Craniofacial Disorders Research Articles

Chemical-induced craniofacial anomalies caused by disruption of neural crest cell development in a zebrafish model.

BackgroundCraniofacial anomalies are among the most frequent birth defects worldwide, and are thought to be caused by gene‐environment interactions. Genetically manipulated zebrafish simulate human diseases and provide great advantages for investigating the etiology and pathology of craniofacial anomalies. Although substantial advances have been made in understanding genetic factors causing craniofacial disorders, limited information about the etiology by which environmental factors, such as teratogens, induce craniofacial anomalies is available in zebrafish.ResultsZebrafish embryos displayed craniofacial malformations after teratogen treatments. Further observations revealed characteristic disruption of chondrocyte number, shape and stacking. These findings suggested aberrant development of cranial neural crest (CNC) cells, which was confirmed by gene expression analysis of the CNC. Notably, these observations suggested conserved etiological pathways between zebrafish and mammals including human. Furthermore, several of these chemicals caused malformations of the eyes, otic vesicle, and/or heart, representing a phenocopy of neurocristopathy, and these chemicals altered the expression levels of the responsible genes.ConclusionsOur results demonstrate that chemical‐induced craniofacial malformation is caused by aberrant development of neural crest. This study indicates that zebrafish provide a platform for investigating contributions of environmental factors as causative agents of craniofacial anomalies and neurocristopathy.

Sleep-Disordered Breathing and Airway Assessment Using Polysomnography in Pediatric Patients With Craniofacial Disorders.

Children with cleft and craniofacial conditions commonly present with concurrent airway anomalies, which often manifest as sleep disordered breathing. Craniofacial surgeons and members of the multidisciplinary team involved in the care of these patients should appreciate and understand the scope of airway pathology as well as the proper means of airway assessment. This review article details the prevalence and assessment of sleep disordered breathing in patients with craniofacial anomalies, with emphasis on indications, limitations, and interpretation of polysomnography.

Regulation of cranial neural crest cell fate by Irf6 and Twist1 interaction

A wide variety of common craniofacial birth defects and pediatric cancers arise from errors in the development of cranial neural crest cells (CNCC) that give rise to craniofacial skeletal and peripheral nervous systems. Identification of the genetic and environmental factors that regulate cell fate of CNCCs is crucial for uncovering the causes behind craniofacial disorders. Our lab has identified a dual‐transcription factor pathway that regulates CNCCs during EMT and migration. Initially, we identified a causative mutation in a TWIST1 binding site within an Interferon Regulatory Factor 6 (IRF6) enhancer in a multi‐generational family affected with syndromic cleft lip and palate called Van der Woude syndrome. Our subsequent animal work has shown that Twist1 and Irf6 genetically interact during early craniofacial development, and that the compound heterozygotes exhibit craniofacial abnormalities. We recently demonstrated that Irf6 is required for neural tube and CNCC development and that it interacts with Twist1 during EMT and migration of CNCCs. We also showed that TWIST1 is highly phosphorylated in CNCCs and its phosphorylation is crucial for regulating Irf6 and potentially miR10 family members in CNCC‐derived craniofacial tissues. Our recent in‐vivo and neural tube explants using dual fluorescent cell tracing system showed that Twist1 conditional knockout (CKO) in CNCCs significantly reduced cell delamination and disrupted EMT. The detached Twist1 CKO in CNCCs retained their epithelial signatures and migrated as clusters of epithelial‐like cells over significantly shorter distances. Finally, Twist1 phospho‐incompetent mice for two serine residues were recently generated to determine their impact on TWIST1 activity. Our preliminary results showed that Twist1S68A/S68A phospho‐mutant mice have craniofacial bone defects and forebrain hemorrhage.Support or Funding InformationUTHealth start‐up funds and a small grant from theRolanette and Berdon Lawrence Bone Disease Program of Texas

Evaluation and Management of Children with Obstructive Sleep Apnea Syndrome.

