Nonsyndromic orofacial clefts (OFCs) are common, heritable birth defects caused by both genetic and environmental risk factors. Despite the identification of many genetic loci harboring OFC-risk variants, there are many unknown genetic determinants of OFC. Furthermore, while the process of embryonic facial development is well characterized, the molecular mechanisms that underly it are not. This represents a major hurdle in understanding how disruptions in these biological processes result in OFC. Thus, we sought to identify novel OFC-risk loci through a genome-wide multi-ancestry study of five nested OFC phenotypes (isolated cleft lip [CLO], isolated cleft palate [CPO], cleft lip and palate [CLP], cleft lip with/without cleft palate [CL/P], and any cleft [ANY]) representing distinct cleft subtypes to identify subtype-specific signals and grouped types to maximize power to detect shared genetic effects. We performed genome-wide meta-analyses of these five OFC phenotypes from three cohorts totaling >14,000 individuals using METAL. In addition to replicating 13 known OFC-risk loci, we observed novel association in three regions: the 1p36.32 locus (lead variant rs584402, an intergenic variant, pCLO = 3.14e-8), the 7q33 locus (lead variant rs17168118, an intronic variant in CALD1, pCLP = 9.17e-9), and the 16p13.3 locus (lead variant rs77075754, an intronic variant in RBFOX1, pCL/P = 1.53e-9, pANY = 1.93e-9). We also observed a novel association within the known risk locus 8q22.1 that was independent of the previously reported signal (lead variant rs4735314, an intronic variant in ESRP1, pCLP = 1.07e-9, pCL/P = 3.88e-8). Next, we performed multi-tissue TWAS with s-MulTiXcan and identified four overlapping genes with significant genetically predicted transcription associated with OFC risk. These genes also overlapped the genome-wide significant association signals from the meta-analysis, including CALD1 and ESRP1 and known OFC-risk genes TANC2 and NTN1. Each of the newly reported loci has potential regulatory effects, including evidence of craniofacial enhancer activity, that offer new clues as to the molecule mechanisms underlying embryonic facial development.

Special educational needs (SEN) provision is designed to help pupils with additional educational, behavioural or health needs. Our aim was to assess the impact of early SEN provision on health and educational outcomes for a well-defined population, pupils with cleft lip and/or cleft palate (CLP) without additional anomalies. We used the ECHILD database, which links educational and health records across England. Our target population consisted of children with a recorded diagnosis of CLP without other major congenital anomalies in hospital admission records in ECHILD. We applied a trial emulation framework to define eligibility into our study and investigate the causal impact of SEN provision in the first year of compulsory school (Year 1 - age five/six years) on various health and educational outcomes accumulated by the end of primary education (Year 6 - age ten/eleven years). SEN provision was categorised as: None, SEN Support, and Education and Health Care Plan (EHCP). The outcomes were: unplanned hospital utilisation, medical and unauthorised school absences, persistent absences, and standardised key stage 1 (KS1) and key stage 2 (KS2) mathematics attainment scores. To account for confounding factors affecting the observed associations and estimate the causal effects of early SEN provision on these outcomes, we used three estimating approaches: propensity score-based methods (inverse probability weighting, [IPW]), g-computation, and augmented IPW (AIPW). Causal effects were measured in terms of average treatment effects (ATE) and average treatment effects on the treated (ATT), expressed as rate ratios (RaR) for hospitalisations and absences, risk ratios (RiR) for persistent absences, and mean differences (Δ) for academic scores. Missing values of the confounders were handled via the missing covariate indicator method. We triangulated these results with those obtained by univariable and multivariable regression. Our study included 6,601 children with CLP and without additional major congenital anomalies. Evaluations involving EHCP were limited by the low numbers of comparative children. Thus, only comparisons of SEN Support (N = 2,009, 31.6%) versus None (N = 4,350, 68.4%) are reported. Observed rates of unplanned hospitalisation (RaRcrude = 1.31, 95% confidence interval (CI): 1.12, 1.52), persistent absence (RiRcrude = 2.21 (1.87, 2.62)) and medical absence (RaRcrude = 1.34 (1.28, 1.40)) were higher amongst children with recorded SEN support, whilst KS1 and KS2 maths scores were lower (Δ crude = -0.85 (-0.90, -0.79) and Δ crude = -0.82 (-0.89, -0.75), respectively). Contrary to the observed relative rates and risks, we found small or no evidence of a causal effect of SEN Support on unplanned hospitalisation (ATE: RaRIPW = 1.16 (1.00, 1.34), RaRg = 0.99 (0.87, 1.12); RaRIAPW = 1.02 (0.87, 1.17) or persistent absences (ATE: RiRIPW = 1.13 (0.92, 1.34); RiRg = 1.08 (0.86, 1.31); RiRAIPW = 1.20 (0.96, 1.45)). We found that SEN support increased rates of medical absences (ATE: RaRIPW = 1.10 (1.04, 1.18); RaRg = 1.09 (1.03, 1.15); RaRAIPW = 1.04 (0.95, 1.13)), decreased those of unauthorised absences (RaRIPW = 0.86 (0.76, 0.97); RaRg = 0.98 (0.86, 1.09); RaRAIPW = 0.80 (0.66, 0.95)) and decreased - but not as extensively as the crude differences suggested- KS1 (ATE: Δ IPW = -0.18 (-0.25, -0.10); Δ g = -0.21 (-0.26, -0.16); Δ AIPW = -0.25 (-0.32, -0.17)) and KS2 maths scores (ATE: Δ IPW = -0.24 (-0.33, -0.15); Δ g = -0.27 (-0.33, -0.21); Δ AIPW = -0.24 (-0.32, -0.17)). Results for the ATT for each of these outcomes were similar to those for the ATE, indicating no observable evidence of heterogeneity of effects by treatment received. Sensitivity analyses confirmed the robustness of these results. In the population of children with CLP without further major congenital anomalies, assignment to receive or not receiving early SEN Support appears to have no harmful impact on the rates of unplanned hospitalisation or persistent absences, but to increase rates of medical absences, whilst reducing rates of unauthorised absences. For the sub-populations of children with key stage results, such hypothetical intervention does not appear to completely reduce the observed disadvantage in KS1 and KS2 mathematics scores. These results relate to the impact of the intention to intervene not the actual delivery of actual SEN Support provision as this information is not available in school administrative records. Furthermore, we cannot discount the impact of unaccounted confounding factors, such as parental education and early home learning environments, particularly for the education attainment results.

