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INTRODUCTION: Orofacial clefts are among the most prevalent birth defects worldwide. Specialized treatment and surveillance of basic health needs are critical. Few studies have investigated primary care practitioners' experience in caring for individuals with clefts. OBJECTIVE: It was to describe experience and current interest of family care practitioners on the management of individuals with clefts. METHODS: Observational cohort of 104 practitioners from Maceió (AL) e Campinas (SP). Demographic, academic and professional characteristics, didactic experience and desire in continuing education on clefts were assessed using a questionnaire RESULTS:Seventy-four practitioners were located in Maceió and 30 in Campinas. Female gender and low academic qualification were predominant. Physicians and nurses prevailed over dentists, 78 (75%) participants had clinical experience with clefts. Use of protocols was mentioned by 3/104 (2.9%), provision of information on clefts by 58/104 (56%) and referrals to the Brazilian Reference Network by 7/104 (6.7%). Almost 50% reported didactic experience and 94%, desire on continuing education in this field CONCLUSION: Results corroborate the literature and reinforce the need of improving family care practitioners' skills to manage individuals with clefts. Education and strengthen ties between primary level of the health system and specialized teams must be focused. Some strategies are presented in this regard.

Objective: To analyze the pattern of cleft lip and cleft palate cases and their operative management at a tertiary-care hospital. Methods: Data of all patients (<18 year) with cleft lip and cleft palate operated between 2011 and 2016 were extracted from the records and analyzed. Results: The final analysis included 1643 cases (60.9% males). Mean (SD) age at the time of surgery was 8.9 (10.17) years. Left-sided cleft clip was more common. Complete hard palate type of cleft palate on left was present in 787 (47.90%). Primary Cleft Palate repair was most common procedure (492, 29.9% children, followed by primary lip nose unilateral in 458 (27.9%) and lip nose revision in 298 (21.1%). Conclusion: Data on age at presentation and procedures used for correction of cleft lip and cleft palate are presented. [ABSTRACT FROM AUTHOR]

Objectives: To assess the attitudes of pregnant women and mothers of children with orofacial clefts toward prenatal diagnosis of clefts and elective termination of pregnancy, and to investigate their opinion about who makes reproductive decisions in the family. Design: Two hundred subjects were included in the study prospectively regarding hypothetical prenatal ultrasound diagnosis of clefts. Setting: The study was done in a private tertiary care institution and a teaching hospital. Subjects/Participants: One hundred pregnant women consulting the Obstetrics department and 100 mothers of children with orofacial clefts in the Cleft and Craniofacial Unit were selected. Materials and Methods: Group I subjects were interviewed using a questionnaire and were shown preoperative and postoperative pictures of children treated for cleft lip and palate. Group II subjects were interviewed using a questionnaire. Results: Only 3% of Group I subjects and 2% of Group II opined that they would choose the elective termination of pregnancy if the fetus was diagnosed with a cleft on an ultrasound scan. In Group II, 70% subjects wished to have known about pregnancy affected with cleft prenatally and 96% said they would definitely avail ultrasound scans to determine pregnancy affected by clefts in future. Conclusions: Majority of the respondents from both the groups chose to continue with the pregnancy affected with a cleft when questioned regarding hypothetical prenatal ultrasound diagnosis of the cleft.

Patients with partial trisomy 3p seldom present major dysmorphic features, and holoprosencephaly occurs in only 10% of the cases with partial trisomy 3p. It has been suggested that multiple genetic hits or environmental exposures are required for the clinical expression of holoprosencephaly. At 16 weeks of gestation, prenatal sonography identified a fetus with holoprosencephaly, orofacial clefts, pyelectasis, and a unilateral duplex renal system. Amniocentesis revealed the karyotype of 46,XX,der(11)t(3;11)(p21;q23)pat with partial trisomy 3p (3p21→pter) and partial monosomy 11q (11q23→qter). The pregnancy was subsequently terminated. Postnatally, the proband showed hypotelorism, a depressed nasal bridge, orofacial clefts and holoprosencephaly-premaxillary agenesis. The present case provides evidence that partial trisomy 3p/monosomy 11q can be a genetic cause of holoprosencephaly and del(11)(q23→qter) is associated with a duplex renal system.

