340 A NOVEL MANDIBULOFACIAL DYSOSTOSIS SYNDROME ASSOCIATED WITH A DE NOVO TRANSLOCATION.

Treacher Collins syndrome (TCS) is the prototypical mandibulofacial dysostosis syndrome, but other mandibulofacial dysostosis syndromes have been described. We report an infant with mandibulofacial dysostosis and an apparently balanced de novo 2;17 translocation. She presented with severe lower eyelid colobomas requiring skin grafting, malar and mandibular hypoplasia, bilateral microtia with external auditory canal atreasia, dysplastic ossicles, hearing loss, bilateral choanal stenosis, cleft palate without cleft lip, several oral frenula of the upper lip/gum, and micrognathia requiring tracheostomy. Her limbs were normal. Chromosome analysis at the 600-band level showed a 46,XX,t(2;17)(q24.3;q23) karyotype. Sequencing of the entire TCOF1 coding region did not show evidence of a sequence variation. High-resolution genomic microarray analysis did not identify a cryptic imbalance. FISH mapping refined the breakpoints to 2q31.1 and 17q24.3-25.1 and showed the 2q31.1 breakpoint likely affects the HOXD gene cluster. Several atypical findings and lack of an identifiable TCOF1 mutation suggest that this child has a provisionally unique mandibulofacial dysostosis syndrome. The apparently balanced de novo translocation provides candidate loci for atypical and TCOF1 mutation negative cases of TCS. Based on the agreement of our findings with one previous case of mandibulofacial dysostosis with a 2q31.1 transocation, we hypothesize that misexpression of genes in the HOXD gene cluster produced the described phenotype in this patient.

SummaryTreacher Collins Syndrome - or mandibulofacial dysostosis – is a rare condition that presents several craniofacial deformities of different levels. This is a congenital malformation involving the first and second branchial arches. Incidence is estimated to range between 1-40,000 to 1-70,000 of live births. The disorder is characterized by abnormalities of the auricular pinna, hypoplasia of facial bones, antimongoloid slanting palpebral fissures with coloboma of the lower eyelids and cleft palate. Treacher Collins Syndrome is rarely associated with choanal atresia. A multidisciplinary team, including craniofacial surgeon, ophthalmologist, speech therapist, dental surgeon and otorhinolaryngologist, is the most appropriate setting to manage these patients. This study reports a rare case of Treacher Collins Syndrome with choanal atresia, presenting literature review and multidisciplinary intervention.

A novel mutation in the TCOF1 gene found in two Chinese cases of Treacher Collins syndrome

Treacher Collins Syndrome or mandibulofacial dysostosis is a rare congenital malformation involving first and second branchial arches and presents several craniofacial deformities. The occurrence of this syndrome is estimated to range between 1 in 40,000 to 1 in 70,000 live births. The syndrome is characterized by anomalies of the auricular pinna, hypoplasia of facial bones, antimongoloid slanting palpebral fissures, coloboma of the lower eyelids and cleft palate. Here we report a case of Treacher Collins Syndrome with a narrative review of the clinical features, radiographic findings, differential diagnosis and various treatment options.

Here, we report two extraordinarily severe cases of Teacher Collins syndrome. Initially, amniotic bands and plical fold disruption were considered, but downslanting eyes made us consider severe Treacher Collins syndrome. A TCOF1 mutation in exon 24 was identified in Patient 1 (c.4355_4356ins14, resulting in p.1456Thrfs*18). Patient 2, who expired on day 4, is so similar to Patient 1 that severe Treacher Collins syndrome may be inferred in this instance. Neither the TCOF1 mutation nor the well-known variability in the expression in affected families with Treacher Collins syndrome (∼40% of reported cases) can explain the severity of these cases; otherwise, we would be aware of such cases within families from time to time. We are unaware of any recent sporadic cases (∼60% of reported cases) exactly like ours either with a single exception in the case reported by Writzl et al. [2008] with a TCOF1 mutation. The case described by Otto in 1841 is spectacular