apert and Crouzon-Pfeiffer syndromes: front or back? Plastic and Reconstructive Surgery , 137 (1), 112e-121e. Stanton, E., Urata, M., Chen, J.-F., & Chai, Y. (2022). The clinical manifestations, molecular mechanisms and treatment of craniosynostosis. Disease Models & Mechanisms , 15 (4), dmm049390. Tan, A. P., & Mankad, K. (2018). Apert syndrome: magnetic resonance imaging (MRI) of associated intracranial anomalies. Child's Nervous System , 34 , 205-216. Taylor, J. A., & Bartlett, S. P. (2017). What’s new in syndromic craniosynostosis surgery? Plastic and Reconstructive Surgery , 140 (1), 82e-93e. Timberlake, A. T., Kiziltug, E., Jin, S. C., Nelson-Williams, C., Loring, E., Analysis, Y. C. f. G., Allocco, A., Marlier, A., Banka, S., & Stuart, H. (2023). De novo mutations in the BMP signaling pathway in lambdoid craniosynostosis. Human Genetics , 142 (1), 21-32. Tønne, E., Due-Tønnessen, B. J., Wiig, U., Stadheim, B. F., Meling, T. R., Helseth, E., & Heimdal, K. R. (2020). Epidemiology of craniosynostosis in Norway. Journal of Neurosurgery: Pediatrics , 26 (1), 68-75. Viechtbauer, W., & Cheung, M. W. L. (2010). Outlier and influence diagnostics for meta‐analysis. Research synthesis methods , 1 (2), 112-125. Wang, N. (2018). How to conduct a meta-analysis of proportions in R: a comprehensive tutorial. New York: John Jay College for Criminal Justice . Additional Declarations The authors declare no competing interests. Supplementary Files Supplimentaryfiles13thapril2024.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-4443370\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Systematic Review\",\"associatedPublications\":[],\"authors\":[{\"id\":304136570,\"identity\":\"86f91706-27f9-4ff9-9fa9-63c8b0b9d059\",\"order_by\":0,\"name\":\"Shalini Dhiman\",\"email\":\"\",\"orcid\":\"https://orcid.org/0000-0001-6539-4029\",\"institution\":\"Genetic Metabolic Unit; Department of Paediatrics, Advanced Paediatrics Center (APC), Postgraduate Institute of Medical Education and Research (PGIMER), Sector-12, Chandigarh- India\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Shalini\",\"middleName\":\"\",\"lastName\":\"Dhiman\",\"suffix\":\"\"},{\"id\":304138695,\"identity\":\"e4b1dc7c-2513-4eed-9cb4-8db6e3167b5a\",\"order_by\":1,\"name\":\"Inusha Panigrahi\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAqklEQVRIiWNgGAWjYBACNghlw8AgQaKWNBK0QMFhErTwSfeYPfi543xi/+zmgw8YamyiCTtM5oy5Ye+Z24kz7hxLNmA4lpbbQFCLRI6ZBG/b7cSGG0AGY8Nh4rRI/m07lzifJC3SvG0HEjeQoCWt3Fi2Ldl44420ZIMEYvwiPyN528O3bXay824kH3zwocaGsBYGaGw6glUmEKEcrsWeSMWjYBSMglEwEgEA7VU8zXKWBA8AAAAASUVORK5CYII=\",\"orcid\":\"https://orcid.org/0000-0001-7375-9892\",\"institution\":\"Genetic Metabolic Unit; 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India.\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Quazi\",\"middleName\":\"Syed\",\"lastName\":\"Zahiruddin\",\"suffix\":\"\"},{\"id\":304140706,\"identity\":\"5445debb-40cf-46e4-b736-095628c9d0ee\",\"order_by\":10,\"name\":\"Ranjit Sah\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Tribhuvan University Teaching Hospital, Kathmandu 46000, Nepal.\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ranjit\",\"middleName\":\"\",\"lastName\":\"Sah\",\"suffix\":\"\"},{\"id\":304140707,\"identity\":\"334943e9-7c46-41a2-974d-7fd8c8f7060a\",\"order_by\":11,\"name\":\"Karandeep Kaur\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Genetic Metabolic Unit; Department of Pediatrics, Advanced Pediatrics Center (APC), Postgraduate Institute of Medical Education and Research (PGIMER), Sector-12, Chandigarh- 160012\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Karandeep\",\"middleName\":\"\",\"lastName\":\"Kaur\",\"suffix\":\"\"},{\"id\":304140708,\"identity\":\"b4b08cc2-f641-4763-bd54-c994cbacba09\",\"order_by\":12,\"name\":\"Mahak Garg\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Genetic Metabolic Unit; Department of Pediatrics, Advanced Pediatrics Center (APC), Postgraduate Institute of Medical Education and Research (PGIMER), Sector-12, Chandigarh- 160012\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mahak\",\"middleName\":\"\",\"lastName\":\"Garg\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-05-19 07:45:36\",\"currentVersionCode\":1,\"declarations\":{\"humanSubjects\":true,\"vertebrateSubjects\":false,\"conflictsOfInterestStatement\":false,\"humanSubjectEthicalGuidelines\":true,\"humanSubjectConsent\":true,\"humanSubjectClinicalTrial\":false,\"humanSubjectCaseReport\":false,\"vertebrateSubjectEthicalGuidelines\":false},\"doi\":\"10.21203/rs.3.rs-4443370/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-4443370/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":56974063,\"identity\":\"feb4a0ed-aace-47d2-a439-745959a8ad05\",\"added_by\":\"auto\",\"created_at\":\"2024-05-23 01:47:36\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":162450,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003ePRISMA (2020) chart detailing the review approach and selection of studies.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4443370/v1/00b8fbf5f4efd550f111bd4d.png\"},{\"id\":56974628,\"identity\":\"d26e5859-7bff-4343-8ed3-8b367a756b76\",\"added_by\":\"auto\",\"created_at\":\"2024-05-23 01:55:36\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":195196,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eForest plot based on the incidence of Apert syndrome and Crouzon syndrome. Forest plots were generated to visualize the heterogeneity of the individual outcomes. The effect size and heterogeneity of the dental arch were greatest in the AS group. The CS procedure did not change the maxillary intercanine width or intermolar width, but the maxillary intercanine width increased in patients with AS.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4443370/v1/a8682c6e7cc19229e9e0408a.png\"},{\"id\":56974065,\"identity\":\"3342e08b-5285-497a-affc-ef717ba38afe\",\"added_by\":\"auto\",\"created_at\":\"2024-05-23 01:47:36\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":130414,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eBubble and funnel plots based on the incidence of Apert syndrome and Crouzon syndrome. Asymmetry in the funnel plot indicates a lack of homogeneity and bias.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4443370/v1/7d86341f0798bbd89e8fec3c.png\"},{\"id\":56974629,\"identity\":\"6a874e33-1b2c-491a-a053-c31caa7d1298\",\"added_by\":\"auto\",\"created_at\":\"2024-05-23 01:55:41\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1086574,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4443370/v1/83c8ccdd-fc04-4c5d-9062-6f29aac5827a.pdf\"},{\"id\":56974067,\"identity\":\"69be63a6-242b-461b-876f-34f930087f92\",\"added_by\":\"auto\",\"created_at\":\"2024-05-23 01:47:36\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":28970,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Supplimentaryfiles13thapril2024.