Background We examined whether prevalences of neural tube defects (NTDs), orofacial clefts, and gastroschisis changed more rapidly after than before folic acid fortification in California. Methods This population-based study used vital statistics and birth defects registry data. The study population included all live births and stillbirths delivered in central California counties from 1989 to 2010. Cases included deliveries with NTDs, orofacial clefts, and gastroschisis. Weighted least squares regression was used to estimate slopes during prefortification (before 1997) and postfortification (after 1998), respectively. The difference of the two slopes with the 95% confidence interval (CI) was calculated. Results For all NTDs combined, slopes indicated that NTD prevalence was decreasing by 8.7 (slope: -8.7; 95% CI, -13.5-−3.9) cases per 100,000 deliveries per year before fortification and by 1.7 (slope: -1.7; 95% CI, -3.7-0.3) after fortification; thus the decline had slowed by 7.0 (95% CI, 2.7-11.3) cases per 100,000 deliveries per year. For orofacial clefts, slopes for cleft lip with/without palate as well as for cleft palate alone indicated that the postfortification slope was lower than the prefortification slope suggesting a more accelerated decrease in the postfortification time period. For gastroschisis, the slope after fortification was lower compared with prefortification, indicating a less accelerated prevalence increase in the postfortification time period. Stratification by race/ethnicity did not substantially alter results. Conclusion We observed a slower decline in prevalence of NTDs, an emergence of a decline in orofacial clefts, and a slower increase in gastroschisis, during the postfortification period in central California, relative to the prefortification period. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1032-1041, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Animal models have shown evidence of the role of maternal methyl donor status and its metabolism (one-carbon metabolism) in normal embryonic maxillofacial development. Nevertheless, studies in humans have shown conflicting results for the association of maternal methylation status biomarkers in the aetiology of the main craniofacial birth defects: non-syndromic orofacial clefts (NSOFCs). The aim of this study was to perform a meta-analysis assessing the relationship between maternal levels of methylation status biomarkers (plasma and erythrocyte folates and plasma vitamin B12 and homocysteine) and the risk of NSOFCs. A literature search of the conventional and grey medical–scientific databases identified 12 studies considering these variables. Based on standardized differences between means among cases and controls (Cohen's d test), evidence was found of an association only with high plasma homocysteine ( d = 0.37; P = 0.026) when single effects were pooled. In addition to its usefulness as a marker of poor methyl-donor intake and/or metabolism, homocysteine appears to have a teratogenic effect. Although the results are based on a relatively small number of reports and/or studies of small sample sizes showing between-study heterogeneity, these problems were resolved by including an additional analysis. Therefore these findings constitute a real contribution towards explaining the complex aetiology of orofacial clefts. [ABSTRACT FROM AUTHOR]

Context: Nonsyndromic cleft lip with or without palate (NSCL ± P) is a genetic predisposition involving defects in shape and makeup of the lip and palate. Elevation of homocysteine (Hcy) levels is seen in medical complications such as developmental anomalies causing neural tube defects, congenital vascular diseases, neurodegenerative and psychiatric conditions. Evaluation of serum Hcy levels forms an important feature to look further into molecular aspects Aims: The aim of this study was to evaluate the Hcy levels in NSCL ± P cases by comparing with control cases having no orofacial deformities. Settings and Design: This study was performed with a biochemical assay in a research laboratory. Materials and Methods: A cross-sectional prevalence study was done to compare the concentrations of Hcy between 25 NSCL ± P patients and 15 healthy controls. Blood samples were collected from both the patients and controls and assessed for serum Hcy level using competent chemiluminescent immunoassay technique. Statistical Analysis Used: Student's t-test was used for statistical analysis. Results: The average Hcy concentration was 9.5 µmol/L in control group. There was an increase in Hcy concentration among the NSCL ± P cases with an average value of 18.4 μmol/L. The results were found to be statistically significant using Student's t-test. Conclusions: The results of this study indicate that Hcy concentration has a significant elevation in NSCL ± P patients when compared with that of control cases.. [ABSTRACT FROM AUTHOR]

Background: Shanxi Province is a region in China with a high incidence of orofacial clefts (OFCs). Our objective is to investigate the effect of maternal exposure to indoor air pollution (IAP) from coal combustion and tobacco smoke on the risk of an infant being born with orofacial clefts. Methods: Data were derived from an ongoing population-based case-control study of major external structural birth defects in Shanxi Province. Subjects included 213 cases with OFCs and 1319 healthy babies born between November 2002 and December 2014 in four rural counties. Exposure information was collected by face-to-face interview with mothers within 1 week of delivery or pregnancy termination. The authors derived an exposure index by integrating a series of IAP-related characteristics concerning dwelling and lifestyle. Results: Increased odds of OFC were associated with IAP exposure from heating (adjusted odds ratio [aOR] = 2.4; 95% confidence interval [CI], 1.2-4.5) and from smoking (aOR = 1.8; 95% CI: 1.3, 2.5), but not with exposure from cooking (aOR = 0.9; 95% CI, 0.6-1.4). Compared with women without IAP exposure, the aORs of OFC for children of women with exposure indices of 1, 2, 3 and ≥ 4 were 1.1 (95% CI, 0.6-1.8), 1.4 (95% CI, 0.8-2.4), 1.8 (95% CI, 1.0-3.2), and 3.4 (95% CI, 1.6-7.4), respectively, demonstrating a clear dose-response trend (p < 0.001). Conclusion: Periconceptional exposure to IAP from coal combustion and tobacco smoking may increase the risk of OFCs in offsprings of women in Shanxi Province. [ABSTRACT FROM AUTHOR]

Purpose: Children with orofacial clefts experience risks for psychosocial and behavioral problems, making it important to evaluate for negative impacts on health-related quality of life. The purpose of this study was to evaluate health-related quality of life (HRQOL) and surgical history to determine if these measures correlated with caries and/or behavior during dental treatment.Methods: Data for this retrospective study were obtained for children encountered between March 2011 and August 2013. Inclusion criteria were four- to 10-year-olds with a non-syndromic orofacial cleft diagnosis. Parent-reported HRQOL data were obtained for 79 children and child-reported data for a subgroup of 23. Pediatric Quality Of Life Inventory (PedsQL) scores, surgeries, and demographics were collected from craniofacial team medical charts. Decayed, missing, and filled teeth (dmft) and behavior (Frankl) scores were collected from dental records.Results: Significant correlations were found between total parent-reported sample PedsQL scores and dmft scores, and between the subgroup's PedsQL scores and Frankl scores.Conclusions: For children with orofacial clefts, higher caries was associated with lower health-related quality of life in the total parent-reported sample. Negative behavior was associated with lower HRQOL in eight- to 10-year-olds, who also more accurately reported psychosocial risks for negative behavior than parents by proxy. Surgeries were not associated with caries or behavior. [ABSTRACT FROM AUTHOR]