Obstructive sleep apnea syndrome (OSAS) is a common pediatric disorder characterized by recurrent events of partial or complete upper airway obstruction during sleep which result in abnormal ventilation and sleep pattern. OSAS in children is associated with neurobehavioral deficits and cardiovascular morbidity which highlights the need for prompt recognition, diagnosis, and treatment. The purpose of this state-of-the-art review is to provide an update on the evaluation and management of children with OSAS with emphasis on children with complex medical comorbidities and those with residual OSAS following first-line treatment. Proposed treatment strategies reflecting recommendations from a variety of professional societies are presented. All children should be screened for OSAS and those with typical symptoms (e.g., snoring, restless sleep, and daytime hyperactivity) or risk factors (e.g., neurologic, genetic, and craniofacial disorders) should undergo further evaluation including referral to a sleep specialist or pediatric otolaryngologist and overnight polysomnography, which provides a definitive diagnosis. A cardiology and/or endocrinology evaluation should be considered in high-risk children. For the majority of children, first-line treatment is tonsillectomy with or without adenoidectomy; however, some children exhibit multiple levels of airway obstruction and may require additional evaluation and management. Anti-inflammatory medications, weight loss, and oral appliances may be appropriate in select cases, particularly for mild OSAS. Following initial treatment, all children should be monitored for residual symptoms and polysomnography may be repeated to identify persistent disease, which can be managed with positive airway pressure ventilation and additional surgical approaches if required.

Craniofacial Syndromes Part I: Craniofacial Growth and Development, Craniosynostosis Syndromes, Craniofacial Microsomia, and Craniofacial Dysostoses

Craniofacial syndromes are a diverse group of congenital disorders primarily affecting structures of the head and face. Recent genetic advances have improved our ability to diagnosis specific syndromes, understand the molecular basis for abnormal embryogenesis, and anticipate future treatment needs. This is the first of a two-part series exploring the most common craniofacial disorders. This article will provide the embryologic and developmental foundation necessary to understand congenital craniofacial pathology. Clinical characteristics and molecular genetics needed to make an accurate diagnosis and formulate a treatment plan will be detailed for craniosynostosis syndromes, craniofacial microsomia, and craniofacial dysostoses. This review contains 13 figures, 4 tables, and 42 references. Keywords: craniofacial embryology, craniofacial growth, craniosynostosis, Apert syndrome, Crouzon syndrome, Pfieffer syndrome, craniofacial microsomia, hemifacial microsomia, Treacher Collins syndrome, Nager syndrome

Technical note on introducing a digital workflow for newborns with craniofacial anomalies based on intraoral scans - part I: 3D printed and milled palatal stimulation plate for trisomy 21

BackgroundAdvanced digital workflows in orthodontics and dentistry often require a combination of different software solutions to create patient appliances, which may be a complex and time-consuming process. The main objective of this technical note is to discuss treatment of craniofacial anomalies using digital technologies. We present a fully digital, linear workflow for manufacturing palatal plates for infants with craniofacial anomalies based on intraoral scanning. Switching to intraoral scanning in infant care is advantageous as taking conventional impressions carries the risk of impression material aspiration and/or infections caused by material remaining in the oronasal cavity.Material and methodsThe fully digital linear workflow presented in this technical note can be used to design and manufacture palatal plates for cleft palate patients as well as infants with functional disorders. We describe the workflow implemented in an infant with trisomy 21. The maxilla was registered using a digital scanner and a stimulation plate was created using dental CAD software and an individual impression tray module on a virtual model. Plates were manufactured using both additive and subtractive methods. Methacrylate based light curing resin and Poly-Ether-Ether-Ketone were the materials used.ResultsThe palatal area was successfully scanned to create a virtual model. The plates fitted well onto the palatal area. Manual post-processing was necessary to optimize a functional ridge along the vestibular fold and remove support structures from the additively manufactured plate as well as the milled plate produced from a blank. The additively manufactured plate fitted better than the milled one.ConclusionImplementing a fully digital linear workflow into clinical routine for treatment of neonates and infants with craniofacial disorders is feasible. The software solution presented here is suitable for this purpose and does not require additional software for the design. This is the key advantage of this workflow, which makes digital treatment accessible to all clinicians who want to deal with digital technology. Whether additive or subtractive manufacturing is preferred depends on the appliance material of choice and influences the fit of the appliance.