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4443370/v1/7876b73737a0a60bdfc9aee3.docx\"}],\"financialInterests\":\"The authors declare no competing interests.\",\"formattedTitle\":\"\\u003cp\\u003e\\u003cem\\u003e\\u003cstrong\\u003eFGFR2\\u003c/strong\\u003e\\u003c/em\\u003e\\u003cstrong\\u003e gene Related Apert and Crouzon Syndrome Patients with Different Craniofacial Dysmorphisms: A Systematic Review and Meta-analysis\\u003c/strong\\u003e\\u003c/p\\u003e\",\"fulltext\":[{\"header\":\"1. Introduction\",\"content\":\"\\u003cp\\u003eThe main manifestation of Apert syndrome (AS) and Crouzon syndrome (CS) is craniosynostosis. Craniosynostosis is a condition of early fusion of the skull bones (Bhoj \\u0026amp; Zackai, 2021; Lu et al., 2020). Early sutural fusion impairs skull growth and gives rise to craniofacial dysmorphism in the AS and CS (Das \\u0026amp; Munshi, 2018; Lu et al., 2021). AS is a complex syndrome that causes craniosynostosis and hand and foot fusions. It was first described by Eugene Apert in 1842. It is also known as acrocephalosyndactyly (Junaid et al., 2023; Ko, 2016; Sawh-Martinez \\u0026amp; Steinbacher, 2019). In addition to craniosynostosis, craniofacial dysmorphism, visual impairments, cleft palate, and hearing loss are found in AS. Bilateral coronal synostosis is most frequently found in the AS (Alsaeed et al., 2023; Kumari et al., 2023; Massimi et al., 2019). Other metopic, lambdoid, and sagittal suture fusions are also rarely found in AS patients. Early closure of cranial sutures is known to occur in patients with AS via genetic factors (Choudhary et al., 2023; Faasse \\u0026amp; Mathijssen, 2023; Koca, 2016; Tan \\u0026amp; Mankad, 2018; Timberlake et al., 2023).\\u003c/p\\u003e \\u003cp\\u003eIn 1912, Octave Crouzon first identified Crouzon syndrome (CS) (Al-Namnam et al., 2019; Balyen et al., 2017). This condition has complete penetrance and variable expressivity. CS is an autosomal dominant disorder with common features, such as a long face, a proptosis prominent jaw, hypertelorism, exophthalmos, maxillary hypoplasia, hearing loss, and a beaked nose, as well as synostosis of coronal, sagittal, and lambdoid sutures (Motch Perrine et al., 2017; Rostamzad et al., 2022; Shlobin et al., 2022; Taylor \\u0026amp; Bartlett, 2017; T\\u0026oslash;nne et al., 2020). The prevalence rate of AS has been estimated to be between 1/65,000 new-borns, and that of CS is estimated to be 1/25000 new-borns, without prediction by sex (Munarriz et al., 2020; Munib et al., 2023). AS and CS are associated with advanced paternal age, maternal infections, maternal drug consumption, and cranial inflammatory processes (Fernandes et al., 2016; Kyprianou \\u0026amp; Chatzigianni, 2018; Lu et al., 2019; Sakamoto et al., 2021). Fibroblast growth factor (FGFR2) gene-specific missense pathogenic mutations at chromosomal region 10q25-10q26 cause more than 98% of AS and CS patients (Azoury et al., 2017; Morice et al., 2020). FGFR belongs to the family of mitogenic signaling molecules that play important roles in the control of cell proliferation and survival (Luong et al., 2019; Ma et al., 2023).\\u003c/p\\u003e \\u003cp\\u003eIn AS and CS patients, fibroblasts cannot produce the essential fibrous material in several craniofacial tissues, including bone sutures and cartilage, or during odontoblast formation and regeneration (Di Rocco et al., 2023; Elarjani et al., 2021; Hoshino et al., 2023). Most of the variations are missense variations in \\u003cem\\u003eFGFR2\\u003c/em\\u003e leading to craniofacial dysmorphism and hand and foot malformations. Several syndromes are associated with the \\u003cem\\u003eFGFR2\\u003c/em\\u003e gene. These phenotypes also include Antley Bixler syndrome, Beare Stevenson syndrome with cutis gyrata, Pfeiffer syndrome, Jackson Weiss syndrome, and Saethre Chotzen syndrome clinically classified as additional digital anomalies, skin furrows and skeletal bowing and synostoses (Kiziltug et al., 2023; Pinto et al., 2023; Stanton et al., 2022).\\u003c/p\\u003e \\u003cp\\u003eIn AS and CS patients, the most commonly explored features are asymmetry in mandibular width, height and length; dental arch dimensions; and cranial suture fusion. In this review, we discuss \\u003cem\\u003eFGFR2\\u003c/em\\u003e gene-related craniofacial dysmorphism in rare syndromes, which include AS and CS. This is the first systematic review focused on craniofacial dysmorphism in two syndromes associated with one \\u003cem\\u003eFGFR2\\u003c/em\\u003e gene. This meta-analysis aimed to better understand craniofacial dysmorphism in AS and CS patients by exploring the previously published scientific literature.\\u003c/p\\u003e\"},{\"header\":\"2. Materials and Methods\",\"content\":\"\\u003cp\\u003e This systematic review was carried out according to the preferred reporting methods for systematic reviews and meta-analysis (PRISMA 2020) guidelines [Table S1] (Page et al., 2021). The protocol was submitted to the International Prospective Register of Systematic Reviews\\u003c/p\\u003e \\u003cp\\u003eCRD42023395454 (\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://www.crd.york.ac.uk/prospero/record_email.php\\u003c/span\\u003e\\u003cspan address=\\\"https://www.crd.york.ac.uk/prospero/record_email.php\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e) accessed 11 February 2023.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e1.1 Search Eligibility\\u003c/h2\\u003e \\u003cp\\u003eThe search included peer-reviewed journals and publications in which full-text articles on AS and CS were discussed. Among the different types of research that have been ruled out are animal mouse studies, clinical case reports, pilot studies, bibliographic reviews, book chapters, and systematic reviews. The four main steps included in selecting the article were identification, screening, eligibility, and inclusion. Case‒control, cross-sectional, cohort studies have compared cephalometric CT scans and radiographs of patients with AS, patients with CS, and nonsyndromic patients. Most related studies have evaluated different conditions, such as maxillary and mandibular dysmorphism, dental arch asymmetry, and cranial vault dysmorphism. All the research papers that met the inclusion criteria were included. The researchers worked independently and reviewed the title and abstract of all the records to select all the relevant studies, and any discrepancies in the results were resolved.