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Objective: To study the effect of infant orthopedics on facial appearance. Design: Prospective two-arm randomized controlled trial in parallel with three participating academic cleft palate centers. Treatment allocation was concealed and performed by means of a computerized balanced allocation method. Setting: Cleft Palate Centers of Amsterdam, Nijmegen, and Rotterdam, the Netherlands. Patients: Infants with complete unilateral cleft lip and palate, no other malformations. Interventions: One group (IO+) wore passive maxillary plates during the first year, the other group (IO−) did not. Main Outcome Measure(s): Two metrical response modalities were used (i.e., visual analog scales and reference scores) to score facial appearance. Full face and cropped photographs were compared with reference photographs and were judged. The photographs were judged by 45 judges, 24 laypeople, and 21 professionals. Transformation of the scores into z scores was applied to compare and to pool both response modalities. The validity of each individual judge was evaluated, as was the reliability of the scales. Differences between the treatment groups were evaluated by means of t tests. Results: Photographs were available of 41 subjects, 21 with and 20 without infant orthopedics. No significant differences were found between groups. Mean z-score values for the full-face photographs were: group IO+ = 0.10 (SD = 0.73) and group IO− = −0.03 (SD = 0.48); for the cropped photographs were: group IO+ = 0.12 (SD = 0.71) and group IO− = −0.06 (SD = 0.55). Conclusions: Infant orthopedics have no effect on facial appearance.

Cleft lip and palate (CLP) is one of the most common congenital anomalies, affecting ~1 in 700 births worldwide. Patients with CLP often experience functional impairments due to the cleft palate, particularly related to feeding and speech. Surgical interventions are essential for addressing these issues, yet no standardized surgical procedure exists. Velar adhesion (VA) is a technique used to reduce the cleft width prior to a palatoplasty, potentially improving surgical outcomes, but its effectiveness remains unclear. The impact of VA on cleft-width reduction and the incidence of otitis media with effusion (OME) were evaluated in patients with unilateral cleft lip and palate (UCLP). The cases of 45 patients with UCLP who underwent a palatoplasty at the University of Tokyo Hospital between January 2013 and December 2023 were analyzed retrospectively. We divided the patients into two groups: those who underwent VA during lip repair (VA group) and those who did not (non-VA group). The cleft width and alveolar cleft width were measured at birth, lip repair, and palatoplasty. The presence of OME was assessed the day before the palatoplasty. Pearson's chi-square test and the two-tailed t-test were applied. Significant cleft-width reduction was observed in the VA group compared to the non-VA group at the time of palatoplasty (4.58 mm vs. 6.55 mm, p < 0.01). The incidence of OME was significantly lower in the VA group (60.00%) versus the non-VA group (90.91%, p < 0.01). No significant between-group differences were identified for the alveolar cleft width or maxillary growth. VA significantly reduces the cleft width at the junction of the hard and soft palates, and it may decrease the incidence of otitis media with effusion in patients with UCLP. VA is a straightforward procedure with potential benefits for improving palatoplasty outcomes and mitigating complications such as OME.

Objective: To evaluate the effect of infant orthopedics (IO) on facial appearance of 54 patients with unilateral cleft lip and palate (UCLP), aged 4 and 6 years. Design: Prospective two-arm randomized controlled clinical trial in three Cleft Palate Centers in the Netherlands (Dutchcleft-trial). Interventions: Patients were divided randomly into two groups. Half of the patients (IO+) had a plate until surgical closure of the soft palate at the age of ± 52 weeks; the other half (IO−) received no intervention. Main Outcome Measures: Facial appearance at 4 and 6 years of age assessed on full face photographs and photographs showing only nose and mouth. Ratings were performed on a VAS-scale by professionals and laymen. Results: At 4 years of age the full face pictures of IO+ children were scored to be more attractive than those of IO− children. However, this difference had disappeared at 6 years of age. At the age of 6, only professionals saw a significant difference on nasolabial photographs between IO+ and IO−. Regression analysis showed a minor effect of occlusion, lip revision, or type of nose reconstruction on the esthetic results. Conclusions: IO had a positive effect on full facial appearance of UCLP children at the age of 4 years, but at the age of 6, only professionals saw a positive effect of IO on the nasolabial photographs. This is irrelevant for UCLP patients since they deal with laymen in their daily life.

Craniofacial bone defect anomalies affect both soft and hard tissues and can be caused by trauma, bone recessions from tumors and cysts, or even from congenital disorders. On this note, cleft/lip palate is the most prevalent congenital craniofacial defect caused by disturbed embryonic development of soft and hard tissues around the oral cavity and face area, resulting in most cases, of severe limitations with chewing, swallowing, and talking as well as problems of insufficient space for teeth, proper breathing, and self-esteem problems as a consequence of facial appearance. Spectacular advances in regenerative medicine have arrived, giving new hope to patients that can benefit from new tissue engineering therapies based on the supportive action of 3D biomaterials together with the synergic action of osteo-inductive molecules and recruited stem cells that can be driven to the process of bone regeneration. However, few studies have focused on the application of tissue engineering to the regeneration of the cleft/lip and only a few have reported significant advances to offer real clinical solutions. This review provides an updated and deep analysis of the studies that have reported on the use of advanced biomaterials and cell therapies for the regeneration of cleft lip and palate regeneration.

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, p CLO  = 3.14e-8), the 7q33 locus (lead variant rs17168118, an intronic variant in CALD1 , p CLP  = 9.17e-9), and the 16p13.3 locus (lead variant rs77075754, an intronic variant in RBFOX1 , p CL/P  = 1.53e-9, p ANY  = 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 , p CLP  = 1.07e-9, p CL/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.

