Congenital Craniofacial Malformations Research Articles

Mixed reality guided advancement osteotomies in congenital craniofacial malformations

We describe the use of mixed reality intra-operative guides, in patients with congenital craniofacial malformations. Our experience shows the potential MR has as an adjunct and possible replacement for conventional cutting guides and intra-operative navigation. SummaryThis paper describes our experience with mixed reality (MR) intra-operative guides, in patients with congenital craniofacial malformations.The first case was a patient with bilateral hemifacial microsomia. He underwent bilateral mandibular distraction osteogenesis. Pre-operative virtual planning determined the sites of osteotomy. Standard Tessellation Language (STL) files of mandibular 3D models with osteotomy sites were uploaded onto the HoloLens 2® MR glasses (Microsoft®, Washington, USA). The superimposed hologram denoted the osteotomy line. This was validated with a physical cutting guide.The second case was a patient with Crouzon’s syndrome. A modified Lefort 2 advancement was performed to correct his midfacial deficiency. Pre-operative virtual planning was performed to determine the sites of osteotomies. Superimposed hologram using the Hololens 2® denoted the osteotomy sites. These were validated with a conventional intra-operative navigation system.The advantages of using MR include its immediate availability for use; saving time and costs. MR allows surgeons to maintain continuous line-of-sight within the operative field. A robust registration system is required to anchor the hologram onto the patient’s skull, without variations in hologram position from different angles of gaze. MR has the potential to function as an adjunct and possible replacement for conventional cutting guides and intra-operative navigation.

Multi-omics analysis of a case of congenital microtia reveals aldob and oxidative stress associated with microtia etiology.

Microtia is reported to be one of the most common congenital craniofacial malformations. Due to the complex etiology and the ethical barrier of embryonic study, the precise mechanisms of microtia remain unclear. Here we report a rare case of microtia with costal chondrodysplasia based on bioinformatics analysis and further verifications on other sporadic microtia patients. One hundred fourteen deleterious insert and deletion (InDel) and 646 deleterious SNPs were screened out by WES, candidate genes were ranked in descending order according to their relative impact with microtia. Label-free proteomic analysis showed that proteins significantly different between the groups were related with oxidative stress and energy metabolism. By real-time PCR and immunohistochemistry, we further verified the candidate genes between other sporadic microtia and normal ear chondrocytes, which showed threonine aspartase, cadherin-13, aldolase B and adiponectin were significantly upregulated in mRNA levels but were significantly lower in protein levels. ROS detection and mitochondrial membrane potential (∆ Ψ m) detection proved that oxidative stress exists in microtia chondrocytes. Our results not only spot new candidate genes by WES and label-free proteomics, but also speculate for the first time that metabolism and oxidative stress may disturb cartilage development and this might become therapeutic targets and potential biomarkers with clinical usefulness in the future.

Long-term mandibular growth in patients with airway obstruction treated with mandibular distraction

Congenital craniofacial malformations play an important role in upper airway obstruction. One of the main causes is mandibular hypoplasia which is present in the pierre robin sequence. Mandibular distraction osteogenesis (MDO) is one of the most commonly used treatments for the resolution of upper airway obstruction in patients that do not respond to a conservative treatment. We performed a long term follow up of syndromic and non-syndromic patients with pierre robin sequence where the lateral xrays were studied before surgery (T1), after MDO (T2) and long-term follow-up (T3, at least 5 years). Possible complications of the surgery were also studied through panoramic x-rays and clinical controls. The results evidenced an increase of mandibular length comparing T1-T2 and a good stability during the long-term follow-up. The Sd patients presented smaller mandible dimensions. We had not found any complications during the follow-up. The scars outcomes are modest, but none of the patients requested a surgical correction. Mandibular distraction osteogenesis is a treatment to be considered in patients with upper airway obstruction that do not respond to conservative treatments. The results of the surgery are stable and the complications in experienced hands are low.