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.2 PICO search strategy\\u003c/h2\\u003e \\u003cp\\u003eThe following electronic databases were used for the search: PubMed, Cochrane Library, Medline, and Web of Science. The articles were published from January 2000 to January 2023 [Table S3]. The main search terms used were craniofacial OR craniosynostosis (Apert syndrome) OR (craniofacial dysmorphism) AND (Crouzon syndrome) OR (craniofacial dysmorphism) AND (((Craniosynostosis [Title/Abstract])) OR (Cranium [Title/Abstract])) OR (FGFR2[Title/Abstract]).\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e\\u003cem\\u003e2.3 Inclusion/exclusion criteria\\u003c/em\\u003e\\u003c/h2\\u003e \\u003cp\\u003eThe systematic review and meta-analysis inclusion criteria for patients were as follows: studies on humans; papers written in English; children with descriptive studies such as case reports, case series, and randomized controlled trials; cohort studies; and case‒control studies of Apert syndrome and Crouzon syndrome with craniofacial dysmorphism. This meta-analysis was not performed on an ethnicity or sex basis. The exclusion criteria for patients were as follows: cross-sectional studies; editorials; systematic reviews; and meta-analyses. Patients who had pathological fractures were excluded. The search strategy for eligibility of studies and variables of interest were prespecified in the protocol. The variables of interest were chosen, and the subsequently anticipated heterogeneity in managing and reporting the variables was also noted [Table S2].\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.4 Data Extraction\\u003c/h2\\u003e \\u003cp\\u003eThe researchers (SD, KD, MG) recaptured the information from different articles as authors with, year, country, and sample and used methodology in the studies, independently screening the retrieved studies for inclusion on the basis of the titles and abstracts. The papers revealed craniofacial dysmorphism in AS and CS based on clinical cephalometric CT scans and radiographs. The program Endnote X20 software was used for reference.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.5 Quality assessment\\u003c/h2\\u003e \\u003cp\\u003eThe Newcastle Ottawa Scale was used for qualitative evaluation of the studies included in the meta-analysis. The risk of bias was assessed based on three criteria, selection, comparability, and outcome, as mentioned in Table S4. The following domains were assessed: confirmed cases, representativeness of the cases, selection of control/comparator, definitions of control/comparator, case, control/comparator, assessment of outcome, the same methodology used for cases for AS, CS, and NS, and nonresponse rate. Each of the domains was assessed as yes, no, or unclear. If the study met the criteria, points were given as (*) in that domain, which was defined as a low risk of bias. If the study did not meet the criteria or was unclear, (-) points were given. The points for each item were summed, resulting in a total quality score. Studies with scores ranging from 7\\u0026ndash;9 were considered high quality, 4\\u0026ndash;6 were considered high risk, and 0\\u0026ndash;3 were considered to have a very high risk of bias. The Newcastle\\u0026ndash;Ottawa Scale contains 9 items within 3 domains, and the total maximum score is 9.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.6 Statistical analysis\\u003c/h2\\u003e \\u003cp\\u003eDescriptive statistics were used for the different craniofacial dysmorphisms in AS and CS patients. These meta-analysis proportions were calculated using the random effects model for the different anomalies, and pooled mean proportions with 95% CIs were calculated. A p value of the small sample sizes and possibly extreme proportions was defined as statistically significant. Heterogeneity was evaluated by the I2 statistic. The software program R version 4.1.2 for Windows was used for the meta-analysis and forest plots (Balshem et al., 2011; Higgins \\u0026amp; Thompson, 2002; Viechtbauer \\u0026amp; Cheung, 2010; Wang, 2018).\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"3. Results\",\"content\":\"\\u003cp\\u003eThe PEPO population, exposure, comparator, and outcome criteria were used to determine craniofacial dysmorphism in AS and CS patients. The PEPO criteria were used in the following ways: people with AS and CS were referred to the research article search, and screening was performed according to the PRISMA 2020 chart.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.1 Study selection\\u003c/h2\\u003e \\u003cp\\u003eOur initial search strategy yielded 8685 papers from databases such as PubMed, Web of Science, Cochrane Library, and Science Direct. After the authors eliminated 6598 papers in the detection phase, the remaining 1198 papers were further screened (review, summary documents, nonhuman, editorials, case reports, commentaries, letters, and duplicate studies). A total of 53 studies were considered worthy, but 39 were excluded due to unusable data formats. Thus, based on the research objectives and inclusion and exclusion criteria, 14 studies were eventually included in this study, and the full texts of all included studies were retrieved [Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e\\u003cb\\u003e3.2 Study\\u003c/b\\u003e characteristics\\u003c/h2\\u003e \\u003cp\\u003eAll of the studies included were published in peer-reviewed journals. The main components of the included studies are summarized in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e. The studies used here were all published in high-quality academic publications. These research articles had cohort, observational, retrospective, and case‒control study designs. In this meta-analysis, three studies were included from different places: one from the Netherlands, one from Brazil, one each from France, the United States, Italy, Japan, and China. The most common gold standard method used in these studies was cephalometric radiographic measurements. Fourteen studies were included that mentioned both AS and CS patients. We included most of the studies that focused on comparing ASs, CSs, and nonsyndromic/healthy controls based on craniosynostosis, dental and maxillary dimensions, and craniofacial manifestations. Craniosynostosis manifestation studies were from Sweden, Brazil, Italy, France, and Brazil. Kahnberg et al., in 2010 (n\\u0026thinsp;=\\u0026thinsp;31), and Lu et al., in 2020 (n\\u0026thinsp;=\\u0026thinsp;32), evaluated the highest number of cases of AS with craniosynostosis manifestations. Bouaound et al. (2020) evaluated the highest number of cases (n\\u0026thinsp;=\\u0026thinsp;25) of CS with craniosynostosis. The dental and maxillary manifestations studied were from the Netherlands, Japan, and China. The highest number of cases (n\\u0026thinsp;=\\u0026thinsp;40) of AS were studied by Reitsma et al., 2014, and CS (n\\u0026thinsp;=\\u0026thinsp;40) were studied by Reitsma et al., 2013. Studies of craniofacial dysmorphism were performed in the United States, the Netherlands, and Brazil. The highest number of cases of AS (n\\u0026thinsp;=\\u0026thinsp;18) and CS (n\\u0026thinsp;=\\u0026thinsp;16) were studied by Pinto et al., 2023.