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BACKGROUND: Clefts of the lip and palate (CL/P) and cleft palate (CP) are the most common craniofacial congenital anomalies. Clefts are classified as syndromic and nonsyndromic. Nonsyndromic clefts have no known genetic causes. OBJECTIVES: This study combines prospective and retrospective studies to review the patterns of CL/P and CP and associated syndromes and conditions in patients registered for CL/P surgery at a tertiary care pediatric center in our tertiary care hospital in Saudi Arabia. METHODS: It included patient data from May 2015 through April 2023. Patient record forms and SPSS (IBM version 20.0) were used to collect and analyze data. A significance level of 5% was used, with p ≤ 0.05 considered statistically significant. RESULTS: Of the 319 patients who met our inclusion criteria, 175 were male. Of the total, 99 had a left unilateral isolated cleft lip, 61 had a right unilateral isolated cleft lip, 69 had a bilateral cleft lip, and 90 had an isolated CP. Of the total, 140 had CL/P. Around 242 were nonsyndromic. The Chi-square test revealed a significant association between the prevalence of isolated CP and CLP and gender. The prevalence of left unilateral isolated cleft lip and bilateral and isolated CP was significantly associated with syndromic and nonsyndromic cases. CONCLUSION: Males are more likely to be affected by orofacial clefts, which is consistent with the global trend. Isolated CP was the most common orofacial cleft. Within the sample, syndromes' association with orofacial clefts was significantly weaker than that of isolated and bilateral clefts.

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The aim of this systematic review is to describe and identify the prospects of ß-Tricalcium Phosphate (ß-TCP) as an alveolar bone grafting (ABG) material in cleft lip/palate (CL/P) or alveolar bone cleft defects. A systematic review protocol based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA 2020) was drafted. The literature search was conducted using MEDLINE/PubMed, Web of Science/ISI Web of Knowledge, Scopus, and the Cochrane Library, with English as the inclusion criterion and no publication year limits. The keywords yielded a total of 5824 publications. After removing duplicates and non-English articles, there were 3196 suitable articles available for evaluation. Subsequently, 1315 studies remained after reviewing titles and abstracts. Furthermore, 85 full articles were assessed for eligibility. After reading the complete texts of those papers, 20 were eventually selected that matched the inclusion requirements. Thirteen out of the twenty studies included in this systematic review were deemed to have a low risk of bias; one had a high risk of bias; and six had a moderate risk of bias due to not reporting randomization. ß-TCP, when used as an ABG material, is biocompatible, visible, practical, offers a less invasive procedure, and does not interfere with orthodontic treatment. Synthetic ß-TCP for ABG can be an alternative to autologous bone grafts under certain terms and conditions. The efficacy of ß-TCP for ABG in CL/P or alveolar bone cleft defects can be enhanced through a tissue engineering approach that combines ß-TCP with growth factors, mesenchymal stem cells, or other graft materials, along with modifications to ß-TCP's physical properties.

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BACKGROUND: This study aimed to investigate the effect of LAMA5 on palatal development in mice. METHODS: The palatine process of C57BL/6 J fetal mice on the embryonic day 13.5 (E13.5) was cultured in vitro via the rotating culture method. The LAMA5-shRNA adenovirus vector was constructed, then transfected into the palatal process of E13.5 for 48 h in vitro. A fluorescence microscope was used to visualize the fusion of palates. The expression of LAMA5 was also detected. The expression of ki67, cyclin D1, caspase 3, E-cadherin, vimentin and SHH signaling pathway-related signaling factors in the blank control group, the negative control group, and the LAMA5 interference group were detected after virus transfection. RESULTS: The bilateral palates in the LAMA5 interference group were not fused after virus transfection. PCR and WB showed that the mRNA and protein expressions of LAMA5 were decreased in the LAMA5 interference group. Furthermore, the mRNA and protein expressions of ki67, cyclin D1 and gli1 were decreased in the LAMA5 interference group, while the mRNA and protein expressions of caspase 3 were increased. However, the mRNA and protein expression of E-cadherin, vimentin, Shh and ptch1 did not significantly change in the LAMA5 interference group. CONCLUSIONS: LAMA5 silencing causes cleft palate by inhibiting the proliferation of mouse palatal cells and promoting apoptosis, which may not be involved in EMT. LAMA5 silencing can also cause cleft palate by interfering with the SHH signaling pathway.