The level of protein in the maternal murine diet modulates the facial appearance of the offspring via mTORC1 signaling

The development of craniofacial skeletal structures is fascinatingly complex and elucidation of the underlying mechanisms will not only provide novel scientific insights, but also help develop more effective clinical approaches to the treatment and/or prevention of the numerous congenital craniofacial malformations. To this end, we performed a genome-wide analysis of RNA transcription from non-coding regulatory elements by CAGE-sequencing of the facial mesenchyme of human embryos and cross-checked the active enhancers thus identified against genes, identified by GWAS for the normal range human facial appearance. Among the identified active cis-enhancers, several belonged to the components of the PI3/AKT/mTORC1/autophagy pathway. To assess the functional role of this pathway, we manipulated it both genetically and pharmacologically in mice and zebrafish. These experiments revealed that mTORC1 signaling modulates craniofacial shaping at the stage of skeletal mesenchymal condensations, with subsequent fine-tuning during clonal intercalation. This ability of mTORC1 pathway to modulate facial shaping, along with its evolutionary conservation and ability to sense external stimuli, in particular dietary amino acids, indicate that the mTORC1 pathway may play a role in facial phenotypic plasticity. Indeed, the level of protein in the diet of pregnant female mice influenced the activity of mTORC1 in fetal craniofacial structures and altered the size of skeletogenic clones, thus exerting an impact on the local geometry and craniofacial shaping. Overall, our findings indicate that the mTORC1 signaling pathway is involved in the effect of environmental conditions on the shaping of craniofacial structures.

Genetics and Epigenetics in the Genesis and Development of Microtia.

Microtia is a congenital malformation of the external and middle ear associated with varying degrees of severity that range from mild structural abnormalities to the absence of the external ear and auditory canal. Globally, it is the second most common congenital craniofacial malformation and is typically caused by inherited defects, external factors, or the interaction between genes and external factors. Epigenetics notably represents a bridge between genetics and the environment. This review has devoted attention to the current proceedings of the genetics and epigenetics of microtia and related syndromes.

Amer1 Regulates Zebrafish Craniofacial Development by Interacting with the Wnt/β-Catenin Pathway.

Microtia-atresia is a rare type of congenital craniofacial malformation causing severe damage to the appearance and hearing ability of affected individuals. The genetic factors associated with microtia-atresia have not yet been determined. The AMER1 gene has been identified as potentially pathogenic for microtia-atresia in two twin families. An amer1 mosaic knockdown zebrafish model was constructed using CRISPR/Cas9. The phenotype and the development process of cranial neural crest cells of the knockdown zebrafish were examined. Components of the Wnt/β-catenin pathway were examined by qPCR, Western blotting, and immunofluorescence assay. IWR-1-endo, a reversible inhibitor of the Wnt/β-catenin pathway, was applied to rescue the abnormal phenotype. The present study showed that the development of mandibular cartilage in zebrafish was severely compromised by amer1 knockdown using CRISPR/Cas9. Specifically, amer1 knockdown was found to affect the proliferation and apoptosis of cranial neural crest cells, as well as their differentiation to chondrocytes. Mechanistically, amer1 exerted an antagonistic effect on the Wnt/β-catenin pathway. The application of IWR-1-endo could partially rescue the abnormal phenotype. We demonstrated that amer1 was essential for the craniofacial development of zebrafish by interacting with the Wnt/β-catenin pathway. These findings provide important insight into the role of amer1 in zebrafish mandibular development and the pathology of microtia-atresia caused by AMER1 gene mutations in humans.

Towards a radiation free numerical modelling framework to predict spring assisted correction of scaphocephaly

Sagittal Craniosynostosis (SC) is a congenital craniofacial malformation, involving premature sagittal suture ossification; spring-assisted cranioplasty (SAC) – insertion of metallic distractors for skull reshaping – is an established method for treating SC. Surgical outcomes are predictable using numerical modelling, however published methods rely on computed tomography (CT) scans availability, which are not routinely performed. We investigated a simplified method, based on radiation-free 3D stereophotogrammetry scans. Eight SAC patients (age 5.1 ± 0.4 months) with preoperative CT and 3D stereophotogrammetry scans were included. Information on osteotomies, spring model and post-operative spring opening were recorded. For each patient, two preoperative models (PREOP) were created: i) CT model and ii) S model, created by processing patient specific 3D surface scans using population averaged skin and skull thickness and suture locations. Each model was imported into ANSYS Mechanical (Analysis System Inc., Canonsburg, PA) to simulate spring expansion. Spring expansion and cranial index (CI - skull width over length) at times equivalent to immediate postop (POSTOP) and follow up (FU) were extracted and compared with in-vivo measurements. Overall expansion patterns were very similar for the 2 models at both POSTOP and FU. Both models had comparable outcomes when predicting spring expansion. Spring induced CI increase was similar, with a difference of 1.2%±0.8% for POSTOP and 1.6%±0.6% for FU. This work shows that a simplified model created from the head surface shape yields acceptable results in terms of spring expansion prediction. Further modelling refinements will allow the use of this predictive tool during preoperative planning.

