Treacher Collins Syndrome Patient Research Articles

Use of adipose derived stem cells in Treacher Collins syndrome.

Treacher Collins syndrome (TCS) is a rare congenital disorder of craniofacial development. TCS occurs with an incidence of 1:50,000, and more than 60% of TCS cases have no previous family history and arise as the result of de novo mutations. The high rate of de novo mutations, together with the extreme variability in the degree to which individuals can be affected, makes the provision of genetic counseling extremely complicated. Consequently, every case of TCS is unique and needs to be assessed individually. Patients with TCS frequently undergo multiple reconstructive surgeries from birth through adulthood, which rarely are fully corrective in the long-term. The nascent field of regenerative medicine offers the promise to improve some of these treatments. In particular, structural fat grafting (SFG) seems to be a good strategy not only to restore the normal volume and contour of the face, but also to provide a source of adipose-derived stem cells (ADSCs) with a multilineage differentiation potential. In this work, we present genetical analyses of ADSC affected by TCS. ADSCs from were analyzed for their stemness properties and shared many characteristics with those of a healthy subject. Screening of the genome of the TCS patient using array-Comparative Genomic Hybridization allowed us to identify some chromosomal imbalances that are probably associated with TCS. We found that some alterations, involving the TIMELESS gene, were usually associated with embryonic stem cells. With the aim to improve the final results, we need to consider combining knowledge of genetic alterations and expression profiles as a fundamental step before starting with surgical procedures.

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

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 knockdownof POLR1D on Drosophila development. 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. 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.

Characterization of Fly POLR1D Mutations in a Clinically Relevant Residue Associated with Treacher Collins Syndrome (TCS)

Treacher Collins Syndrome (TCS) is an extreme craniofacial disorder caused by mutations in genes important for RNA polymerase I (Pol I) transcription. Pol I is a multi‐subunit complex that transcribes ribosomal DNA (rDNA) to synthesize ribosomal RNA (rRNA). Two Pol I subunits often mutated in TCS are POLR1D and POLR1C which form a heterodimer that is important for Pol I complex assembly. Using fruit flies (D. melanogaster) as a model system, we mapped a fly POLR1D mutation that displays a severe developmental arrest phenotype in a clinically relevant residue where in a TCS patient this residue is mutated from a glycine residue to a bulky, negatively charged glutamic acid residue. In the fly mutant collection, this glycine residue is mutated to a bulkier but positively charged arginine residue. We used a simple in vitro co‐expression system to examine the biochemical impact of these mutations on fly and human POLR1D and POLR1C heterodimer formation in vitro. We also complement our in vitro work with a chimeric yeast (S. cerevisiae) model in vivo where together we found that in the same mutated residue, there is a defect that impacts heterodimer formation and Pol I and III complex integrity. Our results show that fly POLR1D is a suitable model system for human TCS mutants.

Generation of a human induced pluripotent stem cell line (PSHi002-A) from a Treacher-Collins syndrome patient carrying a TCOF1 gene mutation (c.1966_1969dup)

Mutations of the Treacle Ribosome Biogenesis Factor 1 (TCOF1) gene can lead to Treacher Collins syndrome (TCS). In present study, the peripheral blood mononuclear cells (PBMCs) of a 33-year-old male TCS patient with the heterozygous TCOF1 mutation c.1966_1969dup (p.Ser657Trpfs*25) were reprogrammed into induced pluripotent stem cells (iPSCs) named PSHi002-A through episomal plasmids encoding hOCT4, hSOX2, hNANOG, hLIN28, hKLF4, and hL-MYC. The established iPSC line expressed pluripotent markers, had a normal karyotype (46, XY), and can be differentiated into the three germ layers in vivo.

Extracraniofacial anomalies in Treacher Collins syndrome: A multicentre study of 248 patients

Treacher Collins syndrome (TCS) is a congenital malformation of the craniofacial structures derived from the first and second pharyngeal arches. The craniofacial deformities are well described in the literature. However, little is known about whether there are associated extracraniofacial anomalies. A retrospective study was conducted using data from four craniofacial units. Medical charts were reviewed for the presence and type of extracraniofacial anomalies, as well as age at diagnosis. A possible correlation between the severity of the phenotype and the presence of extracraniofacial anomalies was assessed using the Hayashi classification. A total of 248 patients with TCS were identified; 240 were confirmed to have TCS, of whom 61 (25.4%) were diagnosed with one or more extracraniofacial anomalies. Ninety-five different extracraniofacial anomalies were found; vertebral (n=32) and cardiac (n=13) anomalies were most frequently seen, followed by reproductive system (n=11), central nervous system (n=7), and limb (n=7) anomalies. No correlations between tracts were found. Extracraniofacial anomalies were more prevalent in these patients with TCS compared to the general population (25.4% vs 0.001–2%, respectively). Furthermore, a positive trend was seen between the severity of the syndrome and the presence of extracraniofacial anomalies. A full clinical examination should be performed on any new TCS patient to detect any extracraniofacial anomalies on first encounter with the craniofacial team.