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OBJECTIVES: To preliminarily analyze factors that affected the prevalence of anxiety in Chinese patients with cleft lip and/or palate (CL/P). METHODS: The Generalized Anxiety Disorder Scale (GAD-7) was used to screen anxiety in Chinese CL/P patients. Non-CL/P individuals were also included as the control group. Sociodemographic and clinical data consisting of diagnosis, gender, only child or not, monthly household income, and current family location were collected to analyze possible factors that could affect the anxiety of this patient population. RESULTS: One hundred forty-two and 78 valid questionnaires were collected from the study and control groups, respectively. The mean GAD-7 score of the study group (3.092 ± 3.381) was significantly lower than the control (3.987 ± 2.505). Moreover, the proportion of patients presenting with moderate-severe anxiety was larger in the study group than in the control group (6.6 vs. 0.0%). Statistically significant differences in GAD-7 scores were observed between the study and control groups when the patient was the only child, living in an urban area, or the monthly household income was between 1,000 and 5,000 yuan. CONCLUSION: Although the severity of anxiety in Chinese CL/P patients was not severer than those without CL/P, there was a relatively high incidence of moderate-severe anxiety in CL/P patients, while the only child, current family location and the monthly household income played significant roles in affecting anxiety psychology.

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BACKGROUND: Patients born with cleft lip and/or palate (CL/P) have orthodontic treatment challenges due to maxilla deficiency, malocclusions, and dental abnormalities. In Norway, orthodontic treatment is done by centralized CL/P teams. Due to traveling restrictions, this treatment might be done locally in the future. The experience of Norwegian community orthodontists in managing such patients has not been investigated previously. OBJECTIVE: To assess Norwegian orthodontists' management of patients with CL/P and need for further education. MATERIAL AND METHODS: All orthodontists in Norway were sent a questionnaire about their experience, challenges, and knowledge and asked about their need of further theoretical education and clinical training in the management of patients with CL/P. RESULTS: Norwegian orthodontists' standard of knowledge of CL/P treatment is adequate. However, few respondents have treated a high number of cleft patients. Eighty-six percent of the participants believed that treating CL/P patients involves challenges, such as time-consuming treatment and technical difficulties. Increased perceived need for more education was revealed among participants stated unpreparedness during education (4 folds), encountered challenges, and lack of knowledge (almost 3 folds). CONCLUSIONS: The study revealed that community orthodontists in Norway lack experience and acknowledged the challenges in treating patients with CL/P. Most of the respondents perceived a need for additional education and clinical training to treat CL/P patients competently. The findings suggested more focus on patients with CL/P management in the curricula and more collaboration between centralized CL/P teams and community orthodontists.

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OBJECTIVE: This article summarizes the recent literature on noncoding ribonucleic acids (ncRNAs) in relation to cleft lip with or without palate and exosomes and their usage in craniofacial diseases. BACKGROUND: Cleft lip with or without cleft palate (CL/P) is a common congenital malformation with genetic and environmental risk factors that affects numerous children and families. Surgical procedures can correct deformations; however, residual sequelae remain after surgery. Studies exploring the pathogenesis of CL/P are crucial for its early diagnosis and treatment and can inform treatment strategy decisions, etiology searches, and treatment during pregnancy. Recently, research has shown that most disease-related genes are ncRNAs, which are important transcripts in the human transcriptome. ncRNAs include microRNAs, long noncoding RNAs, and circular RNAs. These ncRNAs play essential roles in various pathophysiological processes, including cell proliferation, migration, apoptosis, and epithelial-mesenchymal transition. Previous studies on protein-coding genes have identified a number of genes related to CL/P; however, the pathogenesis of CL/P has not yet been thoroughly explained. Exosomes are vehicles that transfer various bioactive molecules between cells and represent a new method of intercellular communication. Research has shown that exosomes are related to some craniofacial diseases. METHODS: We searched the PubMed database for recently published English-language articles using the following keywords: "cleft lip with or without palate," "noncoding RNA," "exosomes," and "craniofacial diseases". We then reviewed the retrieved articles. CONCLUSIONS: As exosomes serve as cellular communicators and the palate consists of epithelial and mesenchymal cells, communication between the two cell types may affect its formation. Thus, exosomes could represent a new indicator and mediator of CL/P.

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Orofacial clefts (OFCs) rank as the second most common congenital birth defect in the United States after Down syndrome and are the most common head and neck congenital malformations. They are classified as cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO). OFCs have significant psychological and socio-economic impact on patients and their families and require a multidisciplinary approach for management and counseling. A complex interaction between genetic and environmental factors contributes to the incidence and clinical presentation of OFCs. In this comprehensive review, the embryology, classification, epidemiology and etiology of clefts are thoroughly discussed and a "state-of-the-art" snapshot of the recent advances in the genetics of OFCs is presented.