Prevotella Denticola Dacryocystitis and Abscess in a Child with Goldenhar Syndrome

Dacryocystitis is the inflammation of the nasolacrimal sac and is due to obstruction of the nasolacrimal system or lacrimal stagnation, leading to favorable environments for infection. Any disruptions to the nasolacrimal pathway can increase the risk of dacryocystitis. Here is a unique case of Prevotella denticola dacryocystitis that progressed into cellulitis and abscess formation in a 7-year-old female with a medical history of Goldenhar syndrome, recurrent dacryocystitis, and periodontal disease. The patient presented with standard dacryocystitis symptoms—tenderness to palpation, erythema, and edema to the medial canthus. The patient was treated empirically with vancomycin, ceftriaxone, and clindamycin. She was discharged home on clindamycin with symptomatic improvement and plans for dacryocystorhinostomy. Goldenhar syndrome is a rare congenital craniofacial malformation disorder due to aberrant morphogenesis in structures derived from the first and second branchial arches. P. denticola is an anaerobic gram-negative bacillus significant to the oral microbiome. There is currently limited research suggesting the relationship between Goldenhar syndrome and dacryocystitis complicated by Prevotella denticola. Based on the patient’s medical history, we predict that her complex presentation was secondary to the dissemination of Prevotella from her oral cavity. This case report emphasizes the importance of gram-negative anaerobic coverage in complicated dacryocystitis in patients with nasolacrimal defects.

Integrating Virtual Surgical Planning and 3D-Printed Tools with Iliac Bone Grafts for Orbital and Zygomatic Reconstruction in Hemifacial Microsomia Patients.

Hemifacial Microsomia (HFM) is the second most common congenital craniofacial malformation syndrome, and the complexity of HFM makes its treatment challenging. The present study aimed to introduce a new approach of utilization of virtual surgical planning (VSP) and 3D-printed surgical adjuncts for maxillofacial reconstruction. Five HFM patients were included in this study. All participants were provided with a full VSP, including the design of osteotomy lines, the design and fabrication of 3D-printed cutting guides, fixation plates, and titanium mesh for implantation. With the assistance of 3D-printed cutting guides and fixation plates, the orbital deformities were corrected, and a 3D-printed titanium mesh combined with iliac cancellous bone graft was applied to reconstruct the zygomatic arch. The surgical accuracy, effectiveness, and bone absorption rate were evaluated. All patients completed the entirely digital treatment process without experiencing severe complications. The surgical adjuncts were effective in aligning the movement of the bone segments with the surgical plan, resulting in mean 3D deviations (1.0681 ± 0.15 mm) and maximum 3D deviations (3.1127 ± 0.44 mm). The image fusion results showed that the patients' postoperative position of the maxilla, zygoma, and orbital rim was consistent with the virtual surgical plan, with only a slight increase in the area of bone grafting. The postoperative measurements showed significant improvement in the asymmetry indices of Er (AI of Er: from 17.91 ± 3.732 to 5.427 ± 1.389 mm, p = 0.0001) and FZ (AI of FZ: from 7.581 ± 1.435 to 4.070 ± 1.028 mm, p = 0.0009) points. In addition, the observed bone resorption rate at the 6-month follow-up across the five patients was 45.24% ± 3.13%. In conclusion, the application of VSP and 3D-printed surgical adjuncts demonstrates significant value in enhancing the precision and effectiveness of surgical treatments for HFM. A 3D-printed titanium mesh combined with iliac cancellous bone graft can be considered an ideal alternative for the reconstruction of the zygomatic arch.

