RNA Polymerases I and III in development and disease.

Ribosomes are macromolecular machines that are globally required for the translation of all proteins in all cells. Ribosome biogenesis, which is essential for cell growth, proliferation and survival, commences with transcription of a variety of RNAs by RNA Polymerases I and III. RNA Polymerase I (Pol I) transcribes ribosomal RNA (rRNA), while RNA Polymerase III (Pol III) transcribes 5S ribosomal RNA and transfer RNAs (tRNA) in addition to a wide variety of small non-coding RNAs. Interestingly, despite their global importance, disruptions in Pol I and Pol III function result in tissue-specific developmental disorders, with craniofacial anomalies and leukodystrophy/neurodegenerative disease being among the most prevalent. Furthermore, pathogenic variants in genes encoding subunits shared between Pol I and Pol III give rise to distinct syndromes depending on whether Pol I or Pol III function is disrupted. In this review, we discuss the global roles of Pol I and III transcription, the consequences of disruptions in Pol I and III transcription, disorders arising from pathogenic variants in Pol I and Pol III subunits, and mechanisms underpinning their tissue-specific phenotypes.

Untangling Zebrafish Genetic Annotation: Addressing Complexities and Nomenclature Issues in Orthologous Evaluation of TCOF1 and NOLC1.

Treacher Collins syndrome (TCS) is a genetic disorder affecting facial development, primarily caused by mutations in the TCOF1 gene. TCOF1, along with NOLC1, play important roles in ribosomal RNA transcription and processing. Previously, a zebrafish model of TCS successfully recapitulated the main characteristics of the syndrome by knocking down the expression of a gene on chromosome 13 (coding for Uniprot ID B8JIY2), which was identified as the TCOF1 orthologue. However, database updates renamed this gene as nolc1 and the zebrafish database (ZFIN) identified a different gene on chromosome 14 as the TCOF1 orthologue (coding for Uniprot ID E7F9D9). NOLC1 and TCOF1 are large proteins with unstructured regions and repetitive sequences that complicate alignments and comparisons. Also, the additional whole genome duplication of teleosts sets further difficulty. In this study, we present evidence that endorses that NOLC1 and TCOF1 are paralogs, and that the zebrafish gene on chromosome 14 is a low-complexity LisH domain-containing factor that displays homology to NOLC1 but lacks essential sequence features to accomplish TCOF1 nucleolar functions. Our analysis also supports the idea that zebrafish, as has been suggested for other non-tetrapod vertebrates, lack the TCOF1 gene that is associated with tripartite nucleolus. Using BLAST searches in a group of teleost genomes, we identified fish-specific sequences similar to E7F9D9 zebrafish protein. We propose naming them "LisH-containing Low Complexity Proteins" (LLCP). Interestingly, the gene on chromosome 13 (nolc1) displays the sequence features, developmental expression patterns, and phenotypic impact of depletion that are characteristic of TCOF1 functions. These findings suggest that in teleost fish, the nucleolar functions described for both NOLC1 and TCOF1 mediated by their repeated motifs, are carried out by a single gene, nolc1. Our study, which is mainly based on computational tools available as free web-based algorithms, could help to solve similar conflicts regarding gene orthology in zebrafish.

Neural Crest.

This chapter discusses the role of cardiac neural crest cells in the formation of the septum that divides the cardiac arterial pole into separate systemic and pulmonary arteries. Further, cardiac neural crest cells directly support the normal development and patterning of derivatives of the caudal pharyngeal arches, including the great arteries, thymus, thyroid, and parathyroids. Recently, cardiac neural crest cells have also been shown to indirectly influence the development of the secondary heart field, another derivative of the caudal pharynx, by modulating signaling in the pharynx. The contribution and function of the cardiac neural crest cells has been learned in avian models; most of the genes associated with cardiac neural crest function have been identified using mouse models. Together these studies show that the neural crest cells may not only critical for normal cardiovascular development but also may be involved secondarily because they represent a major component in the complex tissue interactions in the caudal pharynx and outflow tract. Cardiac neural crest cells span from the caudal pharynx into the outflow tract, and therefore may be susceptible to any perturbation in or by other cells in these regions. Thus, understanding congenital cardiac outflow malformations in human sequences of malformations resulting from genetic and/or environmental insults necessarily requires better understanding the role of cardiac neural crest cells in cardiac development.

