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Risk loci identified through genome-wide association studies have explained about 25% of the phenotypic variations in nonsyndromic orofacial clefts (nsOFCs) on the liability scale. Despite the notable sex differences in the incidences of the different cleft types, investigation of loci for sex-specific effects has been understudied. To explore the sex-specific effects in genetic etiology of nsOFCs, we conducted a genome-wide gene × sex (GxSex) interaction study in a sub-Saharan African orofacial cleft cohort. The sample included 1,019 nonsyndromic orofacial cleft cases (814 cleft lip with or without cleft palate and 205 cleft palate only) and 2,159 controls recruited from 3 sites (Ethiopia, Ghana, and Nigeria). An additive logistic model was used to examine the joint effects of the genotype and GxSex interaction. Furthermore, we examined loci with suggestive significance ( P 2df = 1.16E-08, pGxSex = 1.49E-09, odds ratio [OR] = 0.44, 95% CI = 0.34 to 0.57). For males, the risk of cleft lip with or without cleft palate at this locus decreases with additional copies of the minor allele ( p

Novel or rare damaging mutations have been implicated in the developmental pathogenesis of nonsyndromic cleft lip with or without cleft palate (nsCL ± P). Thus, we investigated the human genome for high-impact mutations that could explain the risk of nsCL ± P in our cohorts.We conducted next-generation sequencing (NGS) analysis of 130 nsCL ± P case-parent African trios to identify pathogenic variants that contribute to the risk of clefting. We replicated this analysis using whole-exome sequence data from a Brazilian nsCL ± P cohort. Computational analyses were then used to predict the mechanism by which these variants could result in increased risks for nsCL ± P.We discovered damaging mutations within theThis is the first report on the contribution of

Objective The etiology of cleft palate (CP) is poorly understood compared with that of cleft lip with or without palate (CL ± P). Recently, variants in Grainyhead like transcription factor 3 ( GRHL3) were reported to be associated with a risk for CP in European and some African populations including Nigeria, Ghana, and Ethiopia. In order to identify genetic variants that may further explain the etiology of CP, we sequenced GRHL3 in a South African population to determine if rare variants in GRHL3 are associated with the presence of syndromic or nonsyndromic CP. Design We sequenced the exons of GRHL3 in 100 cases and where possible, we sequenced the parents of the individuals to determine the segregation pattern and presence of de novo variants. Setting The cleft clinics from 2 public, tertiary hospitals in Durban, South Africa (SA), namely Inkosi Albert Luthuli Central Hospital and KwaZulu-Natal Children's Hospital. Patients, participants One hundred patients with CL ± P and their parents. Interventions Saliva samples were collected. Main outcome measures To ascertain the genetic variants in the GRHL3 gene in patients with CL ± P in SA. Results Five variants in GRHL3 were observed; 3 were novel and 2 were known variants. The novel variants were intronic variants (c.1062 + 77A>G and c.627 + 1G>A) and missense variant (p.Asp169Gly). Conclusions This study provides further evidence that variants in GRHL3 contribute to the risk of nonsyndromic CP in African populations, specifically, in the South African population.

Background We investigated the role of epidermal growth factor (EGF) and transforming growth factor α (TGFα) on Asian head and neck cancer patient cell lines; in terms of Epithelial to Mesenchymal Transition (EMT) and cell migration to determine whether these changes could be reversed using tyrosine kinase inhibitors (Gefitinib and Erlotinib). Methods Cell migration, protrusion and EMT were assessed using both Scatter assay and Scratch assay. Protein expression and localisation were evaluated using Immunofluorescence, SDS-PAGE and Western Blotting techniques to identify the involvement of phosphorylated MAPK (Thr202/Tyr204), phosphorylated EGFR (Y1068) and phosphorylated AKT (Ser473) protein expression. Results EGF and TGFα induced an EMT like phenotypical change, cellular protrusion and cell migration while Gefitinib and Erlotinib blocked these morphological changes and cell migration. We also examined the effect of EGF/TGF α ± tyrosine kinase inhibitors on phosphorylation sites Y1068 of Epidermal Growth Factor Receptor (EGFR). Y1068 was phosphorylated in all test condition and all tested concentration of inhibitors did not inhibit Y1068 phosphorylation. EGF and TGFα increased phosphorylation of MAPK (Thr202/Tyr204) residues compared with serum free control while a one-hour pre-treatment with tyrosine kinase inhibitor(s) before addition of growth factors completely blocked this phosphorylation. Phosphorylation of Akt Ser 473 was also induced by EGF and TGFα and a one-hour pre-treatment with the tyrosine kinas inhibitor(s) reduced this phosphorylation. Conclusion These data suggests that Gefitinib and Erlotinib prevent activation of downstream signalling proteins MAPK (Thr202/Tyr204) and Akt (Ser473) thereby blocking phenotypic change and cell migration. This study supports the potential therapeutic value of Gefitinib and Erlotinib in targeting head and neck cancer.

This study aimed to determine the normative facial anthropometry measurement among Nigerians using three-dimensional stereophotogrammetry analysis.This study was carried out in Lagos, Nigeria over a period of 3 years. The sample population was Nigerians of diverse ethnic groups, age 16 and above with no history of congenital or acquired craniofacial deformities.A total of 452 subjects participated in the study with 56.2% males and 43.8% females. Most of the participants were between the ages of 25 to 49 (54.4%), 40.7% were less than 25 years of age and only 4.4% were more than 50 years old. The mean body mass index (BMI) for males was 22.7 and 23.4 for females. Mean values of upper facial height, midfacial height, lower facial height, intercanthal distance, interpupillary distance, upper facial width, and lower facial width are 69.13 ± 5.91, 49.89 ± 3.56, 67.85 ± 6.12, 35.19 ± 3.20, 67.04 ± 3.67, 139.43 ± 7.11, and 124.29 ± 9.72 mm, respectively. The upper facial height, commissure width, upper lip length, and lower jaw width were significantly affected by age, while the BMI of an individual was a determinant of the interpupillary distance, facial width, and lower jaw width.This study demonstrated that there was a statistically significant difference in the facial dimensions of males when compared to females across all ages among the study population. The authors also observed that age and BMI are significant predictors of variations in some of the measurements.