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This study explored the secondary school transition experiences of children with cleft lip and/or palate (CL/P). Data were collected via semi-structured interviews and analysed using interpretative phenomenological analysis (IPA). Participants were recruited from a National Health Service (NHS) specialist cleft service covering a large geographical area in the United Kingdom. Six participants with CL/P (aged 11-12 years old) in their first 12 months following transition to secondary school were interviewed. Four themes describe participants' transition experiences: (a) managing and valuing difference: the impact on self-worth and identity; (b) managing and valuing difference within the social context; (c) disclosure and the process of informing others about CL/P; and (d) developing positive peer relationships. Children with CL/P experience several psychosocial challenges during the transition to secondary school. Professionals involved with working with and supporting these children (and their families), such as psychologists, school nurses or wellbeing staff, child psychiatrists, social workers, mental health nurses and paediatricians, should attend to these issues when preparing for this transition in order to foster resilience and adjustment.

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OBJECTIVE: To analyze the population prevalence and birth prevalence of oral clefts in Colombia from 2009 to 2017. METHODS: A cross-sectional study using information from the National Administrative Records of Colombia. The data came from 2 types of administrative records (Surveillance System and the Individual Registry of Service Provision) and the oral health national survey. Population prevalence and birth prevalence by type of cleft lip and/or cleft (CL/P) ratios were calculated using Poisson distribution for count data and to assess stationary tests on time series (Dickey-Fuller) and (Phillips-Perron) was used. RESULTS: Population prevalence in Colombia was 3.27 per 10 000 inhabitants (95% confidence interval [CI], 3.21-3.32) and birth prevalence was 6.0 per 10 000 live births (95% CI, 5.67-6.35). Bogotá have the highest population prevalence with CL/P. In the analysis of trends for the prevalence proportion by type of clefts in newborn babies with cleft, it was observed that the highest proportion was for babies with CLP. Cleft lip (CL) has increased from 17.4% in 2014 to 34.2% in 2017, cleft palate (CP) has decreased from 32.9% to 20.2%; and CLP changed from 49.6% to 45.5% in the same period. CONCLUSIONS: The population prevalence was 3.27 per 10 000 inhabitants. Births prevalence was 6.0 per 10 000 live births, and Orinoquia and Amazonia have higher rates than the national average. The administrative registers are adequate systems to know the behavior of oral clefts. The CL/P had a nonstationary trend during the period 2014 to 2017.

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BACKGROUND: Cleft lip and palate is one of the most common human birth defects, but the underlying etiology is poorly understood. The A/WySn mouse is a spontaneously occurring model of multigenic clefting in which 20% to 30% of individuals develop an orofacial cleft. Recent work has shown altered methylation at a specific retrotransposon insertion downstream of the Wnt9b locus in clefting animals, which results in decreased Wnt9b expression. RESULTS: Using a newly developed protocol that allows us to measure morphology, gene expression, and DNA methylation in the same embryo, we relate gene expression in an individual embryo directly to its three-dimensional morphology for the first time. We find that methylation at the retrotransposon relates to Wnt9b expression and morphology. IAP methylation relates to shape of the nasal process in a manner consistent with clefting. Embryos with low IAP methylation exhibit increased among-individual variance in facial shape. CONCLUSIONS: Methylation and gene expression relate nonlinearly to nasal process morphology. Individuals at one end of a continuum of phenotypic states display a clinical phenotype and increased phenotypic variation. Variable penetrance and expressivity in this model is likely determined both by among-individual variation in methylation and changes in phenotypic robustness along the underlying liability distribution for orofacial clefting.