A systematic review on Treacher Collins syndrome: Correlation between molecular genetic findings and clinical severity.

Treacher Collins syndrome (TCS, OMIM: 154500) is a rare congenital craniofacial disorder that is caused by variants in the genes TCOF1, POLR1D, POLR1C, and POLR1B. Studies on the association between phenotypic variability and their relative variants are very limited. This systematic review summarized the 53 literatures from PubMed and Scopus to explore the potential TCS genotype-phenotype correlations with statistical analysis. Studies reporting both complete molecular genetics and clinical data were included. We identified that the molecular anomaly within TCOF1 (88.71%) accounted for most TCS cases. The only true hot spot for TCOF1 was detected in exon 24, with recurrent c.4369_4373delAAGAA variant is identified. While the hot spot for POLR1D, POLR1C, and POLR1B were identified in exons 3, 8, and 15, respectively. Our result suggested that the higher severity level was likely to be observed in Asian patients harboring TCOF1 variants rather than POLR1. Moreover, common 5-bp deletions tended to have a higher severity degree in comparison to any variants within exon 24 of TCOF1. In summary, this report suggested the relationship between genetic and clinical data in TCS. Our findings could be used as a reference for clinical diagnosis and further biological studies.

An automatic facial landmarking for children with rare diseases.

Two to three thousand syndromes modify facial features: their screening requires the eye of an expert in dysmorphology. A widely used tool in shape characterization is geometric morphometrics based on landmarks, which are precise and reproducible anatomical points. Landmark positioning is user dependent and time consuming. Many automatic landmarking tools are currently available but do not work for children, because they have mainly been trained using photographic databases of healthy adults. Here, we developed a method for building an automatic landmarking pipeline for frontal and lateral facial photographs as well as photographs of external ears. We evaluated the algorithm on patients diagnosed with Treacher Collins (TC) syndrome as it is the most frequent mandibulofacial dysostosis in humans and is clinically recognizable although highly variable in severity. We extracted photographs from the photographic database of the maxillofacial surgery and plastic surgery department of Hôpital Necker-Enfants Malades in Paris, France with the diagnosis of TC syndrome. The control group was built from children admitted for craniofacial trauma or skin lesions. After testing two methods of object detection by bounding boxes, a Haar Cascade-based tool and a Faster Region-based Convolutional Neural Network (Faster R-CNN)-based tool, we evaluated three different automatic annotation algorithms: the patch-based active appearance model (AAM), the holistic AAM, and the constrained local model (CLM). The final error corresponding to the distance between the points placed by automatic annotation and those placed by manual annotation was reported. We included, respectively, 1664, 2044, and 1375 manually annotated frontal, profile, and ear photographs. Object recognition was optimized with the Faster R-CNN-based detector. The best annotation model was the patch-based AAM (p < 0.001 for frontal faces, p = 0.082 for profile faces and p < 0.001 for ears). This automatic annotation model resulted in the same classification performance as manually annotated data. Pretraining on public photographs did not improve the performance of the model. We defined a pipeline to create automatic annotation models adapted to faces with congenital anomalies, an essential prerequisite for research in dysmorphology.

A clinically-relevant residue of POLR1D is required for Drosophila development.

BACKGROUND: POLR1D is a subunit of RNA Polymerases I and III, which synthesize ribosomal RNAs. Dysregulation of these polymerases cause several types of diseases, including ribosomopathies. The craniofacial disorder Treacher Collins Syndrome (TCS) is a ribosomopathy caused by mutations in several subunits of RNA Polymerase I, including POLR1D. Here, we characterized the effect of a missense mutation in POLR1D and RNAi knockdown of POLR1D on Drosophila development. RESULTS: We found that a missense mutation in Drosophila POLR1D (G30R) reduced larval rRNA levels, slowed larval growth, and arrested larval development. Remarkably, the G30R substitution is at an orthologous glycine in POLR1D that is mutated in a TCS patient (G52E). We showed that the G52E mutation in human POLR1D, and the comparable substitution (G30E) in Drosophila POLR1D, reduced their ability to heterodimerize with POLR1C in vitro. We also found that POLR1D is required early in the development of Drosophila neural cells. Furthermore, an RNAi screen revealed that POLR1D is also required for development of non-neural Drosophila cells, suggesting the possibility of defects in other cell types. CONCLUSIONS: These results establish a role for POLR1D in Drosophila development, and present Drosophila as an attractive model to evaluate the molecular defects of TCS mutations in POLR1D.

