Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.
Female ; Animals ; Mice ; Humans ; Child, Preschool ; Intellectual Disability/genetics* ; Heart Defects, Congenital/genetics* ; Facies ; Cleft Palate ; Muscle Hypotonia

Background: One of the early problems that children born with cleft lip and palate encounter is difficulty in feeding. This affects the child’s nutritional needs and the timing of the surgical intervention. Information on the appropriate feeding methods for children with cleft lip and palate will enable mothers to feed their babies properly and facilitate the implementation of appropriate interventions. Objectives: The study described the feeding problems experienced by children with cleft lip and palate (CLP), and cleft palate (CP) ages 0-24 months, the feeding methods most preferred by Filipino mothers, the methods they found most useful, and the mothers’ reactions to the feeding issues their children face. Methods. The research is a pilot study which used a quantitative, cross-sectional, descriptive mixed method design. Thirty-two (32) mothers of children with cleft lip and palate, and cleft palate answered an 11-item online survey and participated in focused interviews from January to June 2022. Inferential statistics was used specifically frequency distribution to describe the data, and Fishers’ Exact Test and Pearson’s Chi-Square Test were used to analyze the data quantitatively to determine the significant association between the variables identified. Results: Results showed that the feeding problems encountered by the children included nasal regurgitation, sucking, aspiration of liquids, latching on nipples, and swallowing. Mothers preferred to use regular feeding bottles (24.3%), specialized feeding bottles for children with cleft (21.6%), breast feeding and dropper (17.6%), syringe (9.5%), cup (6.8%), and spoon feeding (2.7%) methods. They also mentioned that they found the following feeding methods to be the most useful, regular feeding bottles (32.7%), specialized feeding bottles for cleft (23.1%), breast feeding (11.5%), spoon and dropper feeding (7.7%), and syringe feeding (1.9%). Conclusion The feeding problems experienced by Filipino children with CLP and CP mirror those that have been reported in other studies. The study revealed that mothers still prefer to use the traditional regular feeding bottles in feeding their babies and found this to be the most useful. Maternal reactions of the participants to the cleft condition and its feeding issues are similar to reported studies in other countries. The internet has been the primary source of information on cleft and feeding of the participants in the study.
Feeding Methods ; Cleft Lip ; Palate

OBJECTIVES: This study aimed to explore the relationship between alveolar cleft and secondary nasal deformity post unilateral cleft lip repair in adults. METHODS: A total of 27 patients aged 16-30 years old with unilateral secondary nasal deformity and alveolar cleft were included, 13 of whom underwent bone grafting. Spiral CT data of all preoperative and postoperative patients who had alveolar bone grafting were collected. Then, Mimics software was used for three-dimensional reconstruction to evaluate the correlation between the width, height, and volume of the alveolar cleft and those of the nasal deformity. The difference in nasal deformity before and after alveolar bone grafting was also explored. RESULTS: The width of the alveolar cleft was positively correlated with the difference in bilateral nostril floor width (P<0.05). As the effective depth of the alveolar cleft increased, the sub-alare inclination angle largened (P<0.05). However, no significant difference was found in the nasal deformity between before and after alveolar bone grafting. CONCLUSIONS Alveolar cleft is closely related to secondary nasal deformities post unilateral cleft lip repair, especially nasal floor deformities. Alveolar bone grafting benefits adult patients for the improvement of secondary nasal deformities post unilateral cleft lip repair.
Humans ; Adult ; Adolescent ; Young Adult ; Nose/surgery* ; Cleft Lip/surgery* ; Rhinoplasty/methods* ; Imaging, Three-Dimensional ; Treatment Outcome ; Cleft Palate/complications*

OBJECTIVE: To explore the genetic characteristics of a Chinese pedigree affected with van der Woude syndrome (VWS). METHODS: A proband who had visited the Drum Tower Hospital Affiliated to Nanjing University Medical School in May 2020 for "two previous pregnancies with cleft lip and palate" was selected as the study subject. Trio-whole exome sequencing (trio-WES) was carried out for the patient. Candidate variants were verified by Sanger sequencing of her pedigree members (8 individuals from four generations) and bioinformatic analysis. Chromosomal microarray analysis (CMA) was used to rule out copy number variations in the fetuses. RESULTS: Trio-WES revealed that the proband and her father had both harbored a heterozygous c.742G>T (p.G248C) missense variant of the IRF6 gene, for which her mother was of the wild type. The variant was located in a region with important functions and has not been reported previously. Prediction with several software suggested that it is likely to have a significant impact on the protein structure/function and is highly correlated with the specific phenotypes in this pedigree. Sanger sequencing confirmed co-segregation of the genotypes and phenotypes in the pedigree. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), this variant was rated as likely pathogenic (PM1+PM2_Supporting+PP1+PP3+PP4). Based on the above results, pre-implantation genetic diagnosis was carried out for the proband, which has led to birth of a healthy offspring with normal results for both site testing and CMA. CONCLUSION The IRF6: c.742G>T (p.G248C) heterozygous variant probably underlay the VWS in this pedigree. Above finding has also enabled reproductive guidance for the proband.
Humans ; Female ; Cleft Lip/genetics* ; Cleft Palate/genetics* ; Pedigree ; DNA Copy Number Variations ; East Asian People ; Interferon Regulatory Factors/genetics* ; Mutation