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Orofacial clefting represents the most common craniofacial birth defect. Cleft lip with or without cleft palate (CL/P) is genetically distinct from cleft palate only (CPO). Numerous transcription factors (TFs) regulate normal development of the midface, comprising the premaxilla, maxilla and palatine bones, through control of basic cellular behaviors. Within the Pbx family of genes encoding Three Amino-acid Loop Extension (TALE) homeodomain-containing TFs, we previously established that in the mouse, Pbx1 plays a preeminent role in midfacial morphogenesis, and Pbx2 and Pbx3 execute collaborative functions in domains of coexpression. We also reported that Pbx1 loss from cephalic epithelial domains, on a Pbx2- or Pbx3-deficient background, results in CL/P via disruption of a regulatory network that controls apoptosis at the seam of frontonasal and maxillary process fusion. Conversely, Pbx1 loss in cranial neural crest cell (CNCC)-derived mesenchyme on a Pbx2-deficient background results in CPO, a phenotype not yet characterized. In this study, we provide in-depth analysis of PBX1 and PBX2 protein localization from early stages of midfacial morphogenesis throughout development of the secondary palate. We further establish CNCC-specific roles of PBX TFs and describe the developmental abnormalities resulting from their loss in the murine embryonic secondary palate. Additionally, we compare and contrast the phenotypes arising from PBX1 loss in CNCC with those caused by its loss in the epithelium and show that CNCC-specific Pbx1 deletion affects only later secondary palate morphogenesis. Moreover, CNCC mutants exhibit perturbed rostro-caudal organization and broadening of the midfacial complex. Proliferation defects are pronounced in CNCC mutants at gestational day (E)12.5, suggesting altered proliferation of mutant palatal progenitor cells, consistent with roles of PBX factors in maintaining progenitor cell state. Although the craniofacial skeletal abnormalities in CNCC mutants do not result from overt patterning defects, osteogenesis is delayed, underscoring a critical role of PBX factors in CNCC morphogenesis and differentiation. Overall, the characterization of tissue-specific Pbx loss-of-function mouse models with orofacial clefting establishes these strains as unique tools to further dissect the complexities of this congenital craniofacial malformation. This study closely links PBX TALE homeodomain proteins to the variation in maxillary shape and size that occurs in pathological settings and during evolution of midfacial morphology.

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OBJECTIVE: Nonsyndromic clefts of the lip and/or palate (NSCL/P) are one of the most common polygenic diseases. Recently, many studies focused on the association between CRISPLD2 polymorphisms and NSCL/P risk. However, some studies have shown opposite results. In this study, meta-analysis was used to confirm whether CRISPLD2 polymorphism was associated with NSCL/P, and the possible mechanism between CRISPLD2 and NSCL/P was explored. METHODS: Relevant studies were conducted on PubMed, Ovid, EBSCO, CINAHL, FMRS, Web of Science, CNKI, and Wanfang databases from their inception up to June 31, 2016. Review Manager 5.0.24 was used to analyze whether CRISPLD2 polymorphism was involved in NSCL/P by pooling odds ratios (ORs) and 95% confidence intervals (CIs). Potential publication bias was evaluated by visual inspection of the funnel plot. RESULTS: CRISPLD2 rs4783099 was associated with cleft lip and/or palate (CL/P) statistically (OR = 3.18, P < .01). Compared to genotype TT, genotypes CC and CT were correlated significantly (OR = 2.04, P = .04) with CL/P. No evidence showed an association between genetic variation at the CRISPLD2 locus and cleft palate only (CP). CONCLUSION: The polymorphism of CRISPLD2 rs4783099 is correlated with an increased risk of CL/P.

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Results from previous studies on maternal folic acid intake and infant oral clefts are inconclusive. The aim of the present study was to investigate the association between women's use of folic acid and/or multivitamin supplements and the risk for oral cleft in the newborn. We used data from the Medical Birth Registry of Norway based on all births in Norway from 1999 to 2013. A total of 528 220 women had 880 568 pregnancies, resulting in 896 674 live births and stillbirths, of which 1623 had oral clefts (isolated oral clefts, n 1311; non-isolated oral clefts, n 312). Altogether, 21·5% of women were vitamin supplement users before pregnancy. The birth prevalence of oral clefts was 1·81/1000 live births and stillbirths. Relative risks (RR) were estimated with log-binomial regression. For pregnancies with maternal use of vitamins, the adjusted RR for clefts overall was 0·90 (95% CI 0·79, 1·04). The adjusted RR for cleft palate only (n 586) was 0·84 (95% CI 0·66, 1·06) and that for cleft lip with or without cleft palate (n 1037) was 0·94 (95% CI 0·79, 1·13). Associations were stronger for cleft cases that occurred in combination with other malformations (adjusted RR 0·63; 95% CI 0·45, 0·88), although vitamin supplements provided no protection against isolated clefts (adjusted RR 0·98; 95% CI 0·84, 1·15). In conclusion, our study demonstrates no statistically significant association between vitamin use and isolated oral clefts. However, we found lower risk for oral clefts that occurred in combination with other malformations.

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Tissue- and cell-type-specific regulators of alternative splicing (AS) are essential components of posttranscriptional gene regulation, necessary for normal cellular function, patterning, and development. Mice with ablation of Epithelial splicing regulatory protein (Esrp1) develop cleft lip and palate. Loss of both Esrp1 and its paralog Esrp2 results in widespread developmental defects with broad implications to human disease. Deletion of the Esrps in the epidermis revealed their requirement for establishing a proper skin barrier, a primary function of epithelial cells comprising the epidermis. We profiled the global Esrp-mediated splicing regulatory program in epidermis, which revealed large-scale programs of epithelial cell-type-specific splicing required for epithelial cell functions. These mice represent a valuable model for evaluating the essential role for AS in development and function of epithelial cells, which play essential roles in tissue homeostasis in numerous organs, and provide a genetic tool to evaluate important functional properties of epithelial-specific splice variants in vivo.