Non-syndromic cleft lip with/without cleft palate (nsCL/P) is one of the most common birth defects and has a multifactorial etiology. To date, over 45 loci harboring common risk variants have been identified. However, the effector genes at these loci, and the cell types that are affected by risk alleles, remain largely unknown. To address this, we combined genetic data from an nsCL/P genome-wide association study (GWAS) with single-cell RNA sequencing data obtained from the heads of unaffected human embryos. Using the recently developed single-cell disease relevance score (scDRS) approach, we identified two major cell types involved in nsCL/P development, namely the epithelium and the HAND2 + pharyngeal arches (PA). Combining scDRS with co-expression networks and differential gene expression analysis, we prioritized nsCL/P candidate genes, some of which were additionally supported by GWAS data (e.g., CTNND1 , PRTG , RPL35A , RAB11FIP1 , KRT19 ). Our results suggest that specific epithelial and PA sub-cell types are involved in nsCL/P development, and harbor a substantial fraction of the genetic risk for nsCL/P.

Cleft lip with or without cleft palate (CL/P) is the most commonly occurring craniofacial birth defect. We provide insight into the genetic etiology of this birth defect by performing genome-wide association studies in two species: dogs and humans. In the dog, a genome-wide association study of 7 CL/P cases and 112 controls from the Nova Scotia Duck Tolling Retriever (NSDTR) breed identified a significantly associated region on canine chromosome 27 (unadjusted p=1.1 x 10(-13); adjusted p= 2.2 x 10(-3)). Further analysis in NSDTR families and additional full sibling cases identified a 1.44 Mb homozygous haplotype (chromosome 27: 9.29 - 10.73 Mb) segregating with a more complex phenotype of cleft lip, cleft palate, and syndactyly (CLPS) in 13 cases. Whole-genome sequencing of 3 CLPS cases and 4 controls at 15X coverage led to the discovery of a frameshift mutation within ADAMTS20 (c.1360_1361delAA (p.Lys453Ilefs*3)), which segregated concordant with the phenotype. In a parallel study in humans, a family-based association analysis (DFAM) of 125 CL/P cases, 420 unaffected relatives, and 392 controls from a Guatemalan cohort, identified a suggestive association (rs10785430; p =2.67 x 10-6) with the same gene, ADAMTS20. Sequencing of cases from the Guatemalan cohort was unable to identify a causative mutation within the coding region of ADAMTS20, but four coding variants were found in additional cases of CL/P. In summary, this study provides genetic evidence for a role of ADAMTS20 in CL/P development in dogs and as a candidate gene for CL/P development in humans.

François Spitz and colleagues identify cis -acting enhancers of Myc in a region orthologous to human 8q24 that are required for normal development of the face in mice. Their results shed light on the role of this region in facial deformities in humans, including cleft lip and palate. Cleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations observed in humans, with 1 occurrence in every 500–1,000 births 1 , 2 . A 640-kb noncoding interval at 8q24 has been associated with increased risk of non-syndromic CL/P in humans 3 , 4 , 5 , but the genes and pathways involved in this genetic susceptibility have remained elusive. Using a large series of rearrangements engineered over the syntenic mouse region, we show that this interval contains very remote cis -acting enhancers that control Myc expression in the developing face. Deletion of this interval leads to mild alteration of facial morphology in mice and, sporadically, to CL/P. At the molecular level, we identify misexpression of several downstream genes, highlighting combined impact on the craniofacial developmental network and the general metabolic capacity of cells contributing to the future upper lip. This dual molecular etiology may account for the prominent influence of variants in the 8q24 region on human facial dysmorphologies.

Cleft lip and/or primary palate (CL/P) represent a prevalent congenital malformation, the aetiology of which is highly intricate. Although it is generally accepted that the condition arises from failed fusion between the upper lip and primary palate, the precise mechanism underlying this fusion process remains enigmatic. In this study, we utilized transposase‐accessible chromatin sequencing (scATAC‐seq) and single‐cell RNA sequencing (scRNA‐seq) to interrogate lambdoidal junction tissue derived from C57BL/6J mouse embryos at critical stages of embryogenesis (10.5, 11.5 and 12.5 embryonic days). We successfully identified distinct subgroups of mesenchymal and ectodermal cells involved in the fusion process and characterized their unique transcriptional profiles. Furthermore, we conducted cell differentiation trajectory analysis, revealing a dynamic repertoire of genes that are sequentially activated or repressed during pseudotime, facilitating the transition of relevant cell types. Additionally, we employed scATAC data to identify key genes associated with the fusion process and demonstrated differential chromatin accessibility across major cell types. Finally, we constructed a dynamic intercellular communication network and predicted upstream transcriptional regulators of critical genes involved in important signalling pathways. Our findings provide a valuable resource for future studies on upper lip and primary palate development, as well as congenital defects.

Orofacial cleft disorders, including cleft lip and/or palate (CL/P), are one of the most frequently-occurring congenital disorders worldwide. The health issues of patients with CL/P encompass far more than just their anatomic anomaly, as patients with CL/P are prone to having a high incidence of infectious diseases. While it has been previously established that the oral microbiome of patients with CL/P differs from that of unaffected patients, the exact nature of this variance, including the relevant bacterial species, has not been fully elucidated; likewise, examination of anatomic locations besides the cleft site has been neglected. Here, we intended to provide a comprehensive review to highlight the significant microbiota differences between CL/P patients and healthy subjects in various anatomic locations, including the teeth inside and adjacent to the cleft, oral cavity, nasal cavity, pharynx, and ear, as well as bodily fluids, secretions, and excretions. A number of bacterial and fungal species that have been proven to be pathogenic were found to be prevalently and/or specifically detected in CL/P patients, which can benefit the development of CL/P-specific microbiota management strategies.