Atypical mandibulofacial dysostosis with microcephaly diagnosed through the identification of a novel pathogenic mutation in EFTUD2.

BACKGROUND: Mandibulofacial dysostosis with microcephaly (MFDM, OMIM# 610536) is a rare monogenic disease that is caused by a mutation in the elongation factor Tu GTP binding domain containing 2 gene (EFTUD2, OMIM* 603892). It is characterized by mandibulofacial dysplasia, microcephaly, malformed ears, cleft palate, growth and intellectual disability. MFDM can be easily misdiagnosed due to its phenotypic overlap with other craniofacial dysostosis syndromes. The clinical presentation of MFDM is highly variable among patients. METHODS: A patient with craniofacial anomalies was enrolled and evaluated by a multidisciplinary team. To make a definitive diagnosis, whole-exome sequencing was performed, followed by validation by Sanger sequencing. RESULTS: The patient presented with extensive facial bone dysostosis, upward slanting palpebral fissures, outer and middle ear malformation, a previously unreported orbit anomaly, and spina bifida occulta. A novel, pathogenic insertion mutation (c.215_216insT: p.Tyr73Valfs*4) in EFTUD2 was identified as the likely cause of the disease. CONCLUSIONS: We diagnosed this atypical case of MFDM by the detection of a novel pathogenetic mutation in EFTUD2. We also observed previously unreported features. These findings enrich both the genotypic and phenotypic spectrum of MFDM.

The Role of Splicing Factor SF3B4 in Congenital Diseases and Tumors.

In eukaryotes, spliceosomes catalyze the splicing of pre-mRNA to mature mRNA. As the core subunit of U2 spliceosome, splicing factor SF3b4 plays not only a crucial role in the splicing process, but also a role in transcription, translation, and cell signal transduction, and participates in the regulation of cell cycle, cell differentiation, and immune deficiency. In recent years, more and more research studies on SF3b4-related diseases, such as Nager syndrome and cancer, have been conducted. It has been found that SF3b4 mutations led to abnormal cell growth and were involved in the development and occurrence of these diseases. In this review, the diseases, mainly congenital diseases and tumors, in which SF3B4 is involved and the pathogenesis of them were summarized, aiming to provide a better understanding of the roles of SF3B4 in the prevention, diagnosis, and treatment of diseases in the future.

Treacher Collins syndrome: Clinical report and retrospective analysis of Chinese patients.

BACKGROUND: Treacher Collins syndrome-1 (TCS1; OMIM# 154500) is a rare autosomal dominant disease that is defined by congenital craniofacial dysplasia. Here, we report four sporadic and one familial case of TCS1 in Chinese patients with clinical features presenting as hypoplasia of the zygomatic complex and mandible, downslanting palpebral fissures, coloboma of the lower eyelids, and conductive hearing loss. MATERIALS AND METHODS: Audiological, radiological, and physical examinations were performed. Targeted next-generation sequencing (NGS) was performed to examine the genetics of this disease in five probands, and Sanger sequencing was used to confirm the identified variants. A literature review discusses the pathogenesis, treatment, and prevention of TCS1. RESULTS: We identified a novel insertion of c.939_940insA (p.Gly314Argfs*35; NM_001135243.1), a novel deletion of c.1766delC (p.Pro589Leufs*7), two previously reported insertions of c.1999_2000insC (p.Arg667Profs*31) and c.4218_4219insG (p.Ser1407Valfs*23), and one previously reported deletion of c.4369_4373delAAGAA (p.Lys1457Glufs*12) in the TCOF1 gene. All five cases exhibited a degree of interfamilial and intrafamilial phenotypic variability. A review of the literature revealed no clear evidence of a genotype-phenotype correlation in TCS1. CONCLUSION: Our results expand the variant spectrum of TCOF1 and highlight that NGS is essential for the diagnosis of TCS and that genetic counseling is beneficial for guiding prevention.

Spliceosomopathies: Diseases and mechanisms.