Single visit feeding plate for infant: A case report.

A child born with cleft lip and palate may experience difficulties while feeding. It is the most common congenital craniofacial malformations. Feeding difficulties should be assessed and intervened as early as possible, as they are an important aspect of the multidisciplinary team approach in the management of cleft lip and palate. Feeding obturators improve feeding thereby contributing to weight gain and a thriving state of health, a prerequisite for surgical repair of the defects. A successful prosthesis should meet the physiological, psychological and aesthetic needs of the patient. This article describes the procedure for rehabilitation of cleft palate patient with feeding plate.

Exposure to the aryl hydrocarbon receptor agonist dioxin disrupts formation of the muscle, nerves, and vasculature in the developing jaw

Human exposure to environmental pollutants can disrupt embryonic development and impact juvenile and adult health outcomes by adversely affecting cell and organ function. Notwithstanding, environmental contamination continues to increase due to industrial development, insufficient regulations, and the mobilization of pollutants as a result of extreme weather events. Dioxins are a class of structurally related persistent organic pollutants that are highly toxic, carcinogenic, and teratogenic. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent dioxin compound and has been shown to induce toxic effects in developing organisms by activating the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor targeted by multiple persistent organic pollutants. Contaminant-induced AHR activation results in malformations of the craniofacial cartilages and neurocranium; however, the mechanisms mediating these phenotypes are not well understood. In this study, we utilized the optically transparent zebrafish model to elucidate novel cellular targets and potential transcriptional targets underlying TCDD-induced craniofacial malformations. To this end, we exposed zebrafish embryos at 4 h post fertilization to TCDD and employed a mixed-methods approach utilizing immunohistochemistry staining, transgenic reporter lines, fixed and in vivo confocal imaging, and timelapse microscopy to determine the targets mediating TCDD-induced craniofacial phenotypes. Our data indicate that embryonic TCDD exposure reduced jaw and pharyngeal arch Sox10+ chondrocytes and Tcf21+ pharyngeal mesoderm progenitors. Exposure to TCDD correspondingly led to a reduction in collagen type II deposition in Sox10+ domains. Embryonic TCDD exposure impaired development of tissues derived from or guided by Tcf21+ progenitors, namely: nerves, muscle, and vasculature. Specifically, TCDD exposure disrupted development of the hyoid and mandibular arch muscles, decreased neural innervation of the jaw, resulted in compression of cranial nerves V and VII, and led to jaw vasculature malformations. Collectively, these findings reveal novel structural targets and potential transcriptional targets of TCDD-induced toxicity, showcasing how contaminant exposures lead to congenital craniofacial malformations.

Case Study in Infants with Cleft Lip and Palate Who Attended the Fundación Operación Sonrisa Consultation in The Period 2015-2019

Cleft lips and palate are considered congenital craniofacial malformations originating in the early stage of embryo development, due to an incomplete fusion of the medial nasal processes and maxillary processes. A multidisciplinary team is required to carry out the ideal treatment for these childhood patients. Aims: The objective of this study was meant to describe the casuistry of patients with cleft lip and palate in infants who attended the Operation Smile Venezuela Foundation in the period from 2015 to 2019. Subjects and Method: This was a non-experimental and descriptive field research. The sample included medical records from patients with cleft lip and palate that were attended since 2015 to 2019, having in account exclusion and inclusion criteria. A questionnaire was used as an instrument through the Google Form application with 34 closed questions of dichotomous answers. The variables studied were epidemiological characteristics such as: age, gender and origin, also we analyzed types of clefts lip and palate and whether they obtained surgical resolution or not, which were collected and evaluated according to our type of research and the objectives. Results: 618 medical records were analyzed, with an average of showing a prevalence in preschool age ( 40%) , followed by minor infants ( 29%) and the age with less prevalence was newborns (1%). In terms of gender there was an almost equal distribution, males (58%) and females (42%). Geographically there was a predominance in the Capital District (20%), Miranda (15%), Aragua (13%) and Monagas (12%) during the period studied. But states such as Amazonas, Barinas, Cojedes, Delta Amacuro, Lara and Nueva Esparta had the lowest percentage (0%). Of the cleft lip the most prevalent was the Complete left Unilateral, followed by the Incomplete Left Unilateral and the Complete Bilateral cleft lip. The Complete Bilateral and the Hard and Soft Posterior Palate Cleft were the most common. Conclusions: It is essential to determine the epidemiological variants, as well as to know the etiology of the cleft lip alveolus palatal and how to prevent them. Likewise, through this work, the activity that Operation Smile Venezuela Foundation carried out day by day is made known.