Misdiagnosis of Tracher-Collins Syndrome Initially Attributed to Drug Teratogenicity: A Moroccan Case Report.

Background: Treacher Collins syndrome (TCS) is a rare congenital disorder of craniofacial development characterized by numerous developmental anomalies that are restricted to the head and neck. Most TCS cases are inherited in an autosomal dominant manner. The diagnosis of TCS relies on clinical and radiographic findings. The four genes involved in TCS are TCOF1, POLR1D, POLR1C, and POLR1B. Case presentation: In this report, we present the case of a 7-year-old Moroccan boy who exhibited distinctive dysmorphic features, including coloboma and zygomatic bone hypoplasia. Upon genetic analysis, a mutation in the TCOF1 gene was identified, conclusively confirming the presence of Treacher Collins Syndrome. It is worthy that the correct etiological diagnosis was significantly delayed due to the initial misperception that the observed malformation syndrome was a result of drug teratogenicity. Conclusions: This case highlights the importance of seeking pharmacovigilance advice if any adverse event occurs following medication use. Furthermore, requesting a genetic consultation to establish a confirmed etiological diagnosis for any malformation syndrome can significantly reduce the protracted social and psychological suffering that patients and their families may endure.

A Novel Missense Variant in the TCOF1 Gene in one Chinese Case With Treacher Collins Syndrome.

The purpose of this study is to analyze the clinical characteristics of a Treacher Collins syndrome (TCS) patient carrying a de novo variant of TCOF1, and briefly analyze the correlation between genetic results and clinical features. Also, the pathogenesis and clinical treatment of TCS are reviewed.A Chinese pedigree with TCS containing 8 members was enrolled. Phenotype of the proband was evaluated by a surgeon, then whole exome sequencing of the proband was performed. Then we verified the proband-derived variants by Sanger sequencing in the pedigree. Correlation between genotype and phenotype was analyzed.The study was conducted in a stomatological hospital.A Chinese pedigree with TCS containing 8 members.To ascertain the genetic variants in the Chinese pedigree with TCS.Blood samples were collected.We reported a case of typical TCS with a de novo missense variant (NM_001371623.1:c.38T>G, p.(Leu13Arg)) in exon 1 of TCOF1, who presented asymmetrical facial abnormalities, including downward slanting of the palpebral fissures, sparse eyebrows, lateral tilt of the eyeballs, bilateral external ears deformities, hypoplasia of midface, reduction of the zygomatic body, bilateral orbital invagination, right external auditory canal atresia, mandibular ramus short deformity, cleft palate and the whole face was convex.This research found a novel variant of TCS in Chinese, expanding the spectrum of TCS pathogenic variants. Genetic results combined with clinical phenotype can make a definite diagnosis and provide genetic counseling for the family.

Description of Total Population Hospital Admissions for Treacher Collins Syndrome in Australia.