Successful intubation of a treachercollins syndrome patient with ‘STRIVE Hi’ and videolaryngoscopy: a case report

Successful intubation of a treachercollins syndrome patient with ‘STRIVE Hi’ and videolaryngoscopy: a case report

Intubating a Treacher Collins Syndrome patient with STRIVE Hi and videolaryngoscopy

Treacher Collins Syndrome (TCS) is characterised by craniofacial abnormalities which pose a unique airway challenge for anaesthetists. For these patients requiring general anaesthesia and endotracheal intubation, maintaining spontaneous breathing throughout induction should be considered foundational to safety. Spontaneous respiration using intravenous anaesthesia and high-flow nasal oxygen (STRIVE Hi) has been previously shown to safely induce patients with difficult airways. This case demonstrates the first described successful intubation of an adult TCS patient with hyperangulated blade videolaryngoscopy “GlideScope LoPro S4” using a STRIVE Hi induction technique. Key Words: Treacher Collins Syndrome intubation, STRIVE Hi, Videolaryngoscopy.

Mandible customized distraction osteogenesis in Treacher Collins patient: Literature review, report of a case and post-distraction analysis

IntroductionTreacher-Collins syndrome is a rare genetic disorder with variable phenotypic expression. Related micrognathia can cause upper airway obstruction in neonatal patients because of posterior tongue displacement. Many approaches have been described to treat upper airway obstruction in such patients; the use of mandibular distraction to this purpose was first proposed in 1994. To our knowledge, only a few authors have employed customized devices to perform mandibular distraction in these syndromic patients.This paper presents a systematic review of the use of customized devices to perform mandibular distraction osteogenesis in patients affected by Treacher-Collins syndrome and upper airway obstruction. A case report of a Treacher-Collins syndrome patient treated in our institution is also presented. ResultsEight articles fulfilled the inclusion criteria and were included in this systematic review; demographic, clinical and surgical features of 13 cases were evaluated.Preoperative assessment, virtual surgical planning and a surgical protocol for a Treacher-Collins patient were performed and set-out in detail; a post-distraction 3D analysis workflow was developed and proposed.The patient had an airway obstruction resolution after the distractors removal and was progressively decannulated. The post-distraction 3D analysis revealed that the oropharynx and hypopharynx airway space acquired greater volumetric dimension in a more antero-superior position; this advancement was comparable to the antero-superior advancement of the distracted mandible. ConclusionIn the author’s opinion, customized devices for mandibular distraction osteogenesis and post-distraction tridimensional analysis should be objected of further investigation in the light of their potential advantage in diagnosis and treatment of syndromic malformation.

Contouring of zygomatic soft tissue using bilateral free groin flaps in a Treacher Collins syndrome patient.

Treacher Collins syndrome is a congenital disorder that is characterized with a wide range of cranio-facial deformities. Zygomatic hypoplasia or aplasia is one of the key features, and surgical reconstruction of the consequent depression on the zygomatic area is deemed necessary by many patients. Various surgical options are available—injectables, alloplastic materials, autologous grafting, and autogenous tissue transfer. It depends on each patient which technique to use. Here, we present a clinical case, in which bilateral free groin flaps were adopted in attempt to resolve the remnant aesthetic deformity associated with zygomatic depression, despite a series of previous surgical efforts, in a 25-year-old Treacher Collins syndrome male patient.