The spliceosome is a complex of RNA and proteins that function together to identify intron-exon junctions in precursor messenger-RNAs, splice out the introns, and join the flanking exons. Mutations in any one of the genes encoding the proteins that make up the spliceosome may result in diseases known as spliceosomopathies. While the spliceosome is active in all cell types, with the majority of the proteins presumably expressed ubiquitously, spliceosomopathies tend to be tissue-specific as a result of germ line or somatic mutations, with phenotypes affecting primarily the retina in retinitis pigmentosa, hematopoietic lineages in myelodysplastic syndromes, or the craniofacial skeleton in mandibulofacial dysostosis. Here we describe the major spliceosomopathies, review the proposed mechanisms underlying retinitis pigmentosa and myelodysplastic syndromes, and discuss how this knowledge may inform our understanding of craniofacial spliceosomopathies.

POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4.

PURPOSE: Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2-1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly. METHODS: We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish. RESULTS: We identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives. CONCLUSION: Pathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS.

Correlation Between Mandible and External Ear in Patients with Treacher-Collins Syndrome.

BACKGROUND: Patients with Treacher-Collins syndrome (TCS) are frequently affected by congenital ear deformities. The external ear in patients with TCS tends to have both abnormal morphology and reduced overall volume. Previous studies considered a correlation exists between TCS mandibular skeletal features and external ear volume. The purpose of this study was to assess the external ear volume in patients with TCS 3-dimensionally. Furthermore, this study evaluated the relationship between mandibular morphology, external ear profile, and external ear volume. METHODS: A total of 36 nonoperated patients with TCS were compared to 39 age- and gender-matched normal controls. Morphologic variables of the mandible and the external ear were compared between TCS group and controls by 3-dimensional cephalometrics. The external ear volume and morphologic variables were analyzed with independent sample T-tests and Pearson correlation coefficient analyses (level of evidence: level III). RESULTS: The external ear volume was reduced by approximately 50% in patients with TCS compared to controls (P < 0.001). External ear length and width were positively correlated with external ear volume (length: r = 0.809, P < 0.001 on left and r = 0.732, P < 0.001 on right; width: r = 0.518, P = 0.001 on left and r = 0.447, P < 0.010 on right). A negative correlation of right ear inclination angle and external ear volume was shown in patients with TCS (r = -0.396, P = 0.027). However, no correlation was shown for the mandibular anatomic variables. CONCLUSIONS: Three-dimensional analysis confirmed that external ear volume is significantly reduced in patients with TCS. The external ear dimensions and orientation correlated significantly with ear volume. There was no intrinsic association between the severity of mandibular deformity and external ear volume.

Difficult airway management in a patient with Treacher Collins syndrome using two-part surgery. / Manejo de la vía aérea en una paciente con síndrome de Treacher Collins en 2 tiempos quirúrgicos.

Treacher Collins syndrome (TCS), Franceschetti-Zwahlen-Klein, or mandibulofacial dysostosis, is a rare disorder of craniofacial development (incidence of approximately 1:50.000 live births). TCS is relevant to the anaesthetist because it can cause difficulties in airway management. A case report is presented of a 24 year-old woman who was referred to our institution for facial reconstruction surgery in two stages. In both surgeries Airtraq™ was essential for airway management. By presenting this case, it is intended to show that planning, communication and teamwork are indispensable for patient safety.

tp53-dependent and independent signaling underlies the pathogenesis and possible prevention of Acrofacial Dysostosis-Cincinnati type.