Objectives: The aim of the study is to highlight variations in facial anthropometric measurements among the major ethnic groups in Nigeria using 3D photogrammetry. Materials and Methods: This study was conducted in Lagos, Nigeria. Acquisition of 3D facial photographs was done using a Vectra H1 portable 3D photogrammetry imaging system. Descriptive analysis of collected data was done and a test of associations performed using independent samples t-test. The level of significance was set at

Dundee Dental Hospital and School has been present on Park Place, Dundee for over 100 years. During this time, it has been at the forefront of dental care and education, first as part of the University of St Andrews and subsequently the University of Dundee. This innovation continues with novel undergraduate curricula for dental and dental therapy students, providing early clinical experience and integrating clinical teaching with the appropriate sciences. We also offer several taught postgraduate programmes, popular particularly with international students. Dundee was at the forefront of the response to the COVID-19 pandemic, with the Scottish Dental Clinical Effectiveness Programme leading the world on guidance for safe clinical practice. Innovative solutions for the ongoing delivery of teaching and assessment also were developed. Research underpins teaching and the delivery of dental care and Dundee has an international reputation for its research portfolio. All of the above can only be achieved by close working relationships between the University and NHS, which will be strengthened further by the creation of the Dundee Dental Research Hospital and School. Our international reputation will continue to attract students and staff from across the world.

Summary Objective Thezygomaticus major is a principal muscle of facial expression which is engaged when smiling. The zygomaticus major origin of the zygomatic bone is often discussed relevant to its importance in the field of plastic surgery. In addition, the zygomaticus major attachment site is also significant for forensic craniofacial reconstruction, separating the cheek into frontal and lateral surfaces. However, there are discrepancies amongst published articles regarding the precise origin of the zygomaticus major muscle. The aim of this study is to investigate more distinctive and palpable landmarks as the bony attachment of the zygomaticus major. Methods This project is the first zygomaticus major dissection study utilising Thiel embalmed cadavers. Fifty-two facial dissections were investigated in 26 Thiel embalmed bodies, bequeathed to the Centre for Anatomy and Human Identification at The University of Dundee between 2013 and 2015. Results This study found that the origin of zygomaticus major muscle was located at the superior margin of the temporal process on the lateral surface of zygomatic bone. Moreover, the zygomaticus major muscle overlapped the anterosuperior border of the masseter muscle. One out of 52 zygomaticus major muscles presented bifurcation. Conclusion The origin site of zygomaticus major is considered important to increase resemblance in forensic craniofacial reconstruction. Furthermore, since zygomaticus major is a salient muscle involved in facial expression, the potential effects for cosmetic/surgical procedures are also relevant to the medical field and successful surgical outcomes. The current study provided easily palpable landmarks of zygomaticus major origin site which is beneficial for both surgeons and forensic craniofacial reconstruction practitioners.

This paper assesses the research literature on OFC in LMIC over the last decade across various geographical settings and project focus of the indexed literature. A scoping review of the indexed literature was performed using a set of predefined keywords. The articles were filtered by a ten-year time frame (2010-2019) and a strict inclusive-exclusive criterion. Two authors screened the titles/abstracts/full text of the final included papers and input the desired data (year of publication, type of publication, geographical country/region and project focus to a coded spreadsheet). Six hundred and twenty publications were inventoried from the indexed literature on OFC in LMIC settings over the 10-year period. Five hundred and eighty-three derived from single LMIC countries and 37 from multi-settings. More than half of the articles were reported from Asia (57%), then from Americas (22.8%), Africa (15.4%) and the rest from cross-regional, Europe and Oceania (4.9%). The top 3 LMIC contributors towards OFC publications were China (21.5%), Brazil (13.1%) and India (11.6%). The most discussed OFC project themes were prevalence, surgical repair, aetiology and genetics. This study helps OFC researchers, humanitarian missions and research grant funders to identify gaps in the literature on issues impacting on children and adults born with OFC, in which issues were subjected to research and which were less explored in which LMIC regions. In addition, this study offers recommendations for established OFC researchers and international research bodies to identify areas of deficiency in the literature and what information is required to support LMIC governments achieve SDGs by 2030.

Background There has been a longstanding debate about the role of folate in the etiology of orofacial clefts (OFCs). Studies of different measures of nutritional intake or folate status have been done to investigate the possible role of folate in the prevention of OFC. Only one knowledge synthesis has attempted to bring together different types of evidence. The aim of the present work was to update it. Methods Evidence for associations between OFC and dietary folate, supplement use, folic acid fortification, biomarkers of folate status, and variants of MTHFR (C677T and A1298C) were included. Potentially eligible articles were systematically identified from PubMed, Medline, Embase, and Web of Science (2007-2020) and combined using random-effects meta-analysis when appropriate. Quality assessments were conducted using the Newcastle-Ottawa scale and Cochrane's risk of bias tool. Results Sixty-four studies published since the previous knowledge synthesis were identified, with eight of these identified through a supplementary search from October, 2018 to August, 2020. There was an inverse association between folic acid-containing supplement use before or during pregnancy and cleft lip with or without cleft palate (CL/P) (OR 0.60, 95% CI 0.51-0.69), with considerable between-study heterogeneity. The prevalence of CL/P showed a small decline post-folic acid fortification in seven studies (OR 0.94, 95% CI 0.86-1.02). No association was found between OFC and genetic markers of folate status. The coronavirus-19 pandemic has threatened food availability globally and therefore there is a need to maintain and even enhance surveillance concerning maternal intake of folate and related vitamins. Conclusions The risk of non-syndromic OFC was reduced among pregnant women with folic acid-containing supplements during the etiologically relevant period. However, high heterogeneity between included studies, incomplete reporting of population characteristics and variation in timing of exposure and supplement types mean that conclusions should be drawn with caution.

The aim of this study is to establish for the first time cephalometric norms for bimaxillary protrusion in Trinidad and Tobago population and to compare findings to previously published norms for o...