Treacher Collins 증후군 환아의 기관 삽관 시 마우스가드의 활용

Treacher collins 증후군(TCS)는 25,000명에서 50,000명당 1명의 빈도로 발생하는 상염색체우성의 유전질환이다. 상, 하악의 발육 부전, 부정교합, 양측성 이개 기형, 안검렬의 반몽고증 사면, 구순구개열, 외이도 폐쇄, 중이와 내이의 기형으로 인한 청각 소실등의 구강악안면 부위의 특징을 보여 태생 이후 성인기에 이르기까지 여러 차례에 걸친 외과적 수술을 거치게 된다. 하악골의 형성저하로 하악골이 짧고 후방 위치되며 후방 위치하는 혀와 후비공의 협착과 폐쇄로 인해 상기도가 좁아지게 되는데 이로 인해 기관삽관의 어려움이 따른다. 따라서 치근 발육이 미약한 소아청소년 시기의 TCS 환자의 기관 삽관 시 상악 전치부의 손상 가능성이 매우 높다. 본 증례는 전신마취 유도를 위한 기관 삽관 도중 상악 전치의 완전 탈구가 발생한 TCS 환아의 치험례를 통해 기도 삽관 시사전의 마우스가드 제작의 유용성에 대하여 알리고자 한다. Treacher Collins syndrome (TCS) is autosomal dominant disorder that occurs approximately 1 in 25,000 to 50,000 live births. The main signs of syndrome are hypoplasia of facial bone and microtia. One in third of them is associated with cleft palate and often shows dental hypoplasia. TCS patients need several number of surgery with general anesthesia throughout their life time for recovery of function and esthetic. Endotracheal intubation of TCS patient is very difficult due to microstomia, retrognathia, choanal stenosis, and decreased oropharyngeal airway. Therefore, general anesthesia of adolescent TCS patient with immature incisor roots has high risk of causing dental trauma. This case is regarding TCS patient who was referred to the Department of Pediatric Dentistry, Yonsei University for avulsed upper left central incisor during endotracheal intubation. The purpose of this report is to emphasize the usefulness of mouth guard to prevent dental trauma when endotracheal intubation is needed for TCS patient.

Planning Surgical Reconstruction in Treacher-Collins Syndrome Using Virtual Simulation

Treacher-Collins syndrome is a rare autosomal dominant condition of varying phenotypic expression. The surgical correction in this syndrome is difficult, and the approach varies between craniofacial departments worldwide. The authors aimed to design standardized tools for planning orbitozygomatic and mandibular reconstruction in Treacher-Collins syndrome using geometric morphometrics. The Great Ormond Street Hospital database was retrospectively identified for patients with Treacher-Collins syndrome. Thirteen children (aged 2 to 15 years) who had suitable preoperative three-dimensional computed tomographic head scans were included. Six Treacher-Collins syndrome three-dimensional computed tomographic head scans were quantitatively compared using a template of 96 anatomically defined landmarks to 26 age-matched normal dry skulls. Thin-plate spline videos illustrated the characteristic deformities of retromicrognathia and maxillary and orbitozygomatic hypoplasia in the Treacher-Collins syndrome population. Geometric morphometrics was used in the virtual reconstruction of the orbitozygomatic and mandibular region in Treacher-Collins syndrome patients. Intrarater and interrater reliability of the landmarks was acceptable and within a standard deviation of less than 1 mm on 97 percent and 100 percent of 10 repeated scans, respectively. Virtual normalization of the Treacher-Collins syndrome skull effectively describes characteristic skeletal deformities and provides a useful guide to surgical reconstruction. Size-matched stereolithographic templates derived from thin-plate spline warps can provide effective intraoperative templates for zygomatic and mandibular reconstruction in the Treacher-Collins syndrome patient. Diagnostic, V.

Airway Management for Treacher Collins Syndrome with Limited Mouth Opening

Patients with Treacher Collins Syndrome (TCS) present unique airway management problems for anesthesiologists due to mandibular micrognathia, the small oral aperture, and temporomandibular joint anomalies. We describe the case of a pediatric TCS patient with limited mouth opening who experienced severe airway obstruction during deep inhalation anesthesia (sevoflurane following i.v. midazolam) for routine dental work. When difficult airway management is expected, intubation of conscious patients is a well-recognized technique in adults; however, it is rarely appropriate for pediatric patients who usually do not cooperate. According to general anesthesia algorithms for pediatric patients with difficult airways, in most pediatric patients, tracheal intubation is performed after the induction of general anesthesia and some authors have reported the usefulness of LMA for maintaining airway patency in patients with TCS. However, in our case LMA could not be used because of severe limitation of mouth opening. In addition, the LMA is so bulky that it is impossible to insert a LMA into patients with narrow airway anatomy. We initially planned to carry out fiber-optic intubation while awake and under sedation if the airway patency could not be secured after the induction of anesthesia. The patient was sedated properly with midazolam and sevoflurane, and awake fiberoptic intubation was performed uneventfully. Our experience in this case highlighted that careful planning of backup contingencies is important in achieving fiberoptic intubation and maintaining airway patency in pediatric TCS patients with limited mouth opening, and that awake intubation can be successful even in pediatric patients.