Ribosome biogenesis is a global process required for growth and proliferation in all cells, but disruptions in this process surprisingly lead to tissue-specific phenotypic disorders termed ribosomopathies. Pathogenic variants in the RNA Polymerase (Pol) I subunit POLR1A cause Acrofacial Dysostosis-Cincinnati type, which is characterized by craniofacial and limb anomalies. In a zebrafish model of Acrofacial Dysostosis-Cincinnati type, we demonstrate that polr1a-/- mutants exhibit deficient 47S rRNA transcription, reduced monosomes and polysomes and, consequently, defects in protein translation. This results in Tp53-dependent neuroepithelial apoptosis, diminished neural crest cell proliferation and cranioskeletal anomalies. This indicates that POLR1A is critical for rRNA transcription, which is considered a rate limiting step in ribosome biogenesis, underpinning its requirement for neuroepithelial cell and neural crest cell proliferation and survival. To understand the contribution of the Tp53 pathway to the pathogenesis of Acrofacial Dysostosis-Cincinnati type, we genetically inhibited tp53 in polr1a-/- mutant embryos. Tp53 inhibition suppresses neuroepithelial apoptosis and partially ameliorates the polr1a mutant phenotype. However, complete rescue of cartilage development is not observed due to the failure to improve rDNA transcription and neural crest cell proliferation. Altogether, these data reveal specific functions for both Tp53-dependent and independent signaling downstream of polr1a in ribosome biogenesis during neural crest cell and craniofacial development, in the pathogenesis of Acrofacial Dysostosis-Cincinnati type. Furthermore, our work sets the stage for identifying Tp53-independent therapies to potentially prevent Acrofacial dysostosis-Cincinnati type and other similar ribosomopathies.

Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders.

Many craniofacial disorders are caused by heterozygous mutations in general regulators of housekeeping cellular functions such as transcription or ribosome biogenesis. Although it is understood that many of these malformations are a consequence of defects in cranial neural crest cells, a cell type that gives rise to most of the facial structures during embryogenesis, the mechanism underlying cell-type selectivity of these defects remains largely unknown. By exploring molecular functions of DDX21, a DEAD-box RNA helicase involved in control of both RNA polymerase (Pol) I- and II-dependent transcriptional arms of ribosome biogenesis, we uncovered a previously unappreciated mechanism linking nucleolar dysfunction, ribosomal DNA (rDNA) damage, and craniofacial malformations. Here we demonstrate that genetic perturbations associated with Treacher Collins syndrome, a craniofacial disorder caused by heterozygous mutations in components of the Pol I transcriptional machinery or its cofactor TCOF1 (ref. 1), lead to relocalization of DDX21 from the nucleolus to the nucleoplasm, its loss from the chromatin targets, as well as inhibition of rRNA processing and downregulation of ribosomal protein gene transcription. These effects are cell-type-selective, cell-autonomous, and involve activation of p53 tumour-suppressor protein. We further show that cranial neural crest cells are sensitized to p53-mediated apoptosis, but blocking DDX21 loss from the nucleolus and chromatin rescues both the susceptibility to apoptosis and the craniofacial phenotypes associated with Treacher Collins syndrome. This mechanism is not restricted to cranial neural crest cells, as blood formation is also hypersensitive to loss of DDX21 functions. Accordingly, ribosomal gene perturbations associated with Diamond-Blackfan anaemia disrupt DDX21 localization. At the molecular level, we demonstrate that impaired rRNA synthesis elicits a DNA damage response, and that rDNA damage results in tissue-selective and dosage-dependent effects on craniofacial development. Taken together, our findings illustrate how disruption in general regulators that compromise nucleolar homeostasis can result in tissue-selective malformations.

Restoration of polr1c in Early Embryogenesis Rescues the Type 3 Treacher Collins Syndrome Facial Malformation Phenotype in Zebrafish.

Treacher Collins syndrome (TCS) is a rare congenital birth disorder (1 in 50,000 live births) characterized by severe craniofacial defects. Recently, the authors' group unfolded the pathogenesis of polr1c Type 3 TCS by using the zebrafish model. Facial development depends on the neural crest cells, in which polr1c plays a role in regulating their expression. In this study, the authors aimed to identify the functional time window of polr1c in TCS by the use of photo-morpholino to restore the polr1c expression at different time points. Results suggested that the restoration of polr1c at 8 hours after fertilization could rescue the TCS facial malformation phenotype by correcting the neural crest cell expression, reducing the cell death, and normalizing the p53 mRNA expression level in the rescued morphants. However, such recovery could not be reproduced if the polr1c is restored after 30 hours after fertilization.