Background: We studied the role of maternal folic acid supplementation in modifying the effects of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) gene polymorphisms in Iranian children with oral clefts. Materials and Methods: Forty-seven newborn infants with orofacial cleft and their mothers were selected randomly. Mothers were matched regarding dietary folate intake. The genotyping on venous blood was carried out. Consistency between maternal and child genotypes was analyzed. Results: Genotype consistency was not statistically significant in both C677T and A1298C gene variants (P > 0.05). Conclusion: Maternal folic acid consumption may not have any significant effect on modifying C677T and A1298C polymorphisms in children. [ABSTRACT FROM AUTHOR]

Background Orofacial clefts ( OFCs) are common birth defects that may impose a large burden on the health and psychosocioeconomic well-being of affected individuals and families. This study aims to identify qualitative factors that affect the quality of life ( QOL) of family caregivers of children with OFCs. Methods A mixed-method study in which family caregivers of OFCs children were consecutively recruited from cleft clinics over a 3-month period. Quantitative data were analyzed using SPSS version 17 and focus group discussion by framework analysis. Results A total of 107 caregivers participated in the entire study, and 24 caregivers participated in the focus group discussions. About 50% of the children had cleft lip and palate ( CLP), 28% with cleft lips only ( CL) and 23.4% with cleft palate only ( CP). Poor access to specific information and lack of empathy of professionals affected the quality of life and delivery of family-centered care. Conclusions To improve the quality of life of family caregivers, individual-focused counseling sessions should be organized for caregivers soon after birth. This will provide an opportunity to discuss the laid out plans for supportive care. It will also be as an avenue to address the arising social issues by health professionals and counselors. [ABSTRACT FROM AUTHOR]

Background: Multidisciplinary management of orofacial clefts may lead to a successful treatment outcome. However, it is quite usual that lack of long-term treatment planning and collaboration among various specialists and lack of standardized surgical protocols result in poor esthetic and functional treatment outcomes. This article aims to hypothesize some critical determinants of outcome in cleft surgery. Methods: Throughout a period of 18 years, 900 patients with different clinical types of congenital cleft anomaly were subject to primary repair of cleft lip, nose, and palate by single surgeon using various procedures, including preoperative nasoalveolar molding, two-stage and one-stage repair of complete cleft lip and palate, two-flap and one-flap palatoplasty, open tip rhinoplasty, and postoperative nasal molding. Results: Clinical results of preoperative nasoalveolar molding and surgical repair of lip, nose, and palate were satisfactory for most patients, parents, and surgeon panel. Conclusions: Treatment based on the individual patient's facial assets and deficits must be the controlling factor in designing therapy. The essential key to successful management of clefts is to figure out the three-dimensional dynamics that govern the deformity and to recognize a fourth dimension for time along these dynamics in order to envision how a small difference in the position of a single suture during the first surgery can bring about a giant deformity upon completion of facial growth, hence the crucial role of the first surgery and its related concepts, techniques, and tactics in dictating the final outcome of the case. Level of Evidence: Level IV, therapeutic study. [ABSTRACT FROM AUTHOR]

The goal of this study was to evaluate the prevalence of orofacial clefts (OFCs) in Tennessee over the span of 2000–2017, and evaluate the effects of race/ethnicity, sex, maternal/paternal age and socioeconomic status on the prevalence. Records of all live births and demographics of newborns in Tennessee from 2000 to 2017 were requested from the Tennessee Department of Health to calculate the prevalence of OFCs. Data from United States Census was also obtained. Data provided were deidentified. Tennessee showed a significant decrease in prevalence rates of cleft lip, with and without cleft palate (CL ± P), when comparing the time periods of 2000–2007 to 2008–2017. A significant positive correlation was found with CL ± P prevalence rates in regions with higher Caucasian populations and a negative correlation in regions with higher African American populations. The CP prevalence rates showed a negative correlation with increased median household income. To our knowledge, this is the first study to show a significant negative correlation with median household income and CP prevalence rates. Our study showing an increase in prevalence rates of OFCs with decreased socioeconomic status indicates that the areas of Tennessee with the lowest median household income averages would likely benefit from understanding other possible modifiable factors that are driving this correlation. • The study evaluates OFC prevalence rate trends in TN from 2000 to 2007 to 2008–2017. • Cleft lip±palate (CL ± P) prevalence decreased in TN over the past two decades. • A positive correlation in birth rates of CL ± P and higher white population regions. • A negative correlation in birth rates of CP and higher median household income. [ABSTRACT FROM AUTHOR]

Introduction: Cleft lip and palate are the most common maxillofacial malformations. Despite advances in science and medicine, research on the etiology of cleft lip and palate has not fully elucidated all possible risk factors. Today, most orofacial clefts are thought to be caused by the interaction of hereditary and external factors (medications, smoking, harmful habits). Few studies have investigated the effects of complications during pregnancy on the development of orofacial clefts and related anomalies. Materials and methods: This is a prospective and retrospective study that included children with cleft lip and/or palate treated at the National Center of the Ministry of Health of the Republic of Croatia for Surgical Treatment of Maxillofacial Malformations from January 2020 to July 2022. The control group consisted of children with cleft lip and/or palate whose mothers had no complications during their pregnancy. Epidemiological and clinical data on the type, extent, and form of cleft formation and the occurrence of additional anomalies were collected in the clinical database and in questionnaires for parents. Results: Based on the data collected and analyzed so far, we found a significant difference between the studied groups. Conclusion: Various complications during pregnancy may influence the severity of orofacial cleft formation and the occurrence of additional malformations. [ABSTRACT FROM AUTHOR]