This systematic review compared children's primary dentition caries experience for those with cleft lip and/or palate (CL/P) and without. Four databases were searched without date restriction for; cross-sectional studies comparing caries experience for children with CL/P to those without. Screening, data extraction and risk assessment were carried out independently (in duplicate). Meta-analyses used a random-effects model. Twenty studies (21 reports) fitting the inclusion criteria comprised 4647 children in primary dentition from 12 countries. For dmft (n = 3016 children; 15 groups), CL/P mean = 3.2; standard deviation = 2.22 and no CL/P mean dmft = 2.5; sd 1.53. For dmfs (n = 1095 children; 6 groups), CL/P mean = 4; sd = 3.5 and no CL/P mean = 3; sd = 2.8. For % caries experience (n = 1094 children; 7 groups), CL/P mean = 65%; sd = 20.8 and no CL/P mean = 52%; sd = 28.1. Meta-analysis showed higher caries experience in children with CL/P, standardised mean difference = 0.46; 95% CI = 0.15, 0.77. Studies' risk of bias was high (n = 7), medium (n-10) and low (n = 3). Children with CL/P had higher caries experience compared to those without CLP.

BACKGROUND: Van der Woude syndrome (VWS) is the most common syndromic orofacial cleft which accounts for approximately 2% of all cleft lip (CL) and/or palate cases. It is characterized by the presence of lower lip pits, in addition to CL, CL with or without cleft palate, cleft palate only, and hypodontia. It is inherited as an autosomal-dominant trait with almost complete penetrance but variable expressivity, and different variants in IRF6 gene have been reported in different populations around the world including African populations (Ethiopian, Ghanaian, and Nigerian). METHODS AND FINDINGS: The authors investigated the role of IRF6 in Ethiopian families with VWS. The DNA of 7 families with VWS from Ethiopia were screened by Sanger sequencing. The authors screened all 9 exons of IRF6 and found a novel missense variant in exon 4 (p. Gly65Glu). This variant was predicted to be deleterious/probably damaging by Sift and PolyPhen, respectively. The IRF6 variant (p. Gly65Glu) segregates in the family since it was identified in the father and a sibling. CONCLUSION: Several of the individuals with lower lip pits in this study did not seek treatment. This is due to lack of awareness about the significance of this minor looking deformity and its consequences, and availability of treatment for birth defects. Therefore, it is important to educate families. Finally, screening for novel variants in known genes has a role in counseling and prenatal diagnosis for high-risk families.

The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact DNMs that contribute to the risk of nsCL/P, we conducted whole genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs that contribute to the risk of nsCL/P. These include novel loss-of-function DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Experimental evidence showed that ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, MINK1, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TTN genes contribute to facial development and mutations in these genes could contribute to CL/P. Association studies have identified TULP4 as a potential cleft candidate gene, while ARHGAP10 interacts with CTNNB1 to control WNT signaling. DLX6, EPHB2, SEMA3C and SEMA4D harbor novel damaging DNMs that may affect their role in neural crest migration and palatal development. This discovery of pathogenic DNMs also confirms the power of WGS analysis of trios in the discovery of potential pathogenic variants.

BACKGROUND Nonsyndromic orofacial clefts (NSOFCs) represent the most common congenital anomalies in the head and neck region. Multiple factors contribute to the occurrence of this anomaly. The etiology of NSOFCs in the Ethiopian population has not been investigated prior to this study. AIMS OF THE STUDY To assess the role of maternal environmental factors in the occurrence of NSOFCs in the Ethiopian Population. METHODS The authors used unmatched case control study design and evaluated the role of environmental factors to the occurrence of NSOFCs in the Ethiopian population. The participants were recruited from the same institution (Yekatit 12 Hospital Medical College). The authors studied 760 mothers (359 mothers of children born with NSOFCs and 401 mothers of children born without any congenital anomalies). Univariate and multivariate logistic regression analyses were used to calculate relative risk by odds ratio and 95% confidence interval. RESULTS Mothers who gave history of bronchial asthma and mothers who were admitted for threatened abortion had a higher risk of delivering a child with NSOFCS P value=0.013; AOR=0.194, 95% CI [0.053-0.712], P value

Objectives To conduct a rapid review to identify any maternal and/or child oral health interventions implemented and/or tested in Middle East and North Africa (MENA) countries generally, and Lebanon, Palestine and Syria specifically, and to compile information on the relative effectiveness of these interventions. Methods A systematic search was conducted for primary and secondary literature indexed in five online databases, and the websites of the World Health Organisation (WHO), the International Union for Health Promotion and Education (IUHPE), the United Nations Children's Fund (UNICEF), United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA), and the United Nations Refugee Agency (UNHCR). Results Two independent researchers reviewed 1,180 records from the online databases, and 3,120 reports from the WHO, UNRWA, UNICEF and UNHCR. Four unique studies were included and conducted in Syria, Saudi Arabia and Iran. No systematic reviews were found for targeted interventions in MENA regions. However, interventions using fluoridated toothpaste (Syria), preventive treatment and fluoridated chewing gum (Saudi Arabia), and oral health education with oral health reminders (Iran) were significantly effective in reducing early child caries (ECC) experience. In Syria and Iran, mother and child oral health promotions integrated into ongoing vaccination programmes were effective in reducing ECC. These interventions formed part of WHO and Ministry of Health programmes. Conclusion Further investigation is essential to verify the effectiveness of incorporating multi-disciplinary, theory-driven oral health interventions into ongoing WHO maternal and child health programmes in MENA countries to assist in promoting oral health and wellbeing.