Unusual Impaction - Rosettes of Multiple Unerupted Molars: Review Article

Background: There is a wide spectrum of syndromes that include dental, oral and craniofacial disorders. Early diagnosis is often crucial for their effective treatment. However, not all syndromes can be clinically identified on time, especially in cases of absence of known family history. Moreover, the treatment of these patients is often complicated because of insufficient medical knowledge and because of the dento-alveolar and craniofacial developmental variations. Objective: The cases of a single impacted tooth are common. But the ones of multiple unerupted permanent molars are a rare phenomenon. They could be either isolated or associated with local or general pathologic factors. When identified, they present a challenging problem for the dentist, or the oral and maxillofacial surgeon. The aim of the article is to review the possible etiology and management modalities in cases of multiple unerupted molars. Results: The Pubmed and Medline database was searched. The information found was presented mainly by case reports. Unfortunately, because of the rarity of this clinical finding and the great clinical diversity, it is difficult to propose clinical procedure protocols. So, we assume, that the real incidence of that condition might be higher than the one mentioned in the literature. Discussion: It seems that due to the rare occurrence of severe complaints, many patients with multiple unerupted molars do not regularly present to their dentists, until other conditions take place. Clinical phenotyping together with reviewed data and evidence-based conclusions will ultimately pave the way for preventive strategies and therapeutic options in the future. This will improve the prognosis for better functional and aesthetic outcome for these patients and lead to a better quality of life. Conclusion: Care of individuals with syndromes affecting craniofacial and dento-alveolar structures is mostly treated by an interdisciplinary team who becomes more frequently involved in the refined diagnostic and etiological processes of these patients. The dentist and the surgical specialist must have a thorough knowledge about the various forms and possible etiology of tooth non-eruption. It can be a sign of various medical conditions. Therefore, detailed and specific investigations are further required, preceding a patient-tailored treatment plan.

Peripheral Nerve Stimulation for Facial Pain Using Conventional Devices: Indications and Results.

Trigeminal branch stimulation is a type of peripheral nerve stimulation (PNS) used to treat a variety of craniofacial pain disorders. Common indications include trigeminal neuralgia, trigeminal neuropathic pain, trigeminal deafferentation pain, trigeminal postherpetic neuralgia, supraorbital neuralgia, and migraine headaches. Supraorbital and infraorbital arrays are the most common electrode configurations, although preauricular, mandibular branch, and subcutaneous peripheral nerve field stimulation arrays have also been described. Trigeminal branch stimulation may be used as a stand-alone neuromodulation therapy or it may be combined with occipital nerve, sphenopalatine ganglion, or Gasserian ganglion stimulation to treat more complex pain patterns. Consistent with other forms of PNS, trigeminal branch stimulation is a minimally invasive, safe, and straightforward method of treating medically refractory neuropathic pain.

Global Burden of Craniofacial Disorders: Where Should Volunteering Plastic Surgeons and Governments Focus Their Care?

Approximately 11% of the global burden of disease is surgically treatable. When located within the head, face, and neck region, plastic surgeons are particularly trained to treat these conditions. The purpose of this study was to describe the etiology, disability, and barriers to receiving care for diseases of the head, face, mouth, and neck region across 4 low-and-middle-income countries. The Surgeons OverSeas Assessment of Surgical Need (SOSAS) instrument is a cluster randomized, cross-sectional, national survey administered in Nepal, Rwanda, Sierra Leone, and Uganda from 2011 to 2014. The survey identifies demographic characteristics, etiology, disease timing, proportion seeking/receiving care, barriers to care, and disability. Across the 4 countries, 1413 diseases of head, face, mouth, and neck region were identified. Masses (22.13%) and trauma (32.8%) were the most common etiology. Nepal reported the largest proportion of masses (40.22%) and Rwanda reported the largest amount of trauma (52.65%) (P < 0.001). Rwanda had the highest proportion of individuals seeking (89.6%) and receiving care (83.63%) while Sierra Leone reported the fewest (60% versus 47.77%, P < 0.001). In our multi-variate analysis literacy and chronic conditions were predictors for receiving care while diseases causing the greatest disability predicted not receiving care (ORa .58 and .48 versus 1.31 P < 0.001). The global volunteering plastic surgeon should be prepared to treat chronic craniofacial conditions. Furthermore, governments should address structural barriers, such as health illiteracy and lack of access to local plastic surgery care by supporting local training efforts.