Orbital volume and shape in Treacher Collins syndrome.

Orbito-palpebral reconstruction is a challenge in Treacher Collins syndrome (TCS). This study investigates orbital phenotypes in TCS using cephalometry and orbital shape analysis. Eighteen TCS and 52 control patients were included in this study, using the Dr Warehouse database. Orbital cephalometry was based on 20 landmarks, 10 planes, 16 angles, and 22 distances. Orbits were segmented. Registration-based, age-specific mean models were generated using semi-automatic segmentation, and aligned and compared using color-coded distance maps - mean absolute distance (MAD), Hausdorff distance (HD), and Dice similarity coefficient (DSC). Symmetry was assessed by mirroring and DSC computing. Central orbital depth (COD) and medial orbital depth (MOD) allowed 100% of orbits to be classified. COD and lateral orbital depth (LOD) were different from the controls. Average MAD between TCS and controls was ≤1.5 mm, while for HD it was >1.5 mm, and for DSC <1. TCS orbits were more asymmetrical than controls, and orbital volumes were smaller when age was considered as a confounding factor, and had a trend for normalization with age. This report emphasizes the importance of combining different morphometric approaches in the phenotype characterization of non-trivial structures such as the orbit, and supports composite skeletal and soft-tissue strategies for the management of the peri-orbital region.

Cephalometric Predictors of Clinical Severity in Treacher Collins Syndrome.

BACKGROUND: The aim of this study was to identify cephalometric measurements associated with clinical severity in patients with Treacher Collins syndrome. METHODS: A retrospective single-institution review of patients with Treacher Collins syndrome was conducted. Preoperative cephalograms and computed tomographic scans (n = 30) were evaluated. Fifty cephalometric measurements were compared to age-specific normative data using analysis of variance. These cephalometric measurements and the patient's Pruzansky classification were correlated to clinical severity using Spearman analysis. Clinical severity was defined as severe (required tracheostomy), moderate (obstructive sleep apnea, oral cleft, or gastrostomy-tube), or mild (absence of listed comorbidities). Cephalometric measurements with a strong correlation (r > 0.60) were identified as predictors of clinical severity. RESULTS: Cephalograms of the study population contained 30 measurements that were found to be significantly different from normative data (p < 0.01). These measurements were related largely to maxillary/mandibular projection, maxillary/mandibular plane angle, mandibular morphology, facial height, facial convexity, and mandible/throat position. Ten of these 30 statistically significant measurements in addition to Pruzansky classification were found to be strongly correlated (r > 0.60) to clinical severity. These measurements include the following: mandibular projection/position (sella-nasion-pogonion, r = -0.64; hyoid-menton, r = -0.62); posterior facial height (posterior facial height/anterior facial height, r = 0.60; condyle-gonion, r = -0.66); maxillary/mandibular plane angle (sella-nasion-mandibular plane, r = 0.62; Frankfort horizontal-mandibular plane, r = 0.61; sella-nasion-palatal plane, r = 0.69; sella-nasion-symphysis, r = -0.69); and Pruzansky classification (r = 0.82). CONCLUSION: Specific cephalometric measurements of increased mandibular retrognathia, decreased posterior facial height, more obtuse maxillary/mandibular plane angle and more obtuse symphysis notch angle are strongly correlated to increased clinical severity in patients with Treacher Collins syndrome.

Cnbp ameliorates Treacher Collins Syndrome craniofacial anomalies through a pathway that involves redox-responsive genes.