Novel or rare damaging mutations have been implicated in the developmental pathogenesis of nonsyndromic cleft lip with or without cleft palate (nsCL ± P). Thus, we investigated the human genome for high-impact mutations that could explain the risk of nsCL ± P in our cohorts. We conducted next-generation sequencing (NGS) analysis of 130 nsCL ± P case-parent African trios to identify pathogenic variants that contribute to the risk of clefting. We replicated this analysis using whole-exome sequence data from a Brazilian nsCL ± P cohort. Computational analyses were then used to predict the mechanism by which these variants could result in increased risks for nsCL ± P. We discovered damaging mutations within the AFDN gene, a cell adhesion molecule (CAMs) that was previously shown to contribute to cleft palate in mice. These mutations include p.Met1164Ile, p.Thr453Asn, p.Pro1638Ala, p.Arg669Gln, p.Ala1717Val, and p.Arg1596His. We also discovered a novel splicing p.Leu1588Leu mutation in this protein. Computational analysis suggests that these amino acid changes affect the interactions with other cleft-associated genes including nectins (PVRL1, PVRL2, PVRL3, and PVRL4) CDH1, CTNNA1, and CTNND1. This is the first report on the contribution of AFDN to the risk for nsCL ± P in humans. AFDN encodes AFADIN, an important CAM that forms calcium-independent complexes with nectins 1 and 4 (encoded by the genes PVRL1 and PVRL4). This discovery shows the power of NGS analysis of multiethnic cleft samples in combination with a computational approach in the understanding of the pathogenesis of nsCL ± P.

Objective Nonsyndromic cleft lip and/or cleft palate (NSCL/P) have multifactorial etiology where genetic factors, gene–environment interactions, stochastic factors, gene–gene interactions, and parent-of-origin effects (POEs) play cardinal roles. POEs arise when the parental origin of alleles differentially impacts the phenotype of the offspring. The aim of this study was to identify POEs that can increase risk for NSCL/P in humans using a genome-wide dataset. Methods The samples (174 case-parent trios from Ghana, Ethiopia, and Nigeria) included in this study were from the African only genome wide association studies (GWAS) that was published in 2019. Genotyping of individual DNA using over 2 million multiethnic and African ancestry-specific single-nucleotide polymorphisms from the Illumina Multi-Ethnic Genotyping Array v2 15070954 A2 (genome build GRCh37/hg19) was done at the Center for Inherited Diseases Research. After quality control checks, PLINK was employed to carry out POE analysis employing the pooled subphenotypes of NSCL/P. Results We observed possible hints of POEs at a cluster of genes at a 1 mega base pair window at the major histocompatibility complex class 1 locus on chromosome 6, as well as at other loci encompassing candidate genes such as ASB18, ANKEF1, AGAP1, GABRD, HHAT, CCT7, DNMT3A, EPHA7, FOXO3, lncRNAs, microRNA, antisense RNAs, ZNRD1, ZFAT, and ZBTB16. Conclusion Findings from our study suggest that some loci may increase the risk for NSCL/P through POEs. Additional studies are required to confirm these suggestive loci in NSCL/P etiology.

BACKGROUND The medial and maxillary aspects of the upper lip originate at separate embryonic stages and therefore may experience different maternal exposure patterns which may affect methylation. Based on this hypothesis, we investigated the level of methylation of the methylene tetrahydrofolate reductase promoter gene (mMTHFR) in tissues from cleft lip, and mMTHFR levels by MTHFR c.677C > T genotype. We further investigated whether mMTHFR mitigates the effect of smoking on long interspersed nuclear element (LINE-1) methylation in these tissues. METHODS DNA extracted from medial and lateral tissues of 26 infants with nonsyndromic cleft lip with or without cleft palate (nsCL/P) was bisulfite converted and mMTHFR was measured on a pyrosequenser. LINE-1 methylation and MTHFR c.677C > T genotype data were obtained in our previous study. RESULTS There was no substantial difference in mMTHFR (p = .733) and LINE-1 (p = .148) between the two tissues. mMTHFR was not influenced by MTHFR c.677C > T genotype, but there was suggestive evidence that the difference was larger among infants exposed to maternal smoking compared to nonexposed. LINE-1 methylation differences were significant (p = .025) in infants born to nonsmoking mothers, but this was not apparent (p = .872) in infants born to mothers who smoked. Our Pearson's correlation analysis suggested a weak inverse association between mMTHFR and LINE-1 (r = -.179, p = .381). CONCLUSION Our preliminary observation of differences in patterns of mMTHFR levels in lip tissue suggests the interplay of gene and environment in the establishment of methylation in tissues at both sides of cleft lip. This requires investigation in a larger cohort, integrated with metabolic assessment.

Made available in DSpace on 2022-05-01T06:02:13Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-06-24 Background: This study was carried out in response to the Zika virus epidemic, which constituted a public health emergency, and to the 2019 WHO calling for strengthened surveillance for the early detection of related microcephaly. The main aim of the study was to phenotype the craniofacial morphology of microcephaly using a novel approach and new measurements, and relate the characteristics to brain abnormalities in Zika-infected infants in Brazil to improve clinical surveillance. Methods: 3D images of the face and the cranial vault of 44 Zika-infected infants and matched healthy controls were captured using a 3D stereophotogrammetry system. The CT scans of the brain of the infected infants were analysed. Principal component analysis (PCA) was applied to characterise the craniofacial morphology. In addition to the head circumference (HC), a new measurement, head height (HH), was introduced to measure the cranial vault. The level of brain abnormality present in the CT scans was assessed; the severity of parenchymal volume loss and ventriculomegaly was quantified. Student's t-test and Spearman's Rho statistical test have been applied. Findings: The PCA identified a significant difference (p < 0.001) between the cranial vaults and the face of the Zika infants and that of the controls. Spearman's rank-order correlation coefficients show that the head height (HH) has a strong correlation (0.87 in Zika infants; 0.82 in controls) with the morphology of the cranial vaults, which are higher than the correlation with the routinely used head circumference (HC). Also, the head height (HH) has a moderate negative correlation (−0.48) with the brain abnormalities of parenchymal volume loss. Interpretation: It is discovered that the head height (HH) is the most sensitive and discriminatory measure of the severity of cranial deformity, which should be used for clinical surveillance of the Zika syndrome, evaluation of other craniofacial syndromes and assessment of various treatment modalities. Scottish Craniofacial Research Group Dental School College of MVLS University of Glasgow Araçatuba Dental School Univ Estadual Paulista Scottish Craniofacial Research Group School of Dentistry University of Dundee Dental School College of MVLS University of Glasgow Orthodontic Department College of Dentistry University of Baghdad Roberto Santos General Hospital UNESP School of Dentistry at Araçatuba São Paulo State University Department of Paediatric Radiology Royal Hospital for Sick Children Edinburgh NHS Lothian Scottish Craniofacial Research Group Medical Devices Unit NHS Greater Glasgow and Clyde Glasgow Araçatuba Dental School Univ Estadual Paulista UNESP School of Dentistry at Araçatuba São Paulo State University