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eCharacteristics of the studies on Apert and Crouzon syndrome included in this analysis [FFMBA: front-facial monobloc advancement; STL: stereolithography; SNA: sella, nasion, A point) indicating whether the maxilla is normal, prognathic, or retrognathic; SNB: sella, nasion, B point) indicating whether the mandible is normal, prognathic, or retrognathic or the PP palatal plane]\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"9\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c9\\\" colnum=\\\"9\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eS.No.\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eCountry\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eStudy type\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eApert\\u003c/p\\u003e \\u003cp\\u003eSyndrome\\u003c/p\\u003e \\u003cp\\u003eAS\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eCrouzon Syndrome CS\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eNon Syndromic NS\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eAge, years, mean\\u003c/p\\u003e \\u003cp\\u003e(SD)/\\u003c/p\\u003e \\u003cp\\u003eMedian\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eMethod used\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eMajor findings in AS/CS\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"9\\\" nameend=\\\"c9\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eCraniosynostosis manifestation:\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eKahnberg et al., (2010)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSweden\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eRetrospe-ctive study\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e31\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e19\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e7-8Y\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eOrthognathic surgical techniques\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003ePatients who had sagittal split of the mandible, disturbances of sensitivity in a range of 10\\u0026ndash;15% developed, as in all other orthognathic patients.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLu et al., (2020)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eBrazil\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eCase- Control\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e2D-16\\u003c/p\\u003e \\u003cp\\u003eY\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eCT scan and Cephalometric measurements\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eThis study attempts to clarify the individual influences of isolated bicoronal synostosis, Apert(AS) and Crouzon (CS) on skull base morphology.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMeazzini et al.,\\u003c/p\\u003e \\u003cp\\u003e(2020)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eItaly\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eCase control\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e20\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e38\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e1\\u0026ndash;12 Y\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eCT Scan\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eThe syndromic group showed a significant earlier ossification of all sutures compared to the nonsyndromic group\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBouaoud et al., (2020)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eFrance\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eRetrospective Study\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eCT Scan analysis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eThe study aimed at assessing the variations in thickness of the supra-orbital bar in CS and AS before and after FFMBA using CT-scan data.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLu et al., (2020)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eBrazil\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eProspective Observatinal\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e32\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e50\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eCT Scan analysis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eMalformation of the middle cranial fossa is an early, perhaps the initial, pivotal cranial morphologic change in Apert syndrome.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"9\\\" nameend=\\\"c9\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eDental and maxillary manifestation:\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eReitsma et al., (2014)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNetherlands\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eCase -Control (Population based)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e28\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e40\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e451\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e3.9\\u0026ndash;15.1 Y AS, others 2.9-17.9Y\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003ePnoramic radiographs analysis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eGirls with AS had a statistically signifcant less mature dental maturity compared with controls\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eReitsma et al., (2013)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNetherlands\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eCase- Control (Population based)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e40\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e28\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e457\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e4\\u0026ndash;14 Y\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eCT scan with Cephalometric analysis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eMaxillary intercanine width for patients with AS were increased, while other arch width variables showed no change\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eKobayashi et al., (2020)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eJapan\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eCohort\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eMean age, 12.3\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;5.0 years),Mean age, 10.8\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.9 years)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eOrthopantomographic images and Cephalometric analysis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eCephalometric analysis revealed that AS patients had significantly more severe maxillary hypoplasia in two dimensions and increased clockwise mandibular rotation.