Perioperative Airway Management in a Child with Treacher Collins Syndrome

We report the perioperative airway management in a 12-year-old boy suffering from Treacher Collins syndrome (TCS) and severe mental retardation who was scheduled for elective dental treatment under general anesthesia. TSC is also known as mandibulofacial dysostosis or Franceschetti syndrome, usually with a potentially difficult airway presentation. It is a major challenge for the anesthesiologist to manage an uncooperative child with such a congenital airway anomaly. A difficult airway was encountered during induction of general anesthesia, and both oral intubation by direct laryngoscopy and classic laryngeal mask airway (LMA) insertion were unsuccessful. In an expedient critical trial, with the cooperation of two anesthesiologists, one performing nasal fiberoptic intubation and the other maintaining oral mask ventilation, a nasal endotracheal tube was successfully placed at the first attempt, although at the expense of prolonged respiratory depression in the patient. Therefore, fiberoptic nasal intubation simultaneously with mask ventilation for placement of the endotracheal tube is a practical substitute for a difficult airway usually managed by LMA with inadequate ventilation. After extubation, tracheostomy may be indicated if the TCS patient suffers from persistent difficult upper airway in consequence of a traumatic intubation.

Mutations and new polymorphic changes in the TCOF1 gene of patients with oculo–auriculo–vertebral spectrum and Treacher–Collins syndrome

Oculo-auriculo-vertebral spectrum, the exact genetic predisposition of which has not yet been resolved, is characterized by varying degrees of the prevalently unilateral underdevelopment of craniofacial structures and spinal anomalies. Here, we analyzed four cases exhibiting multiple features of oculo-auriculo-vertebral spectrum and one case with Treacher-Collins syndrome. The cranium was analyzed using three-dimensional computed tomography, which reliably identifies craniofacial malformations. We detected one typical oculo-auriculo-vertebral spectrum patient who had a missense mutation in exon 9 of the TCOF1 gene complex and two silent mutations in exons 10 and 23, three partial oculo-auriculo-vertebral spectrum patients who had no detectable mutations in the TCOF1 gene complex, and one Treacher-Collins syndrome patient who had a nonsense mutation in exon 14. All five patients had eight previously reported polymorphic changes in the TCOF1 exons 10, 11, 12, 16, 21, 22, and 23, and four unreported polymorphisms in exons 9, 17, and 22 that were also detected in 51 Taiwanese control patients. These observations strongly suggest that the TCOF1 genetic changes observed in these five patients might be related to oculo-auriculo-vertebral spectrum symptoms.

Mandibular Lengthening by Distraction for Airway Obstruction in Treacher-Collins Syndrome

Mandibular lengthening by distraction was performed in a 6-year-old tracheostomy-dependent Treacher-Collins syndrome patient. Detailed preoperative imaging revealed an occluded retrotongue base pharyngeal airway, which, following mandibular distraction, became patent and permitted tracheostomy removal. Mandibular distraction as a technique must be targeted toward clinical problems--management of upper-airway obstruction may be one such scenario.

Chromosomal deletion 4p15.32→p14 in a treacher collins syndrome patient: Exclusion of the disease locus from and mapping of anonymous DNA sequences to this region

Theacher Collins syndrome is an autosomal dominant condition of bilateral craniofacial abnormalities of structures derived from the first and second branchial arches. A patient with severe manifestations of Treacher Collins syndrome and a de novo chromosomal deletion in region 4p15.32→p14 was identified. Anonymous DNA sequences of loci D4S18, D4S19, D4S20, D4S22, and D4S23 were mapped to the deleted region. DNA probes previously mapped to loci on chromosome 4p (D4S10, D4S15, D4S16, D4S26, D4S35, D4S95, D4S144, RAF1P1, QDPR, and HOX7) were not deleted in this patient. Linkage analysis between the D4S18, D4S23, and QDPR loci and Treacher Collins syndrome in eight families excluded the Treacher Collins syndrome locus from the region of the deletion.