Objective: Clinical practice guidelines (CPGs) exist to present recommendations and policies aimed at optimizing the oral health of children and adolescents born with cleft lip and/or palate. The aim of this review is to identify and assess the scope, quality, adequacy, and consistency of CPGs related to oral health in children and adolescents with clefts, along with reporting any differences and shortcomings. Methods: A systematic review of the literature of CPGs following Preferred Reporting Items for Systematic Reviews guidelines was conducted. Assessment of selected CPGs was performed using the Appraisal of Guidelines for Research & Evaluation II methodological quality instrument. Results: Only 7 CPGs fulfilled the criteria. Of these, 4 were from the American Cleft Palate-Craniofacial Association, and 1 each from the American Academy of Pediatrics, the Academy of Breastfeeding Medicine, and the American Academy of Pediatric Dentistry. The lowest overall mean scores were in the domain “Rigor of Development” (mean 29.58%, SD 17.11), revealing lower quality in methodology of the guideline. The domain “Clarity of Presentation” (mean 73.80%, SD 7.87) revealed the best score. Conclusions: Our review results reveal a lack of integrated high-quality CPGs that can be used as universal guidelines by health workers in a range of disciplines for improving oral health in children and adolescents with cleft problems.

Objectives Cleft lip with/without cleft palate and cleft palate only are congenital birth defects where the upper lip and/or palate fail to fuse properly during embryonic facial development. Affecting ~1.2/1000 live births world-wide, these orofacial clefts impose significant social and financial burdens on affected individuals and their families. Orofacial clefts have a complex etiology resulting from genetic variants combined with environmental covariates. Recent genome-wide association studies and whole-exome sequencing for orofacial clefts identified significant genetic associations and variants in several genes. Of these, we investigated the role of common/rare variants in SHH, RORA, MRPL53, ACVR1, and GDF11. Materials and methods We sequenced these five genes in 1255 multi-ethnic cleft lip with/without palate and cleft palate only samples in order to find variants that may provide potential explanations for the missing heritability of orofacial clefts. Rare and novel variants were further analyzed using in-silico predictive tools. Results 19 total variants of interest were found, with variant types including stop-gain, missense, synonymous, intronic, and splice-site variants. Of these, 3 novel missense variants were found, one in SHH, one in RORA, and one in GDF11. Conclusion This study provides evidence that variants in SHH, RORA, MRPL53, ACVR1, and GDF11 may contribute to risk of orofacial clefts in various populations.

The causal role of maternal nutrition in orofacial clefts is uncertain. We tested hypotheses that low maternal vitamin BCase-mothers of CL±P children (n = 47) and control-mothers of unaffected children (n = 50) were recruited an average of 1.4 years after birth of the index child and plasma vitamin BOdds ratios (ORs) contrasting biomarker levels showed associations between case-mothers and low versus high plasma vitamin BMothers of CL±P children in southern India were 6.5 times more likely to have poor vitamin B

Supplemental Digital Content is available in the text., Background: It is anticipated that in due course the burden of emergency care due to COVID-19 infected patients will reduce sufficiently to permit elective surgical procedures to recommence. Prioritizing cleft/craniofacial surgery in the already overloaded medical system will then become an issue. The European Cleft Palate Craniofacial Association, together with the European Cleft and Craniofacial Initiative for Equality in Care, performed a brief survey to capture a current snapshot during a rapidly evolving pandemic. Methods: A questionnaire was sent to the 2242 participants who attended 1 of 3 recent international cleft/craniofacial meetings. Results: The respondents indicated that children with Robin sequence who were not responding to nonsurgical options should be treated as emergency cases. Over 70% of the respondents indicated that palate repair should be performed before the age of 15 months, an additional 22% stating the same be performed by 18 months. Placement of middle ear tubes, primary cleft lip surgery, alveolar bone grafting, and velopharyngeal insufficiency surgery also need prioritization. Children with craniofacial conditions such as craniosynostosis and increased intracranial pressure need immediate care, whilst children with craniosynostosis and associated obstructive sleep apnea syndrome or proptosis need surgical care within 3 months of the typical timing. Craniosynostosis without signs of increased intracranial pressure needs correction before the age of 18 months. Conclusions: This survey indicates several areas of cleft and craniofacial conditions that need prioritization, but also certain areas where intervention is less urgent. We acknowledge that there will be differences in the post COVID-19 response according to circumstances and policies in individual countries.

OBJECTIVE A preliminary study to determine collagen fibril diameter (CF-ED) distribution on medial and lateral sides of cleft lip (CL). MATERIAL AND METHODS Tissue samples from medial and lateral sides of CL were fixed in 2.5% glutaraldehyde and 1% osmium tetroxide and embedded in Araldite CY212 resin for transmission electron microscopy. The analysis of CF-ED was performed using the ImageJ program. To characterize the packaging of collagen fibrils (CFs) in the two tissues, we estimated the collagen number density (CF-ND) and fibril-area-fraction (FAF). Differences in measurements across the two sides were calculated using Wilcoxon signed-rank test. RESULTS The CF-ED was statistically significantly (p

Objective: Cleft lip and/or cleft palate (CL/P) are congenital anomalies of the face and have multifactorial etiology, with both environmental and genetic risk factors playing crucial roles. Though at least 40 loci have attained genomewide significant association with nonsyndromic CL/P, these loci largely reside in noncoding regions of the human genome, and subsequent resequencing studies of neighboring candidate genes have revealed only a limited number of etiologic coding variants. The present study was conducted to identify etiologic coding variants in GREM1, a locus that has been shown to be largely associated with cleft of both lip and soft palate. Patients and Method: We resequenced DNA from 397 sub-Saharan Africans with CL/P and 192 controls using Sanger sequencing. Following analyses of the sequence data, we observed 2 novel coding variants in GREM1. These variants were not found in the 192 African controls and have never been previously reported in any public genetic variant database that includes more than 5000 combined African and African American controls or from the CL/P literature. Results: The novel variants include p.Pro164Ser in an individual with soft palate cleft only and p.Gly61Asp in an individual with bilateral cleft lip and palate. The proband with the p.Gly61Asp GREM1 variant is a van der Woude (VWS) case who also has an etiologic variant in IRF6 gene. Conclusion: Our study demonstrated that there is low number of etiologic coding variants in GREM1, confirming earlier suggestions that variants in regulatory elements may largely account for the association between this locus and CL/P.