Application and development of orthognathic surgery in treatment of syndromic craniosynostosis

To summarize the application and recent development of orthognathic surgery in treating syndromic craniosynostosis. The related literature at home and abroad in recent years was extensively reviewed, and the indications, routine procedures, and protocols of orthognathic surgery in the treatment of syndromic craniosynostosis were summarized and analyzed. Craniosynostosis is a common congenital craniofacial malformation. Syndromic craniosynostosis usually involves premature fusion of multiple cranial sutures and is associated with other deformities. Orthognathic surgery is the necessary and effective means to improve the midfacial hypoplasia and malocclusion. Le Fort I osteotomy combined with sagittal split ramus osteotomy are the common surgical options. Orthognathic surgery should combine with craniofacial surgery and neurosurgery, and a comprehensive long-term evaluation should be conducted to determine the best treatment plan. Orthognathic surgery plays an important role in the comprehensive diagnosis and treatment of syndromic craniosynostosis. The development of digital technology will further promote the application and development of orthognathic surgery in the treatment of syndromic craniosynostosis.

Inverted supernumerary nasal tooth

The eruption of a tooth into the nasal cavity is a rare and incidental finding during routine clinical or radiological examination. Since the 1960s there were more than 60 reported cases of nasal teeth. To the best of our knowledge, this is only the sixth case report of a supernumerary intranasal canine in the selected period. A 22-year-old male presented with a history of recurrent rhinorrhea, nasal congestion, tension headaches, and insomnia but without previous epistaxis or facial trauma episodes, and with no history of congenital craniofacial malformations. Following a computed tomography examination, a diagnosis of a supernumerary inverted ectopic canine eruption into the left nasal cavity was established. To identify such rarities and prevent possible complications, it is essential to acquire detailed patient history, be familiar with both normal and variant maxillofacial structures, and conduct systematic radiological image analysis

Additional diagnoses in children with cleft lip and palate up to five years of age

Cleft lip and palate (CL/P) is the most common congenital craniofacial malformation and is often associated with additional diagnoses. The purpose of this study was to explore the cumulative five-year incidence of additional diagnoses for patients with cleft lip and palate. Further aims were, type of cleft and type of additional diagnose and to validate CLP registry data on additional diagnoses. Data from the CLP registry regarding children with CL/P in the Southern Health Care Region were retrieved and based on the registry, participants were selected. A review of medical records of participants born 2006–2016 was performed and data regarding participant characteristics and additional diagnoses were collected. Of the 250 participants included in the review of medical records, 90 participants (36%) had an additional diagnosis. Of the total number of identified additional diagnoses (n = 137), cardiovascular system (20.4%) and extremities and skeletal system (17.5%) were the most prevalent categories. The comparison between medical records and the CLP registry of all children showed a 14.4 percentage points higher incidence of additional diagnoses in the medical records. Roughly every third child received an additional diagnosis and diagnoses related to the cardiovascular system were the most frequent. This study also shows that additional diagnoses were under-reported in the CLP registry. Future research is necessary to strengthen associations of additional diagnoses to CL/P.