Orofacial clefts (OFCs) require complex care, which is further complicated by associated congenital anomalies and medical conditions. However, the specific patterns of these associated conditions across different OFC subtypes are not well-characterized in the Thai population. This study aimed to determine the prevalence of OFC subtypes and to analyze the distribution of associated congenital malformations, syndromes, and medical conditions specific to each cleft type. We conducted a retrospective analysis of 1,187 patients (0-3 years) treated at Tawanchai Cleft Center, Thailand, between 2011 and 2020. Cases were identified using ICD-10 codes and verified through medical records. Data were analyzed to determine OFC subtype prevalence and characterize the distribution of associated congenital malformations, syndromes, and medical conditions. Cleft lip and palate (CLP) was the most common subtype (49.2%), followed by isolated cleft palate (CP, 28.1%) and isolated cleft lip (CL, 22.7%). A significant portion of patients (45.4%) presented with at least one associated condition. Respiratory system malformations were most prevalent (35.3%), followed by circulatory (12.2%) and musculoskeletal system anomalies (11.1%). The prevalence of associated malformations was highest in the CP group, which was strongly associated with Pierre Robin Sequence (8.2%). Among the 7% of syndromic cases, 22q11.2 deletion syndrome was the most frequent diagnosis (9.6% of syndromic cases). Medically, otitis media (51.7%) and anemia (17.3%) were significant comorbidities across all groups. Our findings demonstrate that the profile of associated anomalies differs significantly across OFC subtypes. This underscores the necessity for subtype-specific screening protocols and highlights the high burden of comorbidity in this population, directing a multidisciplinary approach for effective management.

Gastroesophageal reflux has long been suspected in children with orofacial clefts, but its presence has remained unproven due to the absence of reliable diagnostic methods. The aim of this study was to evaluate the prevalence of acid reflux in children with isolated cleft lip (CL), cleft palate (CP), or cleft lip and palate (CLP), using pH-metry prior to primary surgery. A retrospective study that included patients evaluated between January 1988 and December 2017 was conducted at a tertiary academic centre. A total of 234 patients were included (52 with CL, 87 with CP, and 95 with CLP). The prevalence of acid gastroesophageal reflux disease (GERD) was 17.02% (95% CI: 6.80 to 27.23) in the CL group, 16.09% (95% CI: 8.36 to 23.81) in the CP group, and 19.38% (95% CI: 11.43 to 27.32) in the CLP group. No statistically significant differences were found between the groups in terms of reflux index or secondary pH-metry parameters. In conclusion, nearly one in five infants with an orofacial cleft is affected by acid GERD. Routine gastroenterological evaluation and follow up should be considered as part of the multidisciplinary management of this population.

Cleft lip and palate (CLP) abnormalities are common birth defects encompassing isolated cleft lip, cleft palate, or combined CLP. Current knowledge indicates that CLP has both genetic and environmental causes, with strong associations between a positive family history and maternal factors such as smoking, alcohol consumption, teratogenic substance use, and poor nutrition. The upper lip develops as a result of the fusion of the paired medial nasal prominences to the maxillary prominences, forming the philtrum and lateral portions of the upper lip, respectively. Cleft lip, therefore, arises from a failure in those named structures to fuse. The current best treatment involves surgical repair to reconstruct the lip to restore normal appearance and function, including feeding and speech. This normally occurs around the age of six months (standard time) in most centers, but is performed much earlier, in the neonatal period, in other centers. This study aims to determine whether neonatal cleft lip repair is superior to standard time repair. Secondary aims are to determine both the feasibility and the safety of neonatal repair. Advanced literature searches were carried out using Medline ALL (1946 to date) and Embase (1974 to date); 11 articles were deemed relevant and included in this study. Aesthetic results showed excellent outcomes with neonatal repair with regard to the appearance of the scar, facial (lip and nasal) symmetry, but those aesthetic results are no better than those achieved at standard time. Although early intervention can be beneficial as early repair takes place when the cleft is less severe and when the tissues are more malleable, making the surgery less challenging, and when some aspects of fetal scar healing remain. Additionally, early repair has a positive impact on the development of the alveolar projections and can assist in reducing an alveolar cleft if present, improving the aesthetic outcome. Moreover, neonatal surgery carries with it no greater risk than surgery carried out at six months and will allow feeding to begin at an early stage, promoting recovery. Early repair also brings with it a large positive psychosocial impact, where infants and mothers can build a normal relationship from an early stage. Later in life, children and adults will be less self-conscious following good aesthetic repair. In conclusion, based on the limited available evidence, neonatal repair may be recommended over standard time repair.