Treacher Collins Syndrome (TCS) is a rare congenital disease (1:50 000 live births) characterized by craniofacial defects, including hypoplasia of facial bones, cleft palate and palpebral fissures. Over 90% of the cases are due to mutations in the TCOF1 gene, which codifies the nucleolar protein Treacle. Here we report a novel TCS-like zebrafish model displaying features that fully recapitulate the spectrum of craniofacial abnormalities observed in patients. As it was reported for a Tcof1+/- mouse model, Treacle depletion in zebrafish caused reduced rRNA transcription, stabilization of Tp53 and increased cell death in the cephalic region. An increase of ROS along with the overexpression of redox-responsive genes was detected; furthermore, treatment with antioxidants ameliorated the phenotypic defects of craniofacial anomalies in TCS-like larvae. On the other hand, Treacle depletion led to a lowering in the abundance of Cnbp, a protein required for proper craniofacial development. Tcof1 knockdown in transgenic zebrafish overexpressing cnbp resulted in barely affected craniofacial cartilage development, reinforcing the notion that Cnbp has a role in the pathogenesis of TCS. The cnbp overexpression rescued the TCS phenotype in a dose-dependent manner by a ROS-cytoprotective action that prevented the redox-responsive genes' upregulation but did not normalize the synthesis of rRNAs. Finally, a positive correlation between the expression of CNBP and TCOF1 in mesenchymal cells from both control and TCS subjects was found. Based on this, we suggest CNBP as an additional target for new alternative therapeutic treatments to reduce craniofacial defects not only in TCS but also in other neurocristopathies.

Tcof1-Related Molecular Networks in Treacher Collins Syndrome.

Treacher Collins syndrome (TCS) is a rare, autosomal-dominant disorder characterized by craniofacial deformities, and is primarily caused by mutations in the Tcof1 gene. This article was aimed to perform a comprehensive literature review and systematic bioinformatic analysis of Tcof1-related molecular networks in TCS. First, the up- and down-regulated genes in Tcof1 heterozygous haploinsufficient mutant mice embryos and Tcof1 knockdown and Tcof1 over-expressed neuroblastoma N1E-115 cells were obtained from the Gene Expression Omnibus database. The GeneDecks database was used to calculate the 500 genes most closely related to Tcof1. Then, the relationships between 4 gene sets (a predicted set and sets comparing the wildtype with the 3 Gene Expression Omnibus datasets) were analyzed using the DAVID, GeneMANIA and STRING databases. The analysis results showed that the Tcof1-related genes were enriched in various biological processes, including cell proliferation, apoptosis, cell cycle, differentiation, and migration. They were also enriched in several signaling pathways, such as the ribosome, p53, cell cycle, and WNT signaling pathways. Additionally, these genes clearly had direct or indirect interactions with Tcof1 and between each other. Literature review and bioinformatic analysis finds imply that special attention should be given to these pathways, as they may offer target points for TCS therapies.

Pathogenesis of POLR1C-dependent Type 3 Treacher Collins Syndrome revealed by a zebrafish model.

Treacher Collins Syndrome (TCS) is a rare congenital birth disorder (1 in 50,000 live births) characterized by severe craniofacial defects, including the downward slanting palpebral fissures, hypoplasia of the facial bones, and cleft palate (CP). Over 90% of patients with TCS have a mutation in the TCOF1 gene. However, some patients exhibit mutations in two new causative genes, POLR1C and POLR1D, which encode subunits of RNA polymerases I and III, that affect ribosome biogenesis. In this study, we examine the role of POLR1C in TCS using zebrafish as a model system. Our data confirmed that polr1c is highly expressed in the facial region, and dysfunction of this gene by knockdown or knock-out resulted in mis-expression of neural crest cells during early development that leads to TCS phenotype. Next generation sequencing and bioinformatics analysis of the polr1c mutants further demonstrated the up-regulated p53 pathway and predicted skeletal disorders. Lastly, we partially rescued the TCS facial phenotype in the background of p53 mutants, which supported the hypothesis that POLR1C-dependent type 3 TCS is associated with the p53 pathway.

Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update.

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).