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLu et al., (2019)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eChina\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eCase‒control\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e54\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0-62y\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eCT scan and Cephalometric measurements\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eThe narrowed angle between the mandible and the posterior cranial base in Apert skulls is consistent with the more limited nasopharyngeal and oropharyngeal airway space.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"9\\\" nameend=\\\"c9\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eCraniofacial dysmorphism\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLu et al., (2021)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eUSA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ecase \\u0026ndash;control\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e57\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e59\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0.64\\u0026ndash;9.64 mean age\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eCT Scan\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eApert syndrome, suggest that the associated cranial vault suture synostosis indeed does influence the development of the orbital bony structure.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eReitsma et al., (2013)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNetherlands\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eCase- Control (Population based)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e486\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e8-19Y\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eCT Scan\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eThe SNA, ANB, and SN/PP angles were signifcantly smaller in the syndromic patients, and the LFH ratio was signifcantly larger than control values.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eForte et al., (2014)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eBrazil\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eCase‒control\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e17\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e6-13Y\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eCT Scan\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eMidface retrusion in the Crouzon/Apert group is associated with altered sphenoid morphology (widened and retruded pterygoid plates), with a flatter and wider maxilla, suggesting diminished growth inferiorly and anteriorly\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePinto et al., (2023)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eBrazil\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eretrospective longitudinal case‒control study\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e18\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e16\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e34\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eAS mean age 14.4 years, CS was 13.4 years\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eDigitizing the sample models and obtaining the STL fles\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eDigital models were obtained from the archive of a public tertiary care hospital.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.3 Meta-analysis\\u003c/h2\\u003e \\u003cp\\u003eThe analysis was carried out using the log risk ratio as the outcome measure. A random-effects model was fitted to the data. The amount of heterogeneity (i.e., τ2) was estimated using the restricted maximum-likelihood estimator. In addition to the estimate of τ2, the Q test for heterogeneity and the I2 statistic are reported. When heterogeneity was detected (i.e., τ^2\\u0026thinsp;\\u0026gt;\\u0026thinsp;0^2\\u0026thinsp;\\u0026gt;\\u0026thinsp;0, regardless of the results of the Q test), a prediction interval for the true outcomes was also calculated. Studentized residuals and Cook\\u0026rsquo;s distances are used to examine whether studies may be outliers and/or influential in the context of the model. Studies with a studentized residual larger than the 100\\u0026times;(1\\u0026thinsp;\\u0026minus;\\u0026thinsp;0.05/(2\\u0026times;k))100\\u0026times;(1\\u0026thinsp;\\u0026minus;\\u0026thinsp;0.05/(2\\u0026times;k)th percentile of a standard normal distribution were considered potential outliers (i.e., using a Bonferroni correction with two-sided α\\u0026thinsp;=\\u0026thinsp;0.05 for k studies included in the meta-analysis). Studies with a Cook\\u0026rsquo;s distance larger than the median plus six times the interquartile range of the Cook\\u0026rsquo;s distances were considered to be influential. The analysis was carried out using R (version 4.2.2) and the meta package (version 3.8.1) (Pollock et al., 2016). Only craniofacial and axial skeleton measurements were included in the analysis. For interpretation of the meta-analysis results, caution should be exercised. Due to the large variation in cephalometric measures, only a few were added to the meta-analysis forest plots. This analysis revealed the difference between AS patients and CS patients. The CS patient had a smaller skull and mandible volume than the AS patient. In patients who had a sagittal split of the mandible, disturbances of sensitivity in a range of 10\\u0026ndash;15% developed, as in all other orthognathic patients (Raposo-Amaral et al., 2014; Reitsma et al., 2014; Reitsma et al., 2013). Bicoronal synostosis in the cranium was found mostly in the AS and CS groups on the basis of skull base morphology. The frontal bones were not thick in AS patients, but children with CS had significantly thicker frontal bones. Cephalometric analysis revealed that AS patients had significantly more severe maxillary hypoplasia in two dimensions and increased clockwise mandibular rotation. The CS patients were predicted to have no change in maxillary intercanine width or intermolar width, but the AS patients had increased maxillary intercanine width (Elmi et al., 2015; Kobayashi et al., 2021; Nur et al., 2014). With the growth phase of children, the maxillary and mandibular intercanine thicknesses increase in the CS, whereas no change in mandibular or maxillary intercanine density is predicted in the AS (Forte et al., 2014; Khonsari et al., 2016).