Aim: To pilot investigation of methylation of long interspersed nucleotide element-1 in lip tissues from infants with nonsyndromic cleft lip, and its association with maternal periconceptional exposures. Methods: The lateral and medial sides of the cleft lips of 23 affected infants were analyzed for long interspersed nucleotide element-1 methylation by bisulfite conversion and pyrosequencing. Results: The medial side showed 1.8% higher methylation compared with the lateral side; p = 0.031, particularly in male infants (2.7% difference; p = 0.011) or when the mothers did not take folic acid during periconceptional period (2.4% difference; p = 0.011). These results were not statistically significant when Bonferroni adjustment was used. Conclusion: The observed differences in DNA methylation, although nonsignificant after correction for multiple comparisons, suggest that differential regulation of the two sides may impact lip fusion and warrant larger-scale replication.

This study investigated nose profile morphology and its relationship to the skull in Scottish subadult and Indonesian adult populations, with the aim of improving the accuracy of forensic craniofacial reconstruction. Samples of 86 lateral head cephalograms from Dundee Dental School (mean age, 11.8 years) and 335 lateral head cephalograms from the Universitas Padjadjaran Dental Hospital, Bandung, Indonesia (mean age 24.2 years), were measured. The method of nose profile estimation based on skull morphology previously proposed by Rynn and colleagues in 2010 (FSMP 6:20–34) was tested in this study. Following this method, three nasal aperture-related craniometrics and six nose profile dimensions were measured from the cephalograms. To assess the accuracy of the method, six nose profile dimensions were estimated from the three craniometric parameters using the published method and then compared to the actual nose profile dimensions. In the Scottish subadult population, no sexual dimorphism was evident in the measured dimensions. In contrast, sexual dimorphism of the Indonesian adult population was evident in all craniometric and nose profile dimensions; notably, males exhibited statistically significant larger values than females. The published method by Rynn and colleagues (FSMP 6:20–34, 2010) performed better in the Scottish subadult population (mean difference of maximum, 2.35 mm) compared to the Indonesian adult population (mean difference of maximum, 5.42 mm in males and 4.89 mm in females). In addition, regression formulae were derived to estimate nose profile dimensions based on the craniometric measurements for the Indonesian adult population. The published method is not sufficiently accurate for use on the Indonesian population, so the derived method should be used. The accuracy of the published method by Rynn and colleagues (FSMP 6:20–34, 2010) was sufficiently reliable to be applied in Scottish subadult population.

In contrast to the progress that has been made toward understanding the genetic etiology of cleft lip with or without cleft palate, relatively little is known about the genetic etiology for cleft palate only (CPO). A common coding variant of grainyhead like transcription factor 3 ( GRHL3) was recently shown to be associated with risk for CPO in Europeans. Mutations in this gene were also reported in families with Van der Woude syndrome. To identify rare mutations in GRHL3 that might explain the missing heritability for CPO, we sequenced GRHL3 in cases of CPO from Africa. We recruited participants from Ghana, Ethiopia, and Nigeria. This cohort included case-parent trios, cases and other family members, as well as controls. We sequenced exons of this gene in DNA from a total of 134 nonsyndromic cases. When possible, we sequenced them in parents to identify de novo mutations. Five novel mutations were identified: 2 missense (c.497C>A; p.Pro166His and c.1229A>G; p.Asp410Gly), 1 splice site (c.1282A>C p.Ser428Arg), 1 frameshift (c.470delC; p.Gly158Alafster55), and 1 nonsense (c.1677C>A; p.Tyr559Ter). These mutations were absent from 270 sequenced controls and from all public exome and whole genome databases, including the 1000 Genomes database (which includes data from Africa). However, 4 of the 5 mutations were present in unaffected mothers, indicating that their penetrance is incomplete. Interestingly, 1 mutation damaged a predicted sumoylation site, and another disrupted a predicted CK1 phosphorylation site. Overexpression assays in zebrafish and reporter assays in vitro indicated that 4 variants were functionally null or hypomorphic, while 1 was dominant negative. This study provides evidence that, as in Caucasian populations, mutations in GRHL3 contribute to the risk of nonsyndromic CPO in the African population.

Background In the last comprehensive review of the literature published in 2002, little information on the prevalence of orofacial clefts was available from low- and middle-income countries (LMICs). Objective To analyze published data on the birth prevalence of cleft lip and/or palate ( CL/P) from LMIC. Design Systematic review of the literature and meta-analysis of data from original papers on the birth prevalence of cleft lip and/or cleft palate (CL/P) in LMICs between 1990 and 2014. Secondary inclusion criteria were developed to analyze lower-quality studies from countries with scarce data. Main Outcome Measure Birth prevalence of undifferentiated CL/P (with or without associated syndrome or other anomaly). Results Twenty-eight studies met strict inclusion criteria. Among 31,475,278 total births, the pooled birth prevalence of undifferentiated CL/P was 1.38 per 1000 births (95% confidence interval [CI]: 1.20 to 1.56). Four studies met criteria for secondary analysis, providing data on 75,627 births, with a pooled prevalence of 0.75 CL/P cases per 1000 births (95% CI: 0.56 to 0.95). Comparison of studies was limited by variable definitions of cases and of the reference population and by inconsistent reporting of outcomes. There is significant heterogeneity in the findings. Conclusions In LMICs, approximately 1 in every 730 children is born with CL/P. To optimize comparability across settings, future research should use a standard classification system and standard criteria for data collection and presentation. As clefting is associated with deprivation, understanding the true scale, risks, and preventive measures for orofacial clefts in LMIC is a matter of both scientific and humanitarian importance.