Alterations in Surface Electromyography Are Associated with Subjective Masticatory Muscle Pain

Background Tenderness of masseters and temporalis can be considered a relevant tool for diagnosis of myo-type craniofacial pain disorders, but a limit of pain score systems is that they are based on subjective pain perception. Surface electromyography (sEMG) is a noninvasive and reliable tool for recording muscle activity. Therefore, we investigated whether a correlation exists between tenderness on masseters and temporalis, assessed by subjective pain scale, and muscles activity, evaluated by sEMG, in patients with painful temporomandibular disorder (TMD) and concurrent tension-type headache (TTH). Methods A cross-sectional study on fifty adult volunteer patients with TMD and TTH, who underwent tenderness protocol according to Diagnostic Criteria for TMD (DC/TMD) guidelines, was conducted followed by sEMG recording of temporalis and masseters. Pearson's correlation was performed to investigate the correlation between muscular activity and subjective pain scores. Results An overall moderate correlation between muscle tenderness and sEMG values (y = 1 + 1.2 · x; r2 = 0.62; p < 0.0001), particularly in the temporalis, was observed. Segregation of data occurred according to tenderness and sEMG values. At the highest pain score, the mean sEMG absolute value was higher at the temporalis than the masseters. Conclusions Our study provides evidence that subjective pain perception can be objectively quantified at a magnitude proportional to pain severity. At greater tenderness scores, higher sEMG activity at the level of temporalis could help discriminate clinically prevalent TTH versus prevalent TMD. sEMG confirms to be an accurate tool to reliably objectify the subjective perception of pain. When combined with clinical evaluation and patients' symptoms, sEMG increases diagnostic sensitivity in the field of myo-type craniofacial pain disorders. This trial is registered with NCT02789085.

Risk factors for children requiring adenotonsillectomy and their impact on postoperative complications: a retrospective analysis of 2000 patients.

Adenotonsillectomies are commonly performed procedures and sleep-disordered breathing is becoming increasingly important as an indication for surgery. Because of the higher risks in patients with obstructive sleep apnoea, the required level of postoperative care for these patients is currently under discussion, and better identification of patients at risk may reduce unnecessary postoperative monitoring. To evaluate the influence of obstructive sleep apnoea, and other risk factors, on peri-operative complications in children requiring adenotonsillectomy, we performed a retrospective case-control study that included 1995 patients treated between January 2009 and June 2017. In our analysis, young age (OR 3.8, 95%CI 2.1-7.1), low body weight (OR 2.6, 95%CI 1.5-4.4), obstructive sleep apnoea (OR 2.4, 95%CI 1.5-3.8), pre-existing craniofacial or syndromal disorders (OR 2.3, 95%CI 1.4-3.8) and adenotonsillectomy, compared with adenoidectomy alone, (OR 7.9, 95%CI 4.7-13.1) were identified as risk factors for complications during or after surgery, p<0.001. All 13 patients suffering from complications more than 3h postoperatively had obstructive sleep apnoea plus at least one more of these risk factors. Patients at risk of postoperative complications can therefore be identified by several criteria pre-operatively, and should be monitored postoperatively using pulse oximetry overnight. For all other patients, postoperative observation on a surgical ward without extra monitoring is sufficient. Admission to paediatric intensive care should be reserved for patients suffering serious intra-operative complications.