\\u003c/p\\u003e \\u003cp\\u003eThe anterior maxillary region is more affected in AS patients than in HCs but less affected in CS patients. ASs had an anterior crossbite (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001), and CSs had an edge-to-edge bite (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) (Pinto et al., 2023). CSs tend to have shorter and flatter cranial bases, smaller orbital volumes, and cleft palates. The dental development of both AS and CS children was delayed, as was that of normal children (Spruijt et al., 2016).\\u003c/p\\u003e \\u003cp\\u003eThere was a statistically significant difference in maxillary and dental arch outcomes between patients with AS and those with CS. A total of seven studies reported outcomes. The I2 index provides a better way of assessing effect size heterogeneity. Forest plots were generated to visualize the heterogeneity of the individual outcomes. Subgroup analyses were performed for each outcome to assess the potential differences in effect sizes. The effect size and heterogeneity of the dental arch were greater in the CS group (I2: 58%, 95% CI\\u0026thinsp;=\\u0026thinsp;0.01, 0.29; P\\u0026thinsp;=\\u0026thinsp;0.12) than in the AS group (I2: 52%, 95% CI\\u0026thinsp;=\\u0026thinsp;0.01, 0.27; P\\u0026thinsp;=\\u0026thinsp;0.15). Effect size and heterogeneity of the maxilla of AS patients (I2: 91%, 95% CI 0.09; 0.47, P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01) and CS patients (I2: 94%, 95% CI 0.07; 0.64, P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01). Significant heterogeneity in AS and CS patients was observed [Figure \\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.4 Risk of bias\\u003c/h2\\u003e \\u003cp\\u003eA funnel and bubble plot was generated to visualize the risk of bias among the studies. The bubble plot shows the relationship between study-specific effect size and the size of each bubble, which is proportional to the precision of each study. AS and CS funnel plots showed no obvious risk of bias (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Asymmetry in the funnel plot indicates a lack of homogeneity and bias. This asymmetry can be attributed to differences in methodological designs and sample sizes. In addition to language bias, only English was used, and citation bias may also affect the asymmetry [Figure \\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"4. Discussion\",\"content\":\"\\u003cp\\u003eThe present meta-analysis was performed to compare the craniofacial manifestations of AS and CS patients. The most common \\u003cem\\u003eFGFR2\\u003c/em\\u003e gene on chromosome 10 (10q25-10q26) was found to be the pathogenic cause of AS and CS. Fibroblast growth factors are unable to produce essential fibrous material in craniofacial tissues, such as bone sutures and cartilage, or odontoblast formation (Luong et al., 2019; Morice et al., 2020; Timberlake et al., 2023). This protein is one of the four \\u003cem\\u003eFGFRs\\u003c/em\\u003e responsible for the formation of blood vessels, wound healing, embryonic evolution, and the regulation of cellular division, growth, and maturation (Munib et al., 2023; Sawh-Martinez \\u0026amp; Steinbacher, 2019; Shlobin et al., 2022). Gain of function due to the \\u003cem\\u003eFGFR2\\u003c/em\\u003e pathogenic variant has an impact on dental abnormalities, early fusion of sutures, which functions in the fusion process of skull bones, facial asymmetry, a prominent forehead, abnormal eyelid closing, and limb bone fusion. Due to early closure of the sutures, other health issues, such as intellectual development and increased intracranial pressure, can occur (Munarriz et al., 2020; T\\u0026oslash;nne et al., 2020). Patients with CS tend to have shorter skull bases, v-shaped maxillary arches, wider dental spacing, cleft palate, edge-to-edge bites, and minor limb malformations. This review demonstrated the large variation in cephalometric measurements between AS and CS patients. The maxillary intercanine width in patients with AS increased, whereas that in patients with CS did not. With the growth period of the children, the maxillary and mandibular intercanine indices increased in the CS, whereas no change in mandibular or maxillary intercanine indices during the growth period was predicted in the AS. The anterior maxillary region is more affected in AS patients than in HCs but less affected in CS patients. ASs had an anterior crossbite (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001), and CSs had an edge-to-edge bite (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.011) (Pinto et al., 2023).\\u003c/p\\u003e \\u003cp\\u003eCompared with CS patients, AS patients were found to have clinical features of limb malformations. Increased mandibular asymmetry, increased lower facial height ratios, decreased transverse dimensions, an increased inclination of the palatal plane, and a more protruding mandible were observed in the AS patients. The maxillary and mandibular volume are reduced in CS patients, but these changes are mostly age related (Andersson et al., 2010; Khonsari et al., 2016; Kreiborg \\u0026amp; Cohen Jr, 2010). Orbital sphere expansion is limited in CS patients compared to AS patients. Only a few studies were found to be significant for this meta-analysis. As an outcome of this study, we found some minor differences between the AS and CS patients. More craniofacial measurements from different regions are needed to clarify the estimate of the maxillary and mandibular vertical and anteroposterior positions for a definitive conclusion.\\u003c/p\\u003e \\u003cp\\u003eIn this meta-analysis, we conducted a literature search of English language articles published between January 2000 and 2023 January. Only the relevant information was taken from the previous literature. A literature search was performed to determine the measurements and comparisons of AS and CS with healthy control NS patients.