OBJECTIVE: To describe patterns and demographic characteristics of total-population hospital admissions with a diagnosis of Treacher Collins syndrome (TCS) in Australia. DATA SOURCE: Population summary data for inpatient hospitals admissions (public and private) with a principal diagnosis of TCS (ICD10-AM-Q87.04) were obtained from the Australian Institute of Health and Welfare National Hospital Morbidity Database for a 11-year period (2002-2013). MAIN OUTCOME MEASURES: The primary outcome was hospital separation rate (HSR), calculated by dividing the number of hospital separations by estimated resident population per year. Trends in HSR s adjusted for age and sex were investigated by negative binomial regression presented as annual percent change and the association of rates with age and sex was expressed as incidence rate ratio. RESULTS: In 244 admissions identified, we observed an increase of 4.55% (95% confidence interval [CI] -1.78, 11.29) in HSR's over the 11-year period. Rates were higher during infancy (1.87 [95% CI 1.42, 2.42]), declining markedly with increasing age. The average length of hospital stay was 6.09 days (95% CI 5.78, 6.40) per episode, but longer for females and infants. CONCLUSIONS: Findings indicate an increase in hospitalization rates, especially among infants and females which potentially relates to early airway intervention procedures possibly influenced by sex specific-disease severity and phenotypic variability of TCS. Awareness of the TCS phenotype and improved access to genetic testing may support more personalized and efficient care. Total-population administrative data offers a potential to better understand the health burden of rare craniofacial diseases.

Phenotypic and Molecular Heterogeneity in Mandibulofacial Dysostoses: A Case Series From India.

OBJECTIVE: Facial dysostosis is a group of rare craniofacial congenital disabilities requiring multidisciplinary long-term care. This report presents the phenotypic and genotypic information from South India. DESIGN: The study is a case series. SETTING: This was an international collaborative study involving a tertiary craniofacial clinic and medical genetics unit. PATIENTS, PARTICIPANTS: The participants were 9 families with 17 affected individuals of facial dysostosis. INTERVENTION: Exome analysis focused on known genes associated with acrofacial and mandibulofacial syndromes. MAIN OUTCOME MEASURE: The outcome measure was to report phenotyptic and genetic heterogeneity in affected individuals. RESULTS: A Tessier cleft was seen in 7 (41%), lower eyelid coloboma in 12 (65%), ear anomalies in 10 (59%), uniolateral or bilateral aural atresia in 4 (24%), and deafness in 6 (35%). The facial gestalt of Treacher Collins syndrome (TCS) showed extensive phenotypic variations. Pathogenic variants in TCOF1 (Treacher Collins syndrome) were seen in six families, POLR1A (acrofacial dysostosis, Cincinnati type) and EFTUD2 (mandibulofacial dysostosis with microcephaly) in one each. One family (11.1%) had no detectable variation. Five out of six probands with Treacher Collins syndrome had other affected family members (83.3%), including a non-penetrant mother, identified after sequencing. CONCLUSION: Our report illustrates the molecular heterogeneity of mandibulofacial dysostosis in India.

Phenotype Analysis and Genetic Study of Chinese Patients With Treacher Collins Syndrome.

OBJECTIVE: The aim of this study was to confirm the pathogenic variants, explore the genotype-phenotype correlation and characteristics of Chinese patients with Treacher Collins syndrome (TCS). DESIGN: Clinical details of 3 TCS family cases and 2 sporadic cases were collected and analyzed. Whole-exome sequencing and Sanger sequencing were conducted to detect causative variants. SETTING: Tertiary clinical care. PATIENTS: This study included 8 patients clinically diagnosed with TCS who were from 3 familial cases and 2 sporadic cases. MAIN OUTCOME MEASURES: When filtering the database, variants were saved as rare variants if their frequency were less than 0.005 in the 1000 Genomes Project Database, the Exome Aggregation Consortium (ExAC) browser, and the Novogene database, or they would be removed as common ones. The pathogenic variants identified were verified by polymerase chain reaction. The sequencing results were analyzed by Chromas 2.1 software. RESULTS: Two novel pathogenic variants (NM_000356.3: c.537del and NM_000356.3: c.1965_1966dupGG) and 2 known pathogenic variants (NM_000356.3: c.1535del, NM_000356.3: c.4131_4135del) were identified within TCOF1 which are predicted to lead to premature termination codons resulting in a truncated protein. There was a known missense SNP (NM_015972.3: c.139G>A) within POLR1D. No phenotype-genotype correlation was observed. Instead, these 8 patients demonstrated the high genotypic and phenotypic heterogeneity of TCS. CONCLUSIONS: This study expands on the pathogenic gene pool of Chinese patients with TCS. Besides the great variation among patients which is similar to international reports, Chinese patients have their own characteristics in clinical phenotype and pathogenesis mutations.