Craniofacial disorders in the course of Tourette's syndrome - a review of the literature

Craniofacial disorders in the course of Tourette's syndrome - a review of the literature

Craniofacial disorders in the course of Tourette's syndrome - a review of the literature

Craniofacial disorders in the course of Tourette's syndrome - a review of the literature

S4A-20 SESSION 4A: GENERALITIES IN CRANIOSYNOSTOSIS – PART I A CRITICAL CONTENT ANALYSIS OF SOCIAL MEDIA SUPPORT GROUPS FOR CRANIOSYNOSTOSIS: A VALUABLE TOOL FOR QUALITY IMPROVEMENT AND EDUCATION

Introduction: The parents and caregivers of patients with craniofacial disorders increasingly rely on social media for information and support, yet little is known in the surgical community about the information shared within these groups. We sought to characterize the content of posts in the largest Facebook support group for craniosynostosis to assess how providers can improve quality of outreach, education, and ultimately care for their patients. Methods: The Facebook group “Cranio Kids – Craniosynostosis Support” is the largest support group for craniosynostosis with over 15,000 members. We analyzed the last 1000 posts in this closed group as of January 1, 2019. Posts were categorized to identify the type of information shared within the group as well as how this information might be helpful to craniofacial surgeons to improve the care of their patients. Results: The 1000 examined posts were grouped into two broad categories: questions (n=517) and sharing of information (n=483). Several broad post themes were identified. Sub-groups within questions included questions about experience (n=213), questions seeking advice (n=197), questions regarding a diagnosis (n=41), surgeon inquiry (n=34), requesting support (n=20), requesting pictures (n=6), and others (n=6). Sharing of information consisted largely of medical updates (n=269), which were further characterized into pre-operative (n=58), peri-operative (n=5), and post-operative (n=206). In addition, photos (n=148) comprised a large sub-category within sharing of information, which were further grouped into pre-operative photos (n=77), post-operative photos (n=46), unknown photos (n=12), before/after photos (n=4), and other photos (n=9). Other sub-groups within sharing of information posts included sharing happy holiday wishes (n=22), non-medical social media updates (n=12), sharing fundraisers (n=4), sharing of news/media (n=3), sharing of products (n=3), and others (n=22). Interestingly, only 2 posts shared information regarding surgeons. Conclusion: This is the first study to characterize the content of social media support group posts. There is value to craniofacial surgeons in understanding the content of social media support group posts in order to identify general patient concerns, follow up on their outcomes, and identify areas for quality improvement.

Comparison of MRI with dedicated head and neck signal amplification coil and cone beam computed tomography: MRI is a useful tool in diagnostics of cranio-facial growth disorders

ObjectiveMagnetic resonance imaging (MRI) shows excellent image quality for the depiction of soft tissues and is therefore an important imaging technique in medical diagnostics. However, the practical simultaneous presentation of hard and soft tissue structures of the mouth, jaw and facial area is not fully satisfactory at this time. We investigated the image quality of 1.5 T MRI using a dedicated signal amplifying coil for the application in the oral and maxillofacial field of and compared it with cone beam computed tomography (CBCT). We hypothesized that imaging quality for growth disorders of the facial skull does not differ significantly between the two imaging techniques. Materials and methods12 patients were consecutively enrolled into this study between 01/2016 and 12/2017. Patients received diagnostic imaging for clinical indications using 1,5 T MRI using a dedicated head and neck coil for signal amplification as well as an CBCT. For each patient 5 different MRI sequences and one CBCT protocol were assessed. Images were evaluated by a radiologist and a dentist in consensus. On the basis of 51 anatomical structures and orthodontic, cephalometric reference points, the five datasets were subjectively rated and compared to the CBCT dataset. ResultsPatient age was in the range of 19–78 years. 2614 (69.8%) out of 3744 possible valuations were assessable. Compared to CBCT, MRI images were rated to have a superior image quality of presentation for 42 out of 51 anatomic structures (p < 0.05). Notably, 5 out of 51 structures were not assessable due to missing values. T1-weighted MRI images were rated superiorly to T2-weighted images in displaying anatomically relevant landmarks in the oral and maxillofacial field. MRI datasets were inferior in imaging cephalometric and orthodontic reference points in comparison to CBCT images. ConclusionIn conclusion, this pilot study demonstrates that radiation-free dental MRI enables a reliable detection of important anatomical structures. Thus, the signal amplified MRI presents a radiation-free imaging alternative to established CBCT in craniofacial growth disorders protocols. However, imaging quality in MRI datasets remains inferior to CBCT images for cephalometric and orthodontic reference points.