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Objective Nonsyndromic cleft lip with or without cleft palate (NS-CL/P) are among the most common congenital birth defects worldwide. Several lines of evidence point to the involvement of folate, as well as folate metabolizing enzymes in risk reduction of orofacial clefts. Dihydrofolate reductase (DHFR) enzyme participates in the metabolic cycle of folate and has a crucial role in DNA synthesis, a fundamental feature of gestation and development. A functional polymorphic 19-bp deletion within intron-1 of DHFR has been associated with the risk of common congenital malformations. The present study aimed to evaluate the possible association between DHFR 19-bp deletion polymorphism and susceptibility to NS-CL/P in an Iranian population. Material and Methods The current study recruited 100 NS-CL/P patients and 100 healthy controls. DHFR 19-bp deletion was determined using an allele specific-PCR method. Results We observed the DHFR 19-bp homozygous deletion genotype (D/D) vs. homozygous wild genotype (WW) was more frequent in controls than in NS-CL/P patients (25% vs. 13%), being associated with a reduced risk of NS-CL/P in both codominant (OR=0.33, P=0.027) and recessive (OR=0.45, P=0.046) tested inheritance models. We also stratified the cleft patients and reanalyzed the data. The association trend for CL+CL/P group compared to the controls revealed that the DD genotype in both codominant (OR=0.30, P=0.032) and recessive models (OR=0.35, P=0.031) was associated with a reduced risk of CL+CL/P. Conclusions Our results for the first time suggested the DHFR 19-bp D/D genotype may confer a reduced risk of NS-CL/P and might act as a protective factor against NS-CL/P in the Iranian subjects. .

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Genome-wide association studies (GWAS) for orofacial clefts have identified several susceptibility regions, but have largely focused on non-Hispanic White populations in developed countries. We performed a targeted genome-wide study of single nucleotide polymorphisms (SNPs) in exons using the Illumina HumanExome+ array with custom fine mapping of 16 cleft susceptibility regions in three underserved populations: Congolese (87 case-mother, 210 control-mother pairs), Vietnamese (131 case-parent trios), and Filipinos (42 case-mother, 99 control-mother pairs). All cases were children with cleft lip with or without cleft palate. Families were recruited from local hospitals and parental exposures were collected using interviewer-administered questionnaires. We used logistic regression models for case-control analyses, family-based association tests for trios, and fixed-effect meta-analyses to determine individual SNP effects corrected for multiple testing. Of the 16 known susceptibility regions tested, SNPs in four regions reached statistical significance in one or more of these populations: 1q32.2 (IRF6), 10q25.3 (VAX1), and 17q22 (NOG). Due to different linkage disequilibrium patterns, significant SNPs in these regions differed between the Vietnamese and Filipino populations from the index SNP selected from previous GWAS studies. Among Africans, there were no significant associations identified for any of the susceptibility regions. rs10787738 near VAX1 (P = 4.98E-3) and rs7987165 (P = 6.1E-6) were significant in the meta-analysis of all three populations combined. These results confirm several known susceptibility regions and identify novel risk alleles in understudied populations.

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Objective:To study the association of TGF?2 polymorphisms and maternal smoking with the occurrence of nonsyndromic cleft lip and palate(NSCLP). Methods:TGF?2 genes were amplified from peripheral leukocytes by means of PCR in 272 cases of nonsyndromic cleft lip with or without palate(CL/P), 251 of cleft palate only(CPO) and 312 of unrelated controls in Jilin Province, PCR products were analyzed by single-stranded conformation polymorphism(SSCP) and DNA sequencing. Maternal smoking was investigated. The association of TGF?2 polymorphisms, maternal smoking with the occurrence of CL/P and CPO was analyzed by SAS statistic system. Results:The 322 bp PCR product of TGF?2 was amplified from CL/P, CPO and control samples; SSCP analysis showed three alleles of TGF?2;sequencing results showed that allele1, allele2 and allele3 contained seven, eight and nine ACA repeats respectively. The statistic analysis showed that TGF?2 polymorphisms or maternal smoking was associated with the occurrence of CL/P and CPO respectively(P0.05).Conclusion:TGF?2 polymorphisms and maternal smoking during pregnancy are associated with the occurrence of CL/P and CPO. TGF?2 polymorphisms have no interaction with maternal smoking.