\\u003c/p\\u003e\"},{\"header\":\"5. Conclusion\",\"content\":\"\\u003cp\\u003eOur systematic review provides updated information on the features of AS and CS craniofacial dysmorphism. The main focus is on the maxillary, dental arch dimension, and craniosynostosis. Due to the limited literature on specific craniofacial features, we included some studies focusing on selected craniofacial dysmorphisms, which cover both syndromes. In these two craniosynostosis syndromes, the phenotypes match those of patients with similar phenotypes rather than the patient\\u0026rsquo;s parent\\u0026rsquo;s phenotypes. In AS patients, there is midface protrusion, a decreased mandible (retrognathia), a decreased orbital volume, hypoplasia, delayed dental development, open bites, a cleft palate, and brachycephaly such as craniosynostosis. Additionally, severe limb malformations were noted. Patients with CS tend to have shorter skull bases, v-shaped maxillary arches, wider dental spacing, cleft palates, edge-to-edge bites, and minor limb malformations. This review demonstrated the large variation in cephalometric measurements between AS and CS patients. The maxillary intercanine width in patients with AS increased, whereas that in patients with CS did not. With the growth period of the children, the maxillary and mandibular intercanine indices increased in the CS, whereas no change in mandibular or maxillary intercanine indices during the growth period was predicted in the AS. The anterior maxillary region is more affected in AS patients than in HCs but less affected in CS patients. ASs had an anterior crossbite (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001), and CSs had an edge-to-edge bite (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.011). In the case of craniosynostosis, AS patients experience isolated bicoronal synostosis, and CSs tend to have short and flat cranial bases and smaller orbital volumes of craniofacial morphology. Malformation of the middle cranial fossa is an early, perhaps initial, cranial morphologic change in AS patients. The CS patients had a smaller skull and mandible volume than did the AS patients. CT scans help patients pursue orthodontic and maxillofacial treatment alone or choose assisted surgery for their respective expansion.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003eAS- Apert Syndrome\\u003c/p\\u003e\\n\\u003cp\\u003eCrouzon\\u0026nbsp;syndrome\\u003c/p\\u003e\\n\\u003cp\\u003eCT- Cephalometric\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthical approval\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eEthical approval was not given because we conducted\\u0026nbsp;a\\u0026nbsp;systematic review and\\u0026nbsp;meta-analysis\\u0026nbsp;in which\\u0026nbsp;personal information\\u0026nbsp;was not collected.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eData statement\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe data that our review is based on\\u0026nbsp;are\\u0026nbsp;available in the manuscripts of the included articles.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSource of funding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNone.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eShalini Dhiman, Inusha Panigrahi, and Ranjit Sah: Conceptualization, Study design, Data extraction, Methodology and validation, Data analysis, Interpretation of results, Writing Original Drafting the article and editing\\u003c/p\\u003e\\n\\u003cp\\u003eBijaya Kumar Padhi, Shifali Gupta, Prakasini Satapathy, Mahalaqua Nazli Khatib, and Shilpa Gaidhane: Data curation, Interpretation of results, Writing-Review and Editing\\u003c/p\\u003e\"},{\"header\":\" References\",\"content\":\"\\u003col\\u003e\\n \\u003cli\\u003eAl-Namnam, N., Hariri, F., Thong, M., \\u0026amp; Rahman, Z. 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(2023).\\u0026nbsp;Three-Dimensional Evaluation of Dental Arches in Individuals with Syndromic Craniosynostosis. \\u003cem\\u003eInternational Journal of Dentistry\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;2023\\u003c/em\\u003e.\\u003c/li\\u003e\\n \\u003cli\\u003ePollock, A., Farmer, S. E., Brady, M. C., Langhorne, P., Mead, G. E., Mehrholz, J., van Wijck, F., \\u0026amp; Wiffen, P. J. (2016). An algorithm was developed to assign GRADE levels of evidence to comparisons within systematic reviews. \\u003cem\\u003eJournal of clinical epidemiology\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;70\\u003c/em\\u003e, 106-110.\\u003c/li\\u003e\\n \\u003cli\\u003eRaposo-Amaral, C. E., Neto, J. G. J., Denadai, R., Raposo-Amaral, C. M., \\u0026amp; Raposo-Amaral, C. A. (2014).\\u0026nbsp;Patient-reported quality of life in highest-functioning Apert and Crouzon syndromes: a comparative study. \\u003cem\\u003ePlastic and Reconstructive Surgery\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;133\\u003c/em\\u003e(2), 182e-191e.\\u003c/li\\u003e\\n \\u003cli\\u003eReitsma, J. H., Balk-Leurs, I. H., Ongkosuwito, E. M., Wattel, E., \\u0026amp; Prahl-Andersen, B. (2014). Dental maturation in children with the syndrome of crouzon and apert. \\u003cem\\u003eThe Cleft Palate-Craniofacial Journal\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;51\\u003c/em\\u003e(6), 639-644.\\u003c/li\\u003e\\n \\u003cli\\u003eReitsma, J. H., Ongkosuwito, E. M., Buschang, P. H., Adrichem, L. N. V., \\u0026amp; Prahl-Andersen, B. (2013). Craniofacial stability in patients with Crouzon or Apert syndrome after Le Fort III distraction osteogenesis. \\u003cem\\u003eThe Cleft Palate-Craniofacial Journal\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;50\\u003c/em\\u003e(5), 561-569.\\u003c/li\\u003e\\n \\u003cli\\u003eRostamzad, P., Arslan, Z. F., Mathijssen, I. M., Koudstaal, M. J., Pleumeekers, M. M., Versnel, S. L., \\u0026amp; Loudon, S. E. (2022). Prevalence of ocular anomalies in craniosynostosis: a systematic review and meta-analysis. \\u003cem\\u003eJournal of Clinical Medicine\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;11\\u003c/em\\u003e(4), 1060.\\u003c/li\\u003e\\n \\u003cli\\u003eSakamoto, Y., Takenouchi, T., Miwa, T., \\u0026amp; Kishi, K. (2021). 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E., van Veelen, M.-L. C., \\u0026amp; Mathijssen, I. M. (2016). First vault expansion in Apert and Crouzon-Pfeiffer syndromes: front or back? \\u003cem\\u003ePlastic and Reconstructive Surgery\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;137\\u003c/em\\u003e(1), 112e-121e.\\u003c/li\\u003e\\n \\u003cli\\u003eStanton, E., Urata, M., Chen, J.