Objective The modified Huddart and Bodenham scoring system assesses maxillary arch constriction and surgical outcomes in cleft lip and palate. This project automates modified Huddart and Bodenham scoring using three-dimensional digital models. Design Development of a novel software tool. Setting The design, construction, development, and testing of the system was carried out at Dundee Dental Hospital. Patients, Participants Subjects with cleft lip and palate. Interventions A plug-in has been developed using an open three-dimensional development platform: Rhinoceros, version 5 ( http://www.rhino3d.co.uk ). Users select cusps on mandibular and maxillary teeth on three-dimensional digital models. A three-dimensional cubic spline generates a mandibular curve, and a best-fit horizontal mandibular reference plane is produced using a least-squares method. Horizontal distances projected from the shortest three-dimensional distances were subsequently calculated between the maxillary cusps and the mandibular curve to calculate the modified Huddart and Bodenham score. Main Outcome Measures Automatic scoring of digital models using the modified Huddart and Bodenham system produces similar results to manual scoring. Results By standardizing outcome assessment in cleft care, multicenter comparisons for audit and research can be simplified, allowing centers throughout the world to upload three-dimensional digital models or intraoral scans of the dental arches for remote scoring. Thereafter, these data can feed back into the global database on orofacial clefting as part of the World Health Organization's international collaborative “Global Burden of Disease” research project for craniofacial anomalies. Conclusions The automated system facilitates quicker and more reliable outcome assessments by minimizing human errors.

The descriptive epidemiology of orofacial clefts (OFC) is an essential prerequisite towards improved care, investigations into the etiology, and eventually prevention. In the present study the distribution of OFC in sub-Saharan Africa using post-surgical data from the Smile Train organization, was examined. Data from 46,502 individuals from Ethiopia (16,049), Nigeria (8,209), Uganda (5,138), Kenya (4,084), Tanzania (2,750), Congo DR (1,371), Zambia (1,319), Somalia (1,039), and a total of 6,543 individuals from another 26 African countries were available for analysis. Individuals without a cleft diagnosis and those who indicated non-black African as their racial group were excluded, and a total of 46,502 individuals were available for analysis. There was a significant difference in frequency between unilateral cleft lip and palate (70.24%) versus bilateral cleft lip and palate (29.76%; p < 0.0001), and these were also significant within each sex (p < 0.0001). In the database, there were more females (53.50%) with cleft palate only than males (46.50%) (p = 0.0002). Data reported here did not take into account infant mortality during the perinatal period. Nonetheless, this study provides estimates from the largest recorded body of data for clefts in the continent, therefore providing valuable information on the need for comprehensive cleft registries in Africa. Key words: Clefts, Africa, epidemiology.

Background Cephalometric analysis is used to evaluate facial growth, to study the anatomical relationships within the face. Cephalometric assessment is based on 2D radiographic images, either the sagittal or coronal planes and is an inherently inaccurate methodology. The wide availability of 3D imaging techniques, such as computed tomography and magnetic resonance imaging make routine 3D analysis of facial morphology feasible. 3D cephalometry may not only provide a more accurate quantification of the craniofacial morphology and longitudinal growth, but also the differentiation of subtle changes in occlusion. However, a reliable protocol for the computation of craniofacial symmetry and quantification of craniofacial morphology is still a topic of extensive research. Here, a protocol for 3D cephalometric analysis for both the identification of the natural head position (NHP) and the accurate quantification of facial growth and facial asymmetry is proposed and evaluated. A phantom study was conducted to assess the performance of the protocol and to quantify the ability to repeatedly and reliably align skulls with the NHP and quantify the degree of accuracy with which facial growth and facial asymmetry can be measured. Results The results obtained show that the protocol allows consistent alignment with the NHP, with an overall average error (and standard deviation) of just 0.17 (9.10e-6) mm, with variations of 0.21 (2.77e-17) mm in the frontonasal suture and 0.30 (5.55e-17) mm in the most prominent point in the chin. The average errors associated with simulated facial growth ranged from 1.83 to 3.75% for 2 years’ growth and from − 9.57 to 14.69% for 4 years, while the error in the quantification of facial asymmetry ranged from − 11.38 to 9.31%. Conclusions The protocol for 3D skull alignment produces accurate and landmark free estimation of the true symmetry of the head. It allows a reliable alignment of the skull in the NHP independently of user-defined landmarks, as well as an accurate quantification of facial growth and asymmetry.

Background Orofacial clefts are congenital malformations of the orofacial region, with a global incidence of one per 700 live births. Interferon Regulatory Factor 6 (IRF6) (OMIM:607199) gene has been associated with the etiology of both syndromic and nonsyndromic orofacial clefts. The aim of this study was to show evidence of potentially pathogenic variants in IRF6 in orofacial clefts cohorts from Africa. Methods We carried out Sanger Sequencing on DNA from 184 patients with nonsyndromic orofacial clefts and 80 individuals with multiple congenital anomalies that presented with orofacial clefts. We sequenced all the nine exons of IRF6 as well as the 5′ and 3′ untranslated regions. In our analyses pipeline, we used various bioinformatics tools to detect and describe the potentially etiologic variants. Results We observed that potentially etiologic exonic and splice site variants were nonrandomly distributed among the nine exons of IRF6, with 92% of these variants occurring in exons 4 and 7. Novel variants were also observed in both nonsyndromic orofacial clefts (p.Glu69Lys, p.Asn185Thr, c.175‐2A>C and c.1060+26C>T) and multiple congenital anomalies (p.Gly65Val, p.Lys320Asn and c.379+1G>T) patients. Our data also show evidence of compound heterozygotes that may modify phenotypes that emanate from IRF6 variants. Conclusions This study demonstrates that exons 4 and 7 of IRF6 are mutational ‘hotspots’ in our cohort and that IRF6 mutants‐induced orofacial clefts may be prevalent in the Africa population, however, with variable penetrance and expressivity. These observations are relevant for detection of high‐risk families as well as genetic counseling. In conclusion, we have shown that there may be a need to combine both molecular and clinical evidence in the grouping of orofacial clefts into syndromic and nonsyndromic forms.