Objective:To explore the perioperative airway management and treatment of newborns with micrognathia and laryngomalacia. Methods:From January to December 2022, a total of 6 newborns with micrognathia and laryngomalacia were included. Preoperative laryngoscopy revealed concomitant laryngomalacia. These micrognathia were diagnosed as Pierre Robin sequences. All patients had grade Ⅱ or higher symptoms of laryngeal obstruction and required oxygen therapy or non-invasive ventilatory support. All patients underwent simultaneous laryngomalacia surgery and mandibular distraction osteogenesis. The shortened aryepiglottic folds were ablated using a low-temperature plasma radiofrequency during the operation. Tracheal intubation was maintained for 3-5 days postoperatively. Polysomnography（PSG） and airway CT examination were performed before and 3 months after the surgery. Results:Among the 6 patients, 4 required oxygen therapy preoperatively and 2 required non-invasiveventilatory support. The mean age of patients was 40 days at surgery. The inferior alveolar nerve bundle was not damaged during the operation, and there were no signs of mandibular branch injury such as facial asymmetry after the surgery. Laryngomalacia presented as mixed type: type Ⅱ+ type Ⅲ. The maximum mandibular distraction distance was 20 mm, the minimum was 12 mm, and the mean was 16 mm. The posterior airway space increased from a preoperative average of 3.5 mm to a postoperative average of 9.5 mm. The AHI decreased from a mean of 5.65 to 0.85, and the lowest oxygen saturation increased from a mean of 78% to 95%. All patients were successfully extubated after the surgery, and symptoms of laryngeal obstruction such as hypoxia and feeding difficulties disappeared. Conclusion:Newborns with micrognathia and laryngomalacia have multi-planar airway obstruction. Simultaneous laryngomalacia surgery and mandibular distraction osteogenesis are safe and feasible, and can effectively alleviate symptoms of laryngeal obstruction such as hypoxia and feeding difficulties, while significantly improving the appearance of micrognathia.
Humans ; Infant, Newborn ; Infant ; Micrognathism/surgery* ; Laryngomalacia/surgery* ; Treatment Outcome ; Mandible/surgery* ; Airway Obstruction/surgery* ; Intubation, Intratracheal ; Laryngeal Diseases ; Osteogenesis, Distraction ; Oxygen ; Retrospective Studies

The maxillofacial region has multiple functions such as breathing, language, and facial expressions. Children's maxillofacial development is a complex and long process, which is affected by many factors such as genetics, diseases, bad habits and trauma. Early detection, early diagnosis, and early treatment are important concepts in children's maxillofacial management. Digital technology medicine is an emerging technology based on medical imaging and anatomy that has emerged in recent years. The application of this technology in the field of clinical medicine will undoubtedly bring great benefits to children's maxillofacial management. This article summarizes the research on digital technology in children's maxillofacial management, and focuses on the research on children's malocclusion, children's OSA, cleft lip and palate and other related diseases.
Humans ; Child ; Cleft Lip/surgery* ; Cleft Palate/surgery* ; Digital Technology ; Respiration

OBJECTIVES: Currently, the research results regarding the bilateral temporomandibular joint symmetry in patients at different ages with unilateral complete cleft lip and palate (UCLP) are still controversial. In this study, the position of condyle in the articular fossa and morphology of condyle in UCLP patients at different developmental stages was measured and analyzed to explore the asymmetry difference, which can provide a new theoretical basis for the sequential therapy. METHODS: A total of 90 patients with UCLP were divided into a mixed dentition group (31 cases), a young permanent dentition group (31 cases) and an old permanent dentition group (28 cases) according to age and dentition development. Cone beam computed tomography (CBCT) images were imported into Invivo5 software for 3D reconstruction, and the joint space, anteroposterior diameter, medio-lateral diameter, and height of condylar were measured, and its asymmetry index was calculated. RESULTS: The asymmetry index of condylar height and anteroposterior diameter among the 3 groups, from small to large, was the mixed dentition groupP<0.05). There was no significant difference in condylar anteroposterior diameter and asymmetry index between the mixed dentition group and the young permanent dentition group (both P>0.05), all of them were lower than those in the old permanent dentition group (both P<0.05). Compared with the normal side, the height of fracture condyle was smaller among the 3 groups (all P<0.05), and the anterior joint space was smaller (P<0.05) and the posterior joint space was larger (P<0.05) in the mixed dentition group. CONCLUSIONS In patients with UCLP, the asymmetry of condylar morphology increases with age, but the condylar position tends to normal. These results suggest that early treatment has important clinical significance for the morphologic development of temporomandibular joint in UCLP patients.
Humans ; Cleft Lip/diagnostic imaging* ; Cleft Palate/diagnostic imaging* ; Temporomandibular Joint/diagnostic imaging* ; Clinical Relevance