-F., \\u0026amp; Chai, Y. (2022). The clinical manifestations, molecular mechanisms and treatment of craniosynostosis. \\u003cem\\u003eDisease Models \\u0026amp; Mechanisms\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;15\\u003c/em\\u003e(4), dmm049390.\\u003c/li\\u003e\\n \\u003cli\\u003eTan, A. P., \\u0026amp; Mankad, K. (2018). Apert syndrome: magnetic resonance imaging (MRI) of associated intracranial anomalies. \\u003cem\\u003eChild\\u0026apos;s Nervous System\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;34\\u003c/em\\u003e, 205-216.\\u003c/li\\u003e\\n \\u003cli\\u003eTaylor, J. A., \\u0026amp; Bartlett, S. P. (2017). What\\u0026rsquo;s new in syndromic craniosynostosis surgery? \\u003cem\\u003ePlastic and Reconstructive Surgery\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;140\\u003c/em\\u003e(1), 82e-93e.\\u003c/li\\u003e\\n \\u003cli\\u003eTimberlake, A. T., Kiziltug, E., Jin, S. C., Nelson-Williams, C., Loring, E., Analysis, Y. C. f. G., Allocco, A., Marlier, A., Banka, S., \\u0026amp; Stuart, H. (2023). De novo mutations in the BMP signaling pathway in lambdoid craniosynostosis. \\u003cem\\u003eHuman Genetics\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;142\\u003c/em\\u003e(1), 21-32.\\u003c/li\\u003e\\n \\u003cli\\u003eT\\u0026oslash;nne, E., Due-T\\u0026oslash;nnessen, B. J., Wiig, U., Stadheim, B. F., Meling, T. R., Helseth, E., \\u0026amp; Heimdal, K. R. (2020). Epidemiology of craniosynostosis in Norway. \\u003cem\\u003eJournal of Neurosurgery: Pediatrics\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;26\\u003c/em\\u003e(1), 68-75.\\u003c/li\\u003e\\n \\u003cli\\u003eViechtbauer, W., \\u0026amp; Cheung, M. W. L. (2010). Outlier and influence diagnostics for meta‐analysis. \\u003cem\\u003eResearch synthesis methods\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;1\\u003c/em\\u003e(2), 112-125.\\u003c/li\\u003e\\n \\u003cli\\u003eWang, N. (2018). How to conduct a meta-analysis of proportions in R: a comprehensive tutorial. \\u003cem\\u003eNew York: John Jay College for Criminal Justice\\u003c/em\\u003e.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":true,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"Advanced Pediatric Centre PGIMER Chandigarh 160012\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Apert, Cranium, Crouzon, Craniosynostosis, Dental Arches, FGFR2. Maxillary, Mandibular, Proptosis.\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-4443370/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-4443370/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study aimed to compare the prevalence of craniofacial dysmorphisms, such as maxillary, mandibular, and dental arch dimensions, and cranial suture fusion in Apert and Crouzon syndrome patients from publicly available scientific information and to provide insights to improve the findings of further studies. Over a large-scale interval from January 2000 to January 2023, a comprehensive search was performed on different database platforms: PubMed, Google Scholar, Cochrane, Web of Science, and the Wiley online library. The preferred reporting item for Systematic Review and Meta-Analyses (PRISMA) guidelines were followed to conduct this systematic review. The protocol was submitted to the International Prospective Register of Systematic Reviews (CRC42023395454; https://www.crd.york.ac.uk/prospero/record_email.php) on 11 February 2023. We collected the data from different databases and ranked the publications based on their adherence to the Newcastle‒Ottawa Quality Assessment Scale. The meta-analysis was carried out by calculating the random effects model and pooled mean proportions with 95% confidence intervals (CIs).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults\\u003c/strong\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eA total of 53 studies were considered worthy, but 39 were excluded due to unusable data formats. The meta-analysis was carried out by calculating the random effects model and pooled mean proportions with 95% confidence intervals (CIs). Patients with Apert syndrome were noted as having AS, and Crouzon syndrome was noted as having CS; different studies were included in the systematic review. A total of seven studies reported outcomes. The I2 index provides a better way of assessing effect size heterogeneity. Forest plots were generated to visualize the heterogeneity of the individual outcomes. Subgroup analyses were performed for each outcome to assess the potential differences in effect sizes. The effect size and heterogeneity of the dental arch were greater in the CS group (I2: 58%, 95% CI=0.01, 0.29; P=0.12) than in the AS group (I2: 52%, 95% CI=0.01, 0.27; P=0.15). Effect size and heterogeneity of the maxilla of AS patients (I2: 91%, 95% CI 0.09; 0.47, P\\u0026lt;0.01) and CS patients (I2: 94%, 95% CI 0.07; 0.64, P\\u0026lt;0.01). We observed significant heterogeneity in AS and CS patients.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusion\\u003c/strong\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThis review demonstrated the large variation in cephalometric measurements between CS and AS patients. The CS patient had a smaller skull and mandible volume than the AS patient. The CS procedure did not change the maxillary intercanine width or intermolar width, but the maxillary intercanine width increased in patients with AS. With the growth period of the children, the maxillary and mandibular intercanine indices increased in the CS, whereas no change in mandibular or maxillary intercanine indices during the growth period was predicted in the AS. The anterior maxillary region is more affected in AS patients than in HCs but less affected in CS patients. ASs had an anterior crossbite (p\\u0026lt;0.001), and CSs had an edge-to-edge bite (p\\u0026lt;0.011). CSs tend to have short and flat cranial bases, smaller orbital volumes, and cleft palates.\\u003c/p\\u003e\",\"manuscriptTitle\":\"FGFR2 gene Related Apert and Crouzon Syndrome Patients with Different Craniofacial Dysmorphisms: A Systematic Review and Meta-analysis\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-05-23 01:47:31\",\"doi\":\"10.21203/rs.3.rs-4443370/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"aa8203ac-f21f-44d8-bccc-8d8f5dcf1861\",\"owner\":[],\"postedDate\":\"May 23rd, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2024-05-23T01:47:31+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2024-05-23 01:47:31\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-4443370\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-4443370\",\"identity\":\"rs-4443370\",\"version\":[\"v1\"]},\"buildId\":\"qtupq5eGEP_6zYnWcrvyt\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}