Skeletal and dentoalveolar characteristics of maxillary lateral incisor agenesis patients: a comparative cross-sectional study

BackgroundThe aim of the study was to evaluate the cephalometric and dentoalveolar characteristics of maxillary lateral incisor agenesis patients, and to compare the findings to a matched control group without tooth agenesis, excluding third molars, from the same population.MethodsThe pre-orthodontic records of 72 non-growing patients, who were treated at the Orthodontic Department, Faculty of Dentistry, Alexandria University, were used to address the aim of this retrospective study. Patients having unilateral or bilateral maxillary lateral incisor agenesis, with no history of previous orthodontic treatment, congenital craniofacial malformations, facial trauma, or surgeries were divided into two test groups based on the pattern of maxillary lateral incisors agenesis (group I: unilateral (UMLIA), group II: bilateral (BMLIA)). A control group (group III (CTRL)) having a complete set of permanent dentition (excluding third molars), and having no dental anomalies was age-matched with the test groups. Measurements were performed on the pre-orthodontic lateral cephalometric radiographs and the pre-orthodontic digital dental casts. The measured variables were compared between the groups using one-way ANOVA and Kruskal Wallis tests according to the normality of the variable. In case of significant results, both tests were followed by multiple pairwise comparisons using Bonferroni adjusted significance level. Significance level was set at P < 0.05.ResultsBMLIA group showed a smaller SNA angle and maxillary length, a more negative ANB angle and Wits appraisal, and a larger Maxillo-mandibular differential than UMLIA and/or CTRL group. The dental and soft tissue cephalometric measurements did not show any significant differences between the groups. Dentoalveolar cast measurements showed that BMLIA patients presented with significantly smaller maxillary inter-canine width than UMLIA and CTRL patients.ConclusionsCephalometric analysis has shown that subjects with BMLIA have a statistically significant reduced ANB and maxillary length. Tooth eruption may play a role in the development of the maxillary arch.

Tessier cleft numbers 3 and 4: Presentation of soft tissue and bony deformities in a select South African population

BackgroundTessier cleft numbers 3 and 4 are rare congenital craniofacial malformations. Tessier cleft number 3 runs from the philtrum of the superior lip, traverses the ala of the nose and ends at the medial canthus of the eye. Tessier cleft number 4 commences between the philtrum and oral commissure in the superior lip, and ascends into the orbit, remaining medial to the infraorbital foramen. The associated clinical manifestation of each cleft type varies amongst patients. This study documented the soft tissue and bony deformities of Tessier cleft numbers 3 and 4 in a select South African population. MethodsThe study group was selected from retrospectively reviewed computed tomography (CT) scan records, which were made available via the repository of the Department of Clinical Anatomy at higher education institution in South Africa. Seven out of fifty CT scans that met the inclusion criteria were assessed and analysed. The patient records associated with the selected scans were reviewed. The soft tissue and bony deformities characteristic of Tessier cleft numbers 3 and 4 were documented [Ethical approval number: BE363/19]. Descriptive statistics were used to summarise the results. ResultsThe bony deformities presented in the cases of this study included alveolar clefts, nasal septum deviation, hypertelorism and maxillary bone defects. The soft tissue deformities included cleft lip, nasolacrimal abnormalities, eye dystopia, anophthalmia and nasal ala defects. ConclusionsThe extent of the associated deformities of each case varied; however, the primarily affected regions remained constant i.e., the orbital, nasal and oral regions. The variation in soft tissue and bony presentation warranted the need to document these clefts. This study will contribute to the anatomical interpretation of Tessier cleft numbers 3 and 4 in South Africa, and aid medical professionals in the evaluation, differentiation, and treatment of such clefts.

A Point-of-Care Digital Workflow for 3D Printed Passive Presurgical Orthopedic Plates in Cleft Care.

Cleft lip and palate are one of the most common congenital craniofacial malformations. As an initial treatment, presurgical orthopedics is considered standard treatment at many cleft centers. Digital impressions are becoming feasible in cleft care. Computer-aided design (CAD) and three-dimensional (3D) printing are manufacturing standards in dentistry. The assimilation of these technologies has the potential to alter the traditional workflow for the fabrication of customized presurgical orthopedic plates. We present a digital workflow comprising three steps: 3D digital image acquisition with an intraoral scanner, open-source CAD modeling, and point-of-care 3D printing for the fabrication of personalized passive presurgical plates for newborns with cleft lip and palate. The digital workflow resulted in patient-related benefits, such as no risk of airway obstruction with quicker data acquisition (range 1–2.5 min). Throughput time was higher in the digital workflow 260–350 min compared to 135 min in the conventional workflow. The manual and personal intervention time was reduced from 135 min to 60 min. We show a clinically useful digital workflow for presurgical plates in cleft treatment. Once care providers overcome procurement costs, digital impressions, and point-of-care 3D printing will simplify these workflows and have the potential to become standard for cleft care.