To describe the hearing thresholds of children under 3 years of age with cleft palate with or without cleft lip. This retrospective study from a tertiary care children's hospital included children with cleft palate ± cleft lip born between January 01, 2008, and December 31, 2015. All patients who had the initial palate repair at our institution and at least one behavioral audiogram were included. Behavioral audiograms collected either in the sound field or under insert earphones showed results from the better hearing ear. We collected demographic information, cleft type, parent report of newborn hearing screen, syndrome diagnosis, comorbid conditions, and dates of tympanostomy tube placement and palatoplasty. The main outcome measure was hearing status as measured by behavioral audiograms, and, for a subset of patients, brainstem auditory evoked responses (BAER). Results were grouped by test type (behavioral vs BAER) and characteristics at time of testing (pre- or post-palatoplasty, with or without tympanostomy tube placement) to evaluate the range of severity of hearing loss. Three hundred and sixty patients were included in the cohort. The cohort had two groups: Group 1 included 37 patients who had BAER results prior to surgery and behavioral audiogram results post-surgery; Group 2 included 322 patients who had behavioral audiograms pre-surgery (n = 206) and/or post-surgery (n = 215). The median age of patients at time of BAER in Group 1 was 3.00 months [IQR: 1.00,3.75]; pre-surgery BAER results showed mild (45.9%, n = 17) or moderate hearing loss (29.7%, n = 11) by this age. Patients in Group 2 with pre-surgery behavioral audiograms had a median age of 12.00 months [IQR: 11.00, 14.00] at time of audiogram. Most patients had a mild (33.5%, n = 69) or moderate hearing loss (31.1%, n = 64). Post-surgery, patients had a median age of 13.00 months [IQR: 11.00, 15.00] at time of hearing assessment and typically had normal hearing (86.0%, n = 185). In most patients, hearing improved after palate repair with concurrent tympanostomy tube placement. Most patients with cleft palate ± cleft lip had evidence of mild or moderate hearing loss prior to cleft palate repair, and hearing loss was evident from early infancy. Hearing improved after concurrent tympanostomy tube placement and palatoplasty. Further research is needed to understand the clinical significance of untreated transient hearing loss during the first year of life in this patient population. [ABSTRACT FROM AUTHOR]

Chromium (Cr) exposure during gestation causes malformations in animal experiments. In this multicenter case–control study, we initially involved 130 orofacial clefts (OFCs) and 260 controls to assess the association between Cr concentration and risk for OFCs. Then, umbilical cord serum (49 vs. 119) and cord tissue (84 vs. 142) were used to validate the association between Cr and OFCs. We found that maternal serum Cr concentrations in OFC cases were significantly higher than those in controls. Compared with the lowest tertile of maternal serum Cr concentration, the highest tertile of Cr increased the risk for OFCs [OR = 2.14 (1.14–4.05)]. In the validation cohort of umbilical cord serum and tissue, higher concentrations of Cr were associated with increased risks for OFCs in a dose-dependent manner (all Ps for trends <0.05). Cr concentrations in maternal serum and cord serum showed a positive correlation. The Cr concentration in cord serum was inversely correlated with egg and milk consumption frequencies, and the Cr concentration in cord tissue was positively associated with indoor coal burning. In conclusion, prenatal Cr exposure is a risk factor for OFCs, and indoor coal burning during pregnancy may be one of the sources of Cr exposure. [Display omitted] • Higher Cr levels in maternal serum, cord serum, and cord tissue increase OFC risk. • Cr concentrations in maternal serum were positively correlated to those in cord serum. • Cr concentrations in cord tissue were reversely correlated to those in cord serum. [ABSTRACT FROM AUTHOR]

Orofacial clefting is a common birth defect with wide phenotypic variability. Many systems have been developed to classify cleft patterns to facilitate diagnosis, management, surgical treatment, and research. In this review, we examine the rationale for different existing classification schemes and determine their inter-relationships, as well as strengths and deficiencies for subclassification of clefts of the lip. The various systems differ in how they describe and define attributes of cleft lip phenotypes. Application and analysis of the cleft lip classifications reveal discrepancies that may result in errors when comparing studies that use different systems. These inconsistencies in terminology, variable levels of subclassification, and ambiguity in some descriptions may confound analyses and impede further research aimed at understanding the genetics and etiology of clefts, development of effective treatment options for patients, as well as cross-institutional comparisons of outcome measures. Identification and reconciliation of discrepancies among existing systems is the first step towards creating a common standard to allow for a more explicit interpretation that will ultimately lead to a better understanding of the causes and manifestations of phenotypic variations in clefting.