The cranial neural crest plays a fundamental role in orofacial development and morphogenesis. Accordingly, mutations with impact on the cranial neural crest and its development lead to orofacial malformations such as cleft lip and palate. As a pluripotent and dynamic cell population, the cranial neural crest undergoes vast transcriptional and epigenomic alterations throughout the formation of facial structures pointing to an essential role of factors regulating chromatin state or transcription levels. Using CRISPR/Cas9-guided genome editing and conditional mutagenesis in the mouse, we here show that inactivation of Kat5 or Ep400 as the two essential enzymatic subunits of the Tip60/Ep400 chromatin remodeling complex severely affects carbohydrate and amino acid metabolism in cranial neural crest cells. The resulting decrease in protein synthesis, proliferation and survival leads to a drastic reduction of cranial neural crest cells early in fetal development and a loss of most facial structures in the absence of either protein. Following heterozygous loss of Kat5 in neural crest cells palatogenesis was impaired. These findings point to a decisive role of the Tip60/Ep400 chromatin remodeling complex in facial morphogenesis and lead us to conclude that the orofacial clefting observed in patients with heterozygous KAT5 missense mutations is at least in part due to disturbances in the cranial neural crest.
Animals ; Mice ; Chromatin Assembly and Disassembly ; Cleft Lip/genetics* ; Cleft Palate/genetics* ; DNA Helicases/metabolism* ; DNA-Binding Proteins ; Neural Crest/metabolism* ; Skull ; Transcription Factors/metabolism*

Alveolar cleft is one of the key links of cleft lip and palate reconstruction due to its close relationship with tooth and jaw coordination and nasolabial deformity. The alveolar bone graft repairs the hole in the gum ridge and stabilizes the bone arch, providing better support for the base of the nose and new bone for the roots of the developing teeth to grow into. Unfortunately, bone graft failure in the traditional way, even among minor clefts, bony hypoplasia, or absence that affects the nasal base and piriform rim, is common. Two-stage alveolar bone grafting, which has advantages in addressing the underlying skeleton and deficiency, could be an optional surgical procedure for nasal floor reconstruction in adult patients with a broad alveolar cleft.
Humans ; Adult ; Alveolar Bone Grafting/methods* ; Cleft Lip/surgery* ; Cleft Palate/surgery* ; Treatment Outcome ; Nose/abnormalities* ; Bone Transplantation/methods*

OBJECTIVES: To review the effectiveness of secondary alveolar bone grafting using iliac cancellous bone in patients with unilateral complete alveolar cleft and to investigate the factors influencing it. METHODS: A retrospective study of 160 patients with unilateral complete alveolar clefts who underwent iliac cancellous bone graft repair at the Department of Cleft Lip and Palate Surgery, West China Hospital of Stomatology, Sichuan University, was conducted. Eighty patients in the young age group (6-12 years) and 80 in the old age group (≥13 years) were included. Bone bridge formation was determined using Mimics software, and the volume was measured to calculate the iliac implantation rate, residual bone filling rate, and resorption rate. The factors that affected bone grafting in both subgroups were investigated. RESULTS: Using bone bridge formation as the clinical success criterion, the success rate for the entire population was 71.25%, with a significant difference of 78.75% and 63.75% for the young and old age groups, respectively (P=0.036). The gap volume in the latter was significantly larger than that in the former (P<0.001). The factors that influenced bone grafting in the young group were the palatal bone wall (P=0.006) and history of cleft palate surgery (P=0.012), but only the palatal bone wall affected the outcome in the old age group (P=0.036). CONCLUSIONS The results of alveolar bone grafting for the old age group were worse than those for the young age group. The palatal bone wall was an important factor that affected alveolar bone grafting, and alveolar bone grafting in the young patients was influenced by the history of cleft palate surgery.
Humans ; Child ; Adolescent ; Cleft Palate/surgery* ; Cleft Lip/surgery* ; Retrospective Studies ; Cancellous Bone ; Treatment Outcome ; Alveolar Bone Grafting/methods* ; Bone Transplantation/methods*