Nonsyndromic orofacial clefting (OFC) describes a range of phenotypes that represent the most common craniofacial birth defects in humans, with an overall birth prevalence of 1:700 live births. Because of the lifelong negative implications on health and well-being associated with OFC and the numbers of people affected, quality research into its etiology, diagnosis, treatment outcomes, and preventative strategies is essential. A range of different methods is used for recording and classifying OFC subphenotypes, one of which is the International Classification of Diseases (ICD) system. However, there is a general perception that research is being hampered by a lack of sensitivity and specificity in grouping those with OFC into subphenotypes, with potential heterogeneity and confounding in epidemiologic, genetic, and genotype-phenotype correlation studies. This article provides a background to the necessity of OFC research, discusses current controversies within cleft subphenotyping, and provides a brief overview of current OFC classifications as well as their limitations. The LAHSHAL classification is described in the context of a potentially useful tool for OFC that could complement the ICD-10/ICD-11 Beta coding systems to become a simply understood, universally accepted, clinically friendly, and research-sensitive instrument. Empowering registries, clinicians, and researchers to use a common classification system would have significant implications for OFC research across the world at a time when accurate subphenotyping is crucial and health care research is becoming increasingly tailored toward the individual.

Objectives Nonsyndromic orofacial cleft (NSOFC) etiology is multifactorial and heterogeneous. This study aimed to identify environmental risk factors related to NSOFC in the Western Region of Saudi Arabia. Methods A case-control study carried out in seven hospitals in two main cities (Jeddah and Maddina) over 2 years on parents of 112 infants with NSOFC (infants were also examined) and 138 infant controls, matched for age (≤18 months), gender, and location, completed a questionnaire on 3-month pregestation and first trimester events. Results There was significantly increased NSOFC risk with twin pregnancies ( P = .01, odds ratio [OR] = 9.5, 95% confidence interval [CI]: 1.15 to 78.4), maternal antibiotic use ( P = .021, OR = 2.71, 95% CI: 1.11 to 6.62), antiemetic medication ( P = .005, OR = 2.85, 95% CI: 1.3 to 6), severe morning sickness ( P = .006, OR = 3.6, 95% CI: 1.34 to 9.65), illness ( P = .009, OR = 2.19, 95% CI: 1.17 to 4.08), common cold/flu ( P = .003, OR = 3.32, 95% CI: 1.48 to 7.58), Jorak smoking ( P = .004, OR = 14.07, 95% CI: 1.55 to 128.1), and passive smoking ( P = .05, OR = 2.05, 95% CI: 1.05 to 4.01). Reduced NSOFC risk was found with calcium supplementation ( P = .02, OR = 0.32, 95% CI: 0.11 to 0.88), incense use ( P = .03, OR = 0.58, 95% CI: 0.34 to 0.98), and maternal drinking water, with Zamzam water (which contains a high concentration of minerals) showing a significant protective effect compared with tap water ( P = .01, 95% CI: 0.06 to 0.6) and bottled water ( P = .02, 95% CI: 0.03 to 0.57). Conclusion Twin births, maternal antibiotic use, antiemetic medication, severe morning sickness, common cold/flu, Jorak smoking, and passive smoking were associated with infants born with NSOFC. Calcium supplementation, incense use, and Zamzam water reduced the risk of NSOFC, raising the possibility of community preventive programs.

Objective: To evaluate an automated software tool for the assessment of dental arch relationships using the modified Huddart and Bodenham (MHB) index. Design: Cohort of 43 models of subjects aged 9–21 with UCLP and the ten GOSLON reference models sets. Method: The 53 sets of plaster models were scored using the MHB index and scanned with a benchtop scanner. The digital models were MHB scored visually using a commercial software program and landmarked for automatic scoring using a software plug-in. Scoring/landmarking was undertaken by three observers and repeated after 1 month. Intra- and inter-observer reproducibility were tested using Cronbach’s alpha and intraclass correlation coefficients (ICC) (threshold > 0.9). Bland–Altman plots demonstrated inter-observer agreement for each model format. Random and systematic error with digital landmark identification error were determined using the x , y , and z co-ordinates for 28 models digitized twice 1 month apart using Cronbach’s alpha and a t -test, respectively. Results: Intra-operator landmark identification was excellent (Cronbach’s alpha = 0.933) with no differences between sessions ( P > 0.05). Intra-observer reproducibility was excellent for all examiners (Cronbach’s alpha and ICC 0.986–0.988). Inter-observer reproducibility was highest for the software plug-in (0.991), followed by plaster (0.989) and OrthoAnalyzer (0.979) and Bland–Altman plots confirmed no systematic bias and greater consistency of scores with the automated software. Conclusion: The automated MHB software tool is valid, reproducible, and the most objective method of assessing maxillary arch constriction for patients with UCLP. Conflict of interest statement: The authors declare no conflict of interest or financial relationship with any organization or software used within the study.

Photographs of a person smiling may provide valuable information about their anterior dentition. These images can be an alternative ante-mortem (AM) dental source in cases with no dental records, which gives the forensic odontologist a significant opportunity for comparative dental analysis. There are no reported studies that have investigated the reliability of a superimposition technique using 2D photographs of a smile and 3D dental models in dental identification. The aim of this study was to explore novel odontological methods by combining 2D photographs with 3D dental models, simulating a dental identification scenario. The objective was to increase the accuracy of dental identification using an AM photograph with the aid of 3D imaging as an alternative to post-mortem (PM) photographs. The study comprised of 31 3D dental models (simulating PM information) and 35 digital photographs (simulating AM information). The data was analysed in two phases: Phase I- Visual Comparison of 2D-3D images and Phase II- 2D-3D superimposition after a wash out period. Both methods were analysed by the principal investigator. Further, one-third (ten) of the sample was evaluated by six raters (three experienced forensic odontologists and three forensic odontology MSc. students). The inter-rater agreement was assessed using intra-class correlation (ICC 2, 1, absolute). The results of the study suggest that the inter-rater and intra-rater reliability using 3D superimposition was highest (ICC ≈ 1.0). In summary, there was an increase in match rates and higher certainty among the opinions reached when using the 2D-3D superimposition method. The procedure attempted to reduce the limitations of previously existing 2D methods and is intended to assist forensic experts with an alternative method in dental identification when expressing conclusions on a case using photographs.