Reduced three-dimensional airway volume is a function of skeletal dysmorphology in Treacher Collins syndrome.

BACKGROUND: Children with Treacher Collins syndrome frequently present with obstructive sleep apnea and respiratory insufficiency. The purpose of this study was to three-dimensionally calculate upper airway volume in these patients. The authors also assessed the correlation between bony craniofacial morphology and spatial position with airway volume. METHODS: Thirty Treacher Collins syndrome patients who have not been operated on were compared with a sample of 35 age- and sex-matched unaffected controls. Upper airway volume was stratified into retropalatal and retroglossal aspects. Three-dimensional craniometric findings were compared between patients and controls. Among Treacher Collins syndrome patients, the authors assessed the relationship of craniofacial morphology and spatial positioning to airway volume. Statistical analyses included independent sample t tests and Pearson correlation coefficient analyses. RESULTS: Decreased total upper airway volume (p = 0.034) was found in the Treacher Collins syndrome group, attributable primarily to a decrease in retroglossal airway volume (p = 0.009). Regarding three-dimensional craniometric variables, maxillary and mandibular length (r = 0.76, p < 0.001; and r = 0.68, p < 0.001), and the anterior and posterior cranial base (r = 0.61, p < 0.001; and r = 0.77, p < 0.001) were positively correlated with airway volume in Treacher Collins syndrome patients. Transverse internal diameters of the upper airway were also positively correlated with airway volume (r = 0.635, p = 0.001; and r = 0.511, p = 0.006); however, no correlation was shown for the anteroposterior airway diameters. CONCLUSIONS: Three-dimensional analysis revealed diminished upper airway volume in Treacher Collins syndrome, with the retroglossal region being the most severely constricted. Maxillomandibular dysmorphologies, and their relationship to the cranial base, correlated significantly with airway findings.

Tissue specific roles for the ribosome biogenesis factor Wdr43 in zebrafish development.

During vertebrate craniofacial development, neural crest cells (NCCs) contribute to most of the craniofacial pharyngeal skeleton. Defects in NCC specification, migration and differentiation resulting in malformations in the craniofacial complex are associated with human craniofacial disorders including Treacher-Collins Syndrome, caused by mutations in TCOF1. It has been hypothesized that perturbed ribosome biogenesis and resulting p53 mediated neuroepithelial apoptosis results in NCC hypoplasia in mouse Tcof1 mutants. However, the underlying mechanisms linking ribosome biogenesis and NCC development remain poorly understood. Here we report a new zebrafish mutant, fantome (fan), which harbors a point mutation and predicted premature stop codon in zebrafish wdr43, the ortholog to yeast UTP5. Although wdr43 mRNA is widely expressed during early zebrafish development, and its deficiency triggers early neural, eye, heart and pharyngeal arch defects, later defects appear fairly restricted to NCC derived craniofacial cartilages. Here we show that the C-terminus of Wdr43, which is absent in fan mutant protein, is both necessary and sufficient to mediate its nucleolar localization and protein interactions in metazoans. We demonstrate that Wdr43 functions in ribosome biogenesis, and that defects observed in fan mutants are mediated by a p53 dependent pathway. Finally, we show that proper localization of a variety of nucleolar proteins, including TCOF1, is dependent on that of WDR43. Together, our findings provide new insight into roles for Wdr43 in development, ribosome biogenesis, and also ribosomopathy-induced craniofacial phenotypes including Treacher-Collins Syndrome.

Cholesteatoma of the hypotympanum in a patient with Treacher Collins syndrome.

In the present article we report a cholesteatoma of the hypotympanum extending to the jugular foramen in a 16-year-old male with Treacher Collins syndrome. Preoperative imaging excluded jugular paraganglioma and set the diagnosis of cholesteatoma. We discuss the operative treatment via a large hypotympanotomy and creation of an open hypotympanic cavity. To the authors' knowledge this is the first description of hypotympanal cholesteatoma with such an extension, being treated through this approach.