Effects of mandibular distraction osteogenesis on anesthetic implications in children with hemifacial microsomia.

Hemifacial microsomia (HFM) is a congenital craniofacial malformation, and its features include hypoplasia and asymmetry in skeletal tissue and soft tissue. These features are usually associated with a difficult airway. Mandibular distraction osteogenesis can achieve mandibular advancement, but its effect on the subsequent laryngoscopic views has not been adequately documented. The aim of this study was to determine the change in laryngoscopic views after mandibular distraction osteogenesis (MDO) in children with HFM and to examine the radiological changes after MDO by using computed tomography (CT)-based three-dimensional (3-D) airway reconstruction. An observational prospective study was carried out in children with HFM undergoing MDO. All children underwent 3-D airway reconstruction preoperatively before the placement and removal of the distractor. The temporomandibular joint lesions in children were classified by the Pruzansky-Kaban classification. The Cormack-Lehane grade was assessed after induction under direct laryngoscopy. The relationship between difficult laryngoscopy and the Pruzansky-Kaban classification was assessed. Changes in the upper pharyngeal airway parameters and laryngoscopic views were analyzed. Forty children (ages ranging from 5 to 16 years, males=26, females=14) with HFM underwent 80 anesthesia for MDO. The incidence of difficult laryngoscopy before mandibular distraction was 5/12 (41.7%) in type IIa, 19/24 (79.2%) in type IIb and 1/4 (25%) in type III HFM. The mean difference in the incidence of difficult laryngoscopy before and after MDO was 33.3% (95% CI: -6.7% to 73.3%), 50.0% (95% CI: 8.4% to 91.6%), and 0% for type IIa, type IIb, and type III, respectively. In type IIb, 12/19 cases of difficult laryngoscopy became easy after mandibular distraction: this was associated with an increase in the palatopharyngeal and glossopharyngeal CT parameters (p < .05). In type IIa, 5/5 cases of difficult laryngoscopy became easy after mandibular distraction, and 1/7 cases of easy laryngoscopy became difficult laryngoscopy. However, there were no significant changes in the palatopharyngeal, glossopharyngeal, and hypopharyngeal CT parameters in type IIa and type III HFM (p>.05). MDO can improve the laryngoscopic views in children with HFM. According to the Pruzansky-Kaban classification, children with type IIb showed the highest incidence of difficult laryngoscopy before MDO. After MDO, the improvement in laryngoscopic views under direct laryngoscopy in type IIb was related to the increase in the palatopharyngeal and glossopharyngeal volume.

Mosmo Is Required for Zebrafish Craniofacial Formation.

Hedgehog (Hh) signaling is a highly regulated molecular pathway implicated in many developmental and homeostatic events. Mutations in genes encoding primary components or regulators of the pathway cause an array of congenital malformations or postnatal pathologies, the extent of which is not yet fully defined. Mosmo (Modulator of Smoothened) is a modulator of the Hh pathway, which encodes a membrane tetraspan protein. Studies in cell lines have shown that Mosmo promotes the internalization and degradation of the Hh signaling transducer Smoothened (Smo), thereby down-modulating pathway activation. Whether this modulation is essential for vertebrate embryonic development remains poorly explored. Here, we have addressed this question and show that in zebrafish embryos, the two mosmo paralogs, mosmoa and mosmob, are expressed in the head mesenchyme and along the entire ventral neural tube. At the cellular level, Mosmoa localizes at the plasma membrane, cytoplasmic vesicles and primary cilium in both zebrafish and chick embryos. CRISPR/Cas9 mediated inactivation of both mosmoa and mosmob in zebrafish causes frontonasal hypoplasia and craniofacial skeleton defects, which become evident in the adult fish. We thus suggest that MOSMO is a candidate to explain uncharacterized forms of human congenital craniofacial malformations, such as those present in the 16p12.1 chromosomal deletion syndrome encompassing the MOSMO locus.