Northwest Indigenous Art and the Inspiring Spirits.

Indigenous Art often expresses the complex culture of their creators and provides insight into the origins, histories, and values of that culture. Two examples of Northwest Indigenous Art suggest deeper meanings and the "power" of congenital anomalies.

Mutation analysis of TCOF1 gene in Chinese Treacher Collins syndrome patients.

BACKGROUND: Treacher Collins syndrome (TCS) is a rare autosomal dominant or recessive disorder, that involves unique bilateral craniofacial malformations. The phenotypes of TCS are extremely diverse. Interventional surgery can improve hearing loss and facial deformity in TCS patients. METHOD: We recruited seven TCS families. Variant screening in probands was performed by targeted next-generation sequencing (NGS). The variants identified were confirmed by Sanger sequencing. The pathogenicity of all the mutations was evaluated using the guidelines of the American College of Medical Genetics and Genomics (ACMG) and InterVar software. RESULTS: Three frameshift variants, two nonsense variants, one missense variant, and one splicing variant of TCOF1 were identified in the seven TCS probands. Five variants including c.1393C > T, c.4111 + 5G>C, c.1142delC, c.2285_2286delCT, and c.1719delG had not been previously reported. Furthermore, we report the c.149A > G variant for the first time in a Chinese TCS patient. We provided prenatal diagnosis for family 4. Proband 7 chose interventional surgery. CONCLUSION: We identified five novel variants in TCOF1 in Chinese patients with TCS, which expands the mutation spectrum of TCOF1 in TCS. Bone conduction hearing rehabilitation can improve hearing for TCS patients and prenatal diagnosis can provide fertility guidance for TCS families.

Re-focusing on Agnathia-Otocephaly complex.

OBJECTIVES: Agnathia-otocephaly complex is a rare condition characterized by mandibular hypoplasia or agnathia, ear anomalies (melotia/synotia) and microstomia with aglossia. This severe anomaly of the first branchial arch is most often lethal. The estimated incidence is less than 1 in 70.000 births, with etiologies linked to both genetic and teratogenic factors. Most of the cases are sporadic. To date, two genes have been described in humans to be involved in this condition: OTX2 and PRRX1. Nevertheless, the overall proportion of mutated cases is unknown and a significant number of patients remain without molecular diagnosis. Thus, the involvement of other genes than OTX2 and PRRX1 in the agnathia-otocephaly complex is not unlikely. Heterozygous mutations in Cnbp in mice are responsible for mandibular and eye defects mimicking the agnathia-otocephaly complex in humans and appear as a good candidate. Therefore, in this study, we aimed (i) to collect patients presenting with agnathia-otocephaly complex for screening CNBP, in parallel with OTX2 and PRRX1, to check its possible implication in the human phenotype and (ii) to compare our results with the literature data to estimate the proportion of mutated cases after genetic testing. MATERIALS AND METHODS: In this work, we describe 10 patients suffering from the agnathia-otocephaly complex. All of them benefited from array-CGH and Sanger sequencing of OTX2, PRRX1 and CNBP. A complete review of the literature was made using the Pubmed database to collect all the patients described with a phenotype of agnathia-otocephaly complex during the 20 last years (1998-2019) in order (i) to study etiology (genetic causes, iatrogenic causes…) and (ii), when genetic testing was performed, to study which genes were tested and by which type of technologies. RESULTS: In our 10 patients' cohort, no point mutation in the three tested genes was detected by Sanger sequencing, while array-CGH has allowed identifying a 107-kb deletion encompassing OTX2 responsible for the agnathia-otocephaly complex phenotype in 1 of them. In 4 of the 70 cases described in the literature, a toxic cause was identified and 22 out the 66 remaining cases benefited from genetic testing. Among those 22 patients, 6 were carrying mutation or deletion in the OTX2 gene and 4 in the PRRX1 gene. Thus, when compiling results from our cohort and the literature, a total of 32 patients benefited from genetic testing, with only 34% (11/32) of patients having a mutation in one of the two known genes, OTX2 or PRRX1. CONCLUSIONS: From our work and the literature review, only mutations in OTX2 and PRRX1 have been found to date in patients, explaining around one third of the etiologies after genetic testing. Thus, agnathia-otocephaly complex remains unexplained in the majority of the patients, which indicates that other factors might be involved. Although involved in first branchial arch defects, no mutation in the CNBP gene was found in this study. This suggests that mutations in CNBP might not be involved in such phenotype in humans or that, unlike in mice, a compensatory effect might exist in humans. Nevertheless, given that agnathia-otocephaly complex is a rare phenotype, more patients have to be screened for CNBP mutations before we definitively conclude about its potential implication. Therefore, this work presents the current state of knowledge on agnathia-otocephaly complex and underlines the need to expand further the understanding of the genetic bases of this disorder, which remains largely unknown. CLINICAL RELEVANCE: We made here an update and focus on the clinical and genetic aspects of agnathia-otocephaly complex as well as a more general review of craniofacial development.