Studies have identified the risk factors like folic acid deficiency during gestational period, family history for orofacial clefts, drugs like antiepileptic, vitamin A. But, the data regarding the folic acid status in children with cleft lip/palate is hardly evaluated in depth. Here, an assessment of folic acid and DNA damage were carried out in children with orofacial anomalies. Folic acid level and DNA damage were evaluated by folic acid assay (direct chemiluminescent technology) and single cell gel electrophoresis or comet assay method respectively. The mean value of plasma folic acid by direct chemiluminescent technology was 6.5±3.6 nmol/L and the normal value in children ranges from 11.3 to 47.6 nmol/L. The amount of damaged DNA, measured as the tail length of the comet in cases, was 19.4±8.9 ?m and the mean percentage of DNA in tail was 16.5±3.7. Folic acid deficiency could be the reason for DNA damage.

To analyse the morphological presentation of orofacial clefts, gender, syndromes and systemic anomalies associated with them., This was an epidemiological study performed in the patients who were registered for cleft lip and palate surgeries in our centre. The data was evaluated both retrospectively as well as prospectively., The patients registered from November 2006 to April 2021 were studied. Out of 5276 patients, data of 5004 cases were analysed, rest 272 patients were excluded due to lack of information. Statistical analysis and Chi square test were applied., Cleft deformities were more common in males than females. Cleft lip with palate was the commonest phenotype (52.2%). It was followed by isolated cleft lip (22.9%), isolated cleft palate (22.1%), rare clefts (1.62%) and syndromic clefts (1.18%). Unilateral variants were more frequent than bilateral. In unilateral, left side was more common than the right side. Among bilateral, most of the cases had premaxillary protrusion. In the present study, 3.46% of all the patients had associated anomalies affecting their other organs. Less common cleft phenotypes like microform cleft lip and submucous cleft palate ± bifid uvula showed frequency of 0.62% and 0.64% respectively., Thorough examination of cleft deformity should be done as it may appear as an isolated deformity or part of a syndrome and have associated systemic anomalies. This may help us to deliver comprehensive care to the patients and can prevent potential operative complications.

Aim and Objective: To report on the prevalence and patterns of orofacial clefts (OFC) among Saudi Arabian children by analyzing the results of the studies that have been reported in the literature., Materials and Methods: A data search was carried out for the articles that had reported on the prevalence of OFC among the Saudi Arabian population in databases like Web of Science, PubMed, Google Scholar, Scopus, and Saudi Digital Library. Articles that were published over the last 15 years were included in this study, following which 13 studies were assessed for qualitative data. Newcastle-Ottawa Quality Assessment Scales for cross-sectional studies were used for analyzing the methodological quality of these studies., Results: The prevalence of OFC was within the range of 0.65-1.9/1,000 live births. The highest was witnessed in the Medina region. Parent's consanguinity was the most common risk factor in OFC cases in the included studies. OFC was found to be higher among the male population in comparison with the female., Conclusion: The prevalence of OFC in Saudi Arabian children follows the global patterns of OFC. Isolated cleft lip (CL) and cleft palate (CP) are the most common forms of OFC. The prevalence of orofacial anomalies was reported more among children born to parents who had consanguineous marriages. Considering the higher rate of consanguinity among this population, there is an urgent need of developing educational and counseling programs to address the genetic consequences., How to Cite This Article: Albalawi F Alsaeed S, Alalola B, et al. Prevalence and Patterns of Orofacial Clefts among Children from Different Regions of Saudi Arabia: A Systematic Review. Int J Clin Pediatr Dent 2023;16(1):124-130., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2023; The Author(s).)

This chapter reviews the evidence of gene×environment interactions (G×E) in the etiology of orofacial cleft birth defects (OFCs), specifically cleft lip (CL), cleft palate (CP), and cleft lip with or without cleft palate (CL/P). We summarize the current state of our understanding of the genetic architecture of nonsyndromic OFCs and the evidence that maternal exposures during pregnancy influence risk of OFCs. Further, we present possible candidate gene pathways for these exposures including metabolism of folates, metabolism of retinoids, retinoic acid receptor signaling, aryl hydrocarbon receptor signaling, glucocorticoid receptor signaling, and biotransformation and transport. We review genes in these pathways with prior evidence of association with OFCs, genes with evidence from prior candidate gene G×E studies, and genes identified from genome-wide searches specifically for identifying G×E. Finally, we suggest future directions for G×E research in OFCs., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Orofacial clefts are the most prevalent birth defects that affect craniofacial structures and implicate genetic and environmental factors in their aetiology. Maternal metabolic state and nutrition have been related to these and other structural malformations, and studies of maternal obesity before pregnancy have shown controversial results about its association with the risk of orofacial clefts in their offspring. Our aim was to assess the combined effect of several single studies of maternal obesity on the risk of orofacial clefts using meta-analysis. We searched for these reports in the PubMed database, and selected 8 studies that met our criteria for eligibility. As a result of this analysis, and using maternal normal weight as a reference, we found that maternal obesity does increase the risk of orofacial clefts in their offspring (OR 1.18, 95% CI 1.11 to 1.26). When these clefts are considered separately, maternal obesity is associated with cleft lip with or without cleft palate (OR 1.13, 95% CI 1.04 to 1.23), and with cleft palate alone (OR 1.22, 95% CI 1.09 to 1.35). Our results support the relation between maternal obesity and orofacial clefts, and confirm two previous meta-analyses that considered fewer studies. However, the molecular mechanisms underlying this statistical evidence have not been fully elucidated. [ABSTRACT FROM AUTHOR]