Opinions of Speech-Language Pathologists Regarding Speech Management for Children With Cleft Lip and Palate

The purpose of the present study was to examine practice patterns and opinions that speech-language pathologists (SLPs) have about speech-language intervention for children with cleft lip and palate. One hundred seven speech-language pathology members of the American Speech-Language-Hearing Association Special Interest Group 5: Craniofacial and Velopharyngeal Disorders Special Interest Group completed a 37-item online survey that examined common practices in early intervention as well as opinions about speech characteristics, assessment, and management strategies for children with cleft lip and palate. The overwhelming majority of respondents (96%) agreed that speech-language pathologists (SLPs) should meet with parents before palatal surgery to discuss speech-language issues. Although 90% of the SLPs identified increasing consonant inventory as an early intervention goal, lack of consensus was evident regarding the type of consonant to stimulate. Respondents agreed that while blowing activities are not useful in strengthening labial, lingual, or velopharyngeal movements, they are useful in heightening awareness of oral airflow for children with cleft palate. A large degree of variability was evident in opinions regarding prevalence and treatment of compensatory articulations as well as the effectiveness of treatment strategies designed to reduce perceived hypernasality and audible nasal emission. The findings of this study indicate a large degree of variability in opinions of SLP respondents regarding assessment and treatment of children with cleft lip and palate.

Examination of rare genetic variants in dental enamel genes: The potential role of next-generation sequencing in primary dental care.

To examine the potential role of next-generation sequencing (NGS) and genetic testing to guide preventive care in dental enamel disorders using publicly available databases to access the frequency of deleterious alleles in AMTN, AMLEX and ENAM, associated with amelogenesis imperfecta (AI). Public resources, including gnomAD (The Broad Institute) and the Center for Pediatric Genomic Medicine's warehouse, which together contain variants from nearly 145000 exomes and genomes. Public resources, including sequencing data from ~145000 exomes and genomes were queried for predicted loss of function variants with a minor allele frequency <1% in AMTN, AMLEX and ENAM. A total of 95 variants were identified in the combined dataset. If confirmed, this could be diagnostic for autosomal dominant AI. The rapid integration of NGS into clinical care allows for the expansion of genetic testing for disorders that are not currently tested routinely, including non-syndromic dental enamel disorders. A genotypic-driven diagnosis of a disorder of enamel development could impact dental care, especially in young children, including early and more frequent monitoring to prevent complications. As new gene-disease associations continue to emerge, including those for common and non-syndromic craniofacial disorders, the possibility of genomic-guided precision medicine and dentistry and the development of targeted, individualized therapeutics into standard clinical care will increase substantially.

Hedgehog Signaling and Embryonic Craniofacial Disorders.

Since its initial discovery in a Drosophila mutagenesis screen, the Hedgehog pathway has been revealed to be instrumental in the proper development of the vertebrate face. Vertebrates possess three hedgehog paralogs: Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh). Of the three, Shh has the broadest range of functions both in the face and elsewhere in the embryo, while Ihh and Dhh play more limited roles. The Hedgehog pathway is instrumental from the period of prechordal plate formation early in the embryo, until the fusion of the lip and secondary palate, which complete the major patterning events of the face. Disruption of Hedgehog signaling results in an array of developmental disorders in the face, ranging from minor alterations in the distance between the eyes to more serious conditions such as severe clefting of the lip and palate. Despite its critical role, Hedgehog signaling seems to be disrupted through a number of mechanisms that may either be direct, as in mutation of a downstream target of the Hedgehog ligand, or indirect, such as mutation in a ciliary protein that is otherwise seemingly unrelated to the Hedgehog pathway. A number of teratogens such as alcohol, statins and steroidal alkaloids also disrupt key aspects of Hedgehog signal transduction, leading to developmental defects that are similar, if not identical, to those of Hedgehog pathway mutations. The aim of this review is to highlight the variety of roles that Hedgehog signaling plays in developmental disorders of the vertebrate face.

A coupled reaction-diffusion-strain model predicts cranial vault formation in development and disease.

How cells utilize instructions provided by genes and integrate mechanical forces generated by tissue growth to produce morphology is a fundamental question of biology. Dermal bones of the vertebrate cranial vault are formed through the direct differentiation of mesenchymal cells on the neural surface into osteoblasts through intramembranous ossification. Here we join a self-organizing Turing mechanism, computational biomechanics, and experimental data to produce a 3D representative model of the growing cerebral surface, cranial vault bones, and sutures. We show how changes in single parameters regulating signaling during osteoblast differentiation and bone formation may explain cranial vault shape variation in craniofacial disorders. A key result is that toggling a parameter in our model results in closure of a cranial vault suture, an event that occurred during evolution of the cranial vault and that occurs in craniofacial disorders. Our approach provides an initial and important step toward integrating biomechanics into the genotype phenotype map to explain the production of variation in head morphology by developmental mechanisms.

Human Craniofacial Spliceosomopathies

Germline mutation of core components of the spliceosomes have been associated with a range of clinical disorders from isolated retinitis pigmentosa (RP) to developmental syndromes, while somatic mutations of spliceosome components are linked to cell cycle dysregulation and cancer. Recently a group of craniofacial and skeletal disorders caused by dominant mutations in spliceosomal genes has emerged. The first of these to be identified is mandibulofacial dysostosis type Guion‐Almeida (MFDGA), caused by haploinsufficiency of the U5 snRNP component EFTUD2. We recently identified haploinsufficiency of SF3B4 as the cause of Nager syndrome, an acrofacial dysostosis (AFD), although only in 60% of cases suggesting genetic heterogeneity. Mutation of SF3B4 was subsequently reported in AFD Rodriquez type. SF3B4 is part of the U2 snRNP of the major spliceosome. We also identified heterozygous mutations in a highly conserved regulatory exon of SNRPBas the cause of cerebro‐costo‐mandibular syndrome (CCMS). Our experimental data show that these mutations disturb highly conserved exonic splicing silencer sequences crucial to the regulation of the gene's expression. SNRPB encodes a component of the Sm complex of the spliceosome. Additional craniofacial spliceosomopathies result from mutations in splicing factors TXNL4A, RBM8A and CWC27. The frequent involvement of craniofacial structures invite questions on the sensitivity of craniofacial and in particular pharyngeal arch development to spliceosomal defects, and on the role of the spliceosome in the regulation of development. The report of a young patient with Nager syndrome with bilateral synchronous breast cancer raises the possibility of a link between germline mutation of splicing factors and cancer predisposition. We also have a patient with a pathogenic SNRPB mutation who is non‐penetrant for CCMS syndrome but was diagnosed with early onset breast cancer, further linking heritable splicing mutations with cancer predisposition.Many of the craniofacial spliceosomopathies share overlapping features with Treacher‐Collins syndrome (TCS), a ribosomopathy. We are currently validating mutations in a ribosomal gene in two patients with typical Nager syndrome. This finding may provide unique insight into the overlapping roles of transcription and translation in craniofacial development. A combination of human genetics and model systems research will be required to further unravel the role of the spliceosome and the ribosome in craniofacial and skeletal development.Support or Funding InformationGenome Canada, Alberta Children's Hospital Research Institute, Genome AlbertaThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.