The Role of TCOF1 Gene in Health and Disease: Beyond Treacher Collins Syndrome.

The nucleoli are membrane-less nuclear substructures that govern ribosome biogenesis and participate in multiple other cellular processes such as cell cycle progression, stress sensing, and DNA damage response. The proper functioning of these organelles is ensured by specific proteins that maintain nucleolar structure and mediate key nucleolar activities. Among all nucleolar proteins, treacle encoded by TCOF1 gene emerges as one of the most crucial regulators of cellular processes. TCOF1 was initially discovered as a gene involved in the Treacher Collins syndrome, a rare genetic disorder characterized by severe craniofacial deformations. Later studies revealed that treacle regulates ribosome biogenesis, mitosis, proliferation, DNA damage response, and apoptosis. Importantly, several reports indicate that treacle is also involved in cancer development, progression, and response to therapies, and may contribute to other pathologies such as Hirschsprung disease. In this manuscript, we comprehensively review the structure, function, and the regulation of TCOF1/treacle in physiological and pathological processes.

Broad-spectrum next-generation sequencing-based diagnosis of a case of Nager syndrome.

BACKGROUND: Nager syndrome is a rare genetic syndrome characterized by craniofacial and preaxial limb anomalies. Haploinsufficiency of the SF3B4 gene has been identified as a significant reason for Nager syndrome. Treacher Collins syndrome (TCS) has similar facial features; however, the TCOF1, POLR1D, and POLR1C genes have been reported as the critical disease-causing genes. Similar phenotypes make it easy to misdiagnose. CASE REPORT: In this report, we have presented a case of one newborn with acrofacial dysostosis, who was first diagnosed with TCS. Expanded next-generation sequencing eventually detected a (c.1A>G) heterozygous mutation in the SF3B4 gene at chr1:149899651 that was confirmed by Sanger sequencing. Combined with his preaxial limb anomalies discovered after his death, a diagnosis of Nager syndrome was made. CONCLUSIONS: This report presents one patient with Nager syndrome who was initially misdiagnosed with TCS. Correct genetic testing will be beneficial to future prenatal diagnosis.

Imaging of the Fetal Zygomatic Bone: A Key Role in Prenatal Diagnosis of First Branchial Arch Syndrome.

OBJECTIVES: First arch syndromes are congenital defects caused by failure of neural crest cells to migrate into the first branchial arch. First arch syndrome is classified into 2 main clinical manifestations: Treacher Collins syndrome, characterized by bilateral underdevelopment of the zygomatic bones; and Pierre Robin sequence. The aim of this study was to describe the feasibility of visualization of the fetal zygomatic bone and assess its application in cases referred for features suggestive of first arch syndrome. METHODS: A prospective cohort study was conducted. The feasibility of visualization of the zygomatic bone was performed in 50 sequential fetuses with a normal anatomic scan between 12 and 24 weeks' gestation using 3-dimensional sonography. Following this, cases referred for targeted scans for suspected first branchial arch syndrome were assessed for the presence or absence of the zygomatic bones. RESULTS: Visualization of the fetal zygomatic bone was feasible in all low-risk cases. Cases referred for targeted scans included 11 isolated cases of micrognathia or retrognathia, 3 cases of microtia, and 3 cases of auricular or facial vestiges. Within this group, the zygomatic bones were visualized in all but 2 cases. No associated extrafacial malformations were detected; therefore, this phenotype was consistent with Treacher Collins syndrome. CONCLUSIONS: Prenatal imaging of the zygomatic bones offers a clinically based sonographic approach to cases referred for features suggestive of first arch syndrome and enables differentiation between the 2 main clinical manifestations: Treacher Collins syndrome and Pierre Robin sequence.