Objectives Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common craniofacial birth defects and little is known about its aetiology. Initial studies of cytogenetic analysis provided the clues for possible genes involved in the pathogenesis of NSCL/P. This approach led to the identification of SATB2 gene on 2q32-q33. The aim of this study was to determine the association between SATB2 mutations and NSCL/P. Materials and methods The rs137853127, rs200074373 and rs1992950 mutations of the SATB2 gene were investigated in 173 patients with NSCL/P and 176 normal controls using Kbioscience KASPar chemistry, which is a competitive allele-specific PCR SNP genotyping system. Results The mutations in exon 6 (rs137853127 and rs200074373) were monomorphic, the intronic variant (rs1992950) was polymorphic and genotype distribution was in agreement with Hardy–Weinberg equilibrium. The rs1992950 genotype distribution is not statistically significant between NSCL/P and controls. Conclusion Our findings suggest that the SATB2 gene variations do not contribute to the development of NSCL/P in the south Indian population. [ABSTRACT FROM AUTHOR]

Objective Non-syndromic cleft lip, with or without cleft palate (NSCL/P) is a common craniofacial birth defect, characterised by an incomplete separation between nasal and oral cavities without any other congenital anomaly in humans. Several genes which play a role in cell differentiation, migration, growth and apoptosis, have been associated with clefting. The purpose of this study was to investigate the association between single-nucleotide polymorphisms (SNPs) near MSX1 gene and NSCL/P among South Indian population. Methods A case-control analysis of five single nucleotide polymorphisms near MSX1 gene (rs11726039, rs868257, rs6446693, rs1907998 and rs6832405) was carried out in 173 patients with NSCL/P and 176 unaffected controls to determine their association with NSCL/P. Results All SNPs were polymorphic in the study population. Comparisons of allele and genotype frequencies revealed that the C variant allele and the TC/CC genotypes of rs11726039 was significantly higher in controls than in the NSCL/P group (OR: 0.63; 95% CI: 0.41 − 0.097; p = 0.037). However, neither of these findings remained significant after Bonferroni correction for multiple comparisons. The frequencies of rs868257, rs6446693, rs1907998 and rs6832405 minor alleles and genotypes were similar between the control and NSCL/P groups. No significant linkage disequilibrium (LD) was observed. Genotype-genotype interaction and the haplotype analysis did not reveal any significant association with NSCL/P. Conclusions The study results were suggestive of a positive association between MSX1 rs11726039 and NSCL/P in the South Indian population. [ABSTRACT FROM AUTHOR]

BACKGROUND Nonresponse bias assessment is an important and underutilized tool in survey research to assess potential bias due to incomplete participation. This study illustrates a nonresponse bias sensitivity assessment using a survey on perceived barriers to care for children with orofacial clefts in North Carolina. METHODS Children born in North Carolina between 2001 and 2004 with an orofacial cleft were eligible for inclusion. Vital statistics data, including maternal and child characteristics, were available on all eligible subjects. Missing 'responses' from nonparticipants were imputed using assumptions based on the distribution of responses, survey method (mail or phone), and participant maternal demographics. RESULTS Overall, 245 of 475 subjects (51.6%) responded to either a mail or phone survey. Cost as a barrier to care was reported by 25.0% of participants. When stratified by survey type, 28.3% of mail respondents and 17.2% of phone respondents reported cost as a barrier. Under various assumptions, the bias-adjusted estimated prevalence of cost as barrier to care ranged from 16.1% to 30.0%. Maternal age, education, race, and marital status at time of birth were not associated with subjects reporting cost as a barrier. CONCLUSION As survey response rates continue to decline, the importance of assessing the potential impact of nonresponse bias has become more critical. Birth defects research is particularly conducive to nonresponse bias analysis, especially when birth defect registries and birth certificate records are used. Future birth defect studies which use population-based surveillance data and have incomplete participation could benefit from this type of nonresponse bias assessment. Birth Defects Research (Part A) 103:603-609, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The article presents a study comparing the academic outcomes between children with orofacial cleft (OFC) and children without major birth defects. The study involved a random sample of mothers of children aged 5-12 years with isolated OFC identified by the North Carolina Birth Defects Monitoring Program (NCBDMP) and unaffected children. It finds that most children with OFC are successful in school but may be more likely to have poorer academic outcomes than their peers without birth defects.

Our main aim was to investigate the association between the interferon regulatory factor (IRF6) gene and non-syndromic cleft lip and palate (nsCLP) in the Xinjiang Uyghur population. Twelve single nucleotide polymorphisms (SNP) were screened in a group of 100 patients with nsCLP and in a control group of 60 unaffected subjects by next generation sequencing using a MiSeq Benchtop Sequencer (Illumina). Our case–control association analysis showed that the SNP marker rs7545538 differed significantly in genotype (codominant model; CC compared with CG compared with GG; p = 0.038) and allele frequencies (odds ratio (OR) = 1.89, 95% CI 1.18–3.03, p = 0.007) between patients with nsCLP and controls. Analysis of the recessive model of inheritance showed that distribution of the recessive model of rs7545538 (GG compared with CC + GC) was significantly higher in patients with nsCLP than in controls (OR = 2.5, 95% CI 1.13–5.37, p = 0.021) and had a borderline association with an increased risk of nsCLP (OR = 2.5, 95% CI 1.13–5.37, p = 0.021). Markers rs2235377 and rs2235371 also differed significantly in dominant and over-dominant models of inheritance ( p = 0.037) while increased G allele frequency was seen in SNP rs2235373 ( p = 0.03). A haplotype analysis showed four common haplotypes in Block 1: CCGGT > CCGAT > CACAT > TAGAC (in frequency). The 5-marker combination haplotype CCGAT was significantly more common in patients with nsCLP than in controls ( p = 0.032). In Block 2, the overall distribution of the haplotypes TAC and TAG predicted by the three SNP differed significantly between the patients with nsCLP and control subjects ( p = 0.009 and 0.003, respectively). Our results showed that genetic polymorphism of the IRF6 gene is associated with increased risk of nsCLP in a Xinjiang Uyghur population. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to identify direct AP2a target genes implicated in craniofacial morphogenesis. Design: AP2α, a product of the TFAP2A gene, is a master regulator of neural crest differentiation and development. AP2α is expressed in ectoderm and in migrating cranial neural crest (NC) cells that provide patterning information during orofacial development and generate most of the skull bones and the cranial ganglia. Mutations in TFAP2A cause branchio-oculo-facial syndrome characterized by dysmorphic facial features including cleft or pseudocleft lip/ palate. We hypothesize that AP2α primes a distinctive group of genes associated with NC development. Human promoter ChlP-chip arrays were used to define chromatin regions bound by AP2α in neural crest progenitors differentiated from human embryonic stem cells. Results: High-confidence AP2α-binding peaks were detected in the regulatory regions of many target genes involved in the development of facial tissues including MSX1, IRF6, TBX22, and MAFB. In addition, we uncovered multiple single-nucleotide polymorphisms (SNPs) disrupting a conserved AP2a consensus sequence. Conclusions: Knowledge of noncoding SNPs in the genomic loci occupied by AP2a provides an insight into the regulatory mechanisms underlying craniofacial development. [ABSTRACT FROM AUTHOR]

Background: Orofacial clefts (OFC) are common congenital malformations in humans. They impact negatively on the life of the affected and often regarded as stigma in the society especially among the rural folks. The aim of this study was to analyze retrospectively the cases managed by a Ghanaian indigenous plastic surgery outreach team and prospectively outline the social impacts on the lives of those treated and their communities. Methods: The study reviewed the medical records of patients treated during OFC outreaches in rural Ghana from January 2003 to December 2012 (10 years). This involved visiting and interviewing patients and their parents/relatives, as well as the community leaders comprising chiefs, assemblymen, church leaders, etc., using structured pretested questionnaires within 5 days (September 1-5, 2013) in communities in southeast of Ghana. Results: A total of 32 outreach services were handled over the 10-year period, treating 303 OFC patients (among other pathologies), comprising 175 (57.8 %) males and 128 (42.2 %) females. Out of the 303, 159 (52.5 %) were located and interviewed; also, 65 community/opinion leaders/relatives were interviewed. Sixty-one percent (61 % = 35 patients) of the females and 48 % ( n = 49) of the males got married after the surgery; 83 % ( n = 45) of the school-going-age patients continued and completed basic schools. Conclusions: OFC outreaches help to restore the lives and dignity of cleft patients and their families improving their quality of life. Stigmatization and psychological effects on them were removed; they were well accepted in their societies and family gatherings. Level of Evidence: Level III, risk-prognostic study. [ABSTRACT FROM AUTHOR]

Background Little is known about population-based maternal, child, and system characteristics associated with high hospital resource use for children with orofacial clefts (OFC) in the US. Methods This was a statewide, population-based, retrospective observational study of children with OFC born between 1998 and 2006, identified by the Florida Birth Defects Registry whose records were linked with longitudinal hospital discharge records. We stratified the descriptive results by cleft type [cleft lip with cleft palate, cleft lip, and cleft palate] and by isolated versus nonisolated OFC (accompanied by other coded major birth defects). We used Poisson regression to analyze associations between selected characteristics and high hospital resource use (≥90th percentile of estimated hospitalized days and inpatient costs) for birth, postbirth, and total hospitalizations initiated before age 2 years. RESULTS Our analysis included 2,129 children with OFC. Infants who were born low birth weight (<2500 grams) were significantly more likely to have high birth hospitalization costs for CLP (adjusted prevalence ratio: 1.6 [95% confidence interval: 1.0-2.7]), CL (adjusted prevalence ratio: 3.0 [95% confidence interval: 1.1-8.1]), and CP (adjusted prevalence ratio: 2.3 [95% confidence interval: 1.3-4.0]). Presence of multiple birth defects was significantly associated with a three- to eleven-fold and a three- to nine-fold increase in the prevalence of high costs and number of hospitalized days, respectively; at birth, postbirth before age 2 years and overall hospitalizations. Conclusion Children with cleft palate had the greatest hospital resources use. Additionally, the presence of multiple birth defects contributed to greater inpatient days and costs for children with OFC. Birth Defects Research (Part A) 103:127-143, 2015 © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Our objective was to evaluate associations between twinning and maternal demographic factors and periconceptional exposures among infants with and without orofacial clefts. Methods We used data from the National Birth Defects Prevention Study; 228 twins and 8242 singletons without birth defects (controls), and 117 twins and 2859 singletons with orofacial clefts, born 1997 to 2007, were included in the analyses. Because of the occurrence of twinning due to the use of assisted reproductive technologies, logistic regression models were computed to estimate odds ratios and 95% confidence intervals for each exposure, stratified by fertility treatment use. To evaluate factors by zygosity, we used sex-pairing data and a simulation approach to estimate the zygosity of like-sex twin pairs for unassisted conceptions. Results Among control mothers who did not use fertility treatments, predictors of twinning included non-Hispanic black maternal race (adjusted odds ratio, 1.6; 95% confidence interval, 1.0-2.4), and tobacco smoking (adjusted odds ratio, 1.6; 95% confidence interval, 1.1-2.4). Among control mothers who used fertility treatments, older maternal age, higher income, and state of residence were associated with twinning. Associations were generally stronger among mothers of dizygotic (estimated) twins than monozygotic (estimated) twins. Results for mothers of infants with isolated orofacial clefts were similar to those of controls. Conclusion We observed an increased twinning frequency with increasing maternal age, but factors such as maternal race/ethnicity and socioeconomic status may also contribute. Among women receiving fertility treatments, factors associated with twinning suggested a relation with treatment specifics (e.g., treatment type and number of embryos implanted) and availability of insurance coverage. Birth Defects Research (Part A) 103:85-99, 2015 © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objective: To contribute to the understanding of potential genetic differences between different cleft types. Method: Analysis of family history concerning cleft type and search for cleft-type-specific associations in candidate genes performed in 98 individuals from 98 families. Results: In a given family, the cleft type of a second case was more often identical to the index case than expected by chance. Each type of cleft (cleft lip [CL], cleft lip and palate [CLP], cleft palate only [CP], and submucous cleft palate only [SMCP]) was associated with different genes. Conclusion: Family history indicates some specificity of cleft types. The observed phenotype-genotype associations were compatible with this interpretation in that significant associations occurred with disjoint sets of genes in each cleft type. These observations indicate that CL, CLP, CP, and SMCP might represent genetically different entities. [ABSTRACT FROM AUTHOR]

Classification systems proposed are based on the cleft lip and palate morphology and a few are based on the embryonic principles, the main aim to propose these classification systems was to ease the treatment planning. Not only this it helps the patient to name, grade, remember, plan and discuss the clinical scenario. Some of the classifications are Tessier type, Veau, and Davis and Ritchie classifications. The American Cleft Palate Association and Kernahan and Stark classifications probably represent the best variable systems today, and they are presented in some detail for comparison. But a more standard classification is still awaited. [ABSTRACT FROM AUTHOR]

Background: We studied the role of maternal folic acid supplementation in modifying the effects of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) gene polymorphisms in Iranian children with oral clefts. Materials and Methods: Forty-seven newborn infants with orofacial cleft and their mothers were selected randomly. Mothers were matched regarding dietary folate intake. The genotyping on venous blood was carried out. Consistency between maternal and child genotypes was analyzed. Results: Genotype consistency was not statistically significant in both C677T and A1298C gene variants (P > 0.05). Conclusion: Maternal folic acid consumption may not have any significant effect on modifying C677T and A1298C polymorphisms in children.

© 2014 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

BACKGROUND: According to the 2014 Surgeon General's Report, smoking in early pregnancy can cause orofacial clefts. We sought to examine the implications of this causal link for the potential prevention of orofacial clefts in the United States. METHODS: Using published data on the strength of the association between orofacial clefts and smoking in early pregnancy and the prevalence of smoking at the start of pregnancy, we estimated the attributable fraction for smoking as a cause of orofacial clefts. We then used the prevalence of orofacial clefts in the United States to estimate the number of orofacial clefts that could be prevented in the United States each year by eliminating exposure to smoking during early pregnancy. We also estimated the financial impact of preventing orofacial clefts caused by maternal smoking based on a published estimate of attributable healthcare costs through age 10 for orofacial clefts. RESULTS: The estimated attributable fraction of orofacial clefts caused by smoking in early pregnancy was 6.1% (95% uncertainty interval 4.4%, 7.7%). Complete elimination of smoking in early pregnancy could prevent orofacial clefts in approximately 430 infants per year in the United States, and could save an estimated $40.4 million in discounted healthcare costs through age 10 for each birth cohort. CONCLUSION: Understanding the magnitude of the preventable burden of orofacial clefts related to maternal smoking could help focus smoking cessation efforts on women who might become pregnant. Birth Defects Research (Part A) 100:822-825, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Little is known about the barriers faced by families of children with birth defects in obtaining healthcare. We examined reported perceived barriers to care and satisfaction with care among mothers of children with orofacial clefts. Methods In 2006, a validated barriers to care mail/phone survey was administered in North Carolina to all resident mothers of children with orofacial clefts born between 2001 and 2004. Potential participants were identified using the North Carolina Birth Defects Monitoring Program, an active, state-wide, population-based birth defects registry. Five barriers to care subscales were examined: pragmatics, skills, marginalization, expectations, and knowledge/beliefs. Descriptive and bivariate analyses were conducted using chi-square and Fisher's exact tests. Results were stratified by cleft type and presence of other birth defects. Results Of 475 eligible participants, 51.6% ( n = 245) responded. The six most commonly reported perceived barriers to care were all part of the pragmatics subscale: having to take time off work (45.3%); long waits in the waiting rooms (37.6%); taking care of household responsibilities (29.7%); meeting other family members' needs (29.5%); waiting too many days for appointments (27.0%); and cost (25.0%). Most respondents (72.3%, 175/242) felt 'very satisfied' with their child's cleft care. Conclusion Although most participants reported being satisfied with their child's care, many perceived barriers to care were identified. Due to the limited understanding and paucity of research on barriers to care for children with birth defects, including orofacial clefts, additional research on barriers to care and factors associated with them are needed. Birth Defects Research (Part A) 100:837-847, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]