Retrospective study of Langerhans cell histiocytosis in ear, nose and neck.

OBJECTIVE: Langerhans cell histiocytosis (LCH) is a rare clinical disorder. We retrospectively analysed the clinical manifestations, treatments and prognoses of LCH cases involving the ear, nose, and neck. MATERIALS AND METHODS: 28 cases with confirmed LCH in ear, nose or neck were reviewed. We recorded patient age, sex, chief complaints, accompanying symptoms, lesional sites, radiological data, treatments and pathologies. Whole-exome sequencing was performed on the patient diagnosed with LCH and Treacher-Collins syndrome (TCS). RESULTS: The mean age was 14.86 years. Most LCH was in the ear (93%), usually in the mastoid. The most common symptoms were an ear mass and a purulent discharge. Imaging was not very useful. Treatments included surgery, chemotherapy, and radioactive particle implantation. Some cases exhibited multisystem involvement. Most patients enjoyed good prognoses. One patient was diagnosed with both temporal LCH and TCS. Whole-exome sequencing revealed a heterozygous c.261_272delAGGTACCCTTCC(p.87_91delRGTLPinsR) mutation in exon 2 of the POLR1D gene (NM_015972). CONCLUSION: LCH mostly occurs in children. In head and neck it affects principally the mastoid part of the temporal bone. Treatments include surgery, chemotherapy, and irradiation. Most patients enjoy good prognoses. LCH accompanied by TCS is rare and increases the difficulty of diagnosis; molecular data aid in TCS identification.

Autosomal recessive Treacher Collins syndrome due to POLR1C mutations: Report of a new family and review of the literature.

Treacher Collins syndrome (TCS) is a frequent cause of mandibulofacial dysostosis. To date, TCS-causing mutations in three genes, namely TCOF1, POLR1D, and POLR1C have been identified. TCS is usually inherited in an autosomal dominant manner, with a high clinical variability and no phenotype-genotype correlation. Up-to now, five families have been reported with an autosomal recessive mode of inheritance due to mutations in POLR1D or POLR1C. We report here a new family with two sisters affected by mild TCS carrying compound POLR1C heterozygous mutations, and review the literature on mild forms of TCS, autosomal recessive inheritance in this syndrome and POLR1C mutations.

Mutation screening of Chinese Treacher Collins syndrome patients identified novel TCOF1 mutations.

Treacher Collins syndrome (TCS) (OMIM 154500) is a rare congenital craniofacial disorder with an autosomal dominant manner of inheritance in most cases. To date, three pathogenic genes (TCOF1, POLR1D and POLR1C) have been identified. In this study, we conducted mutational analysis on Chinese TCS patients to reveal a mutational spectrum of known causative genes and show phenotype-genotype data to provide more information for gene counselling and future studies on the pathogenesis of TCS. Twenty-two TCS patients were recruited from two tertiary referral centres, and Sanger sequencing for the coding exons and exon-intron boundaries of TCOF1, POLR1D and POLR1C was performed. For patients without small variants, further copy number variations (CNVs) analysis was conducted using high-density SNP array platforms. The Sanger sequencing overall mutation detection rate was as high as 86.3% (19/22) for our cohort. Fifteen TCOF1 pathogenic variants, including ten novel mutations, were identified in nineteen patients. No causative mutations in POLR1D and POLR1C genes and no CNVs mutations were detected. A suspected autosomal dominant inheritance case that implies germinal mosaicism was described. Our study confirmed that TCOF1 was the main disease-causing gene for the Chinese TCS population and revealed its mutation spectrum. We also addressed the need for more studies of mosaicism in TCS cases, which could explain the mechanism of autosomal dominant inheritance in TCS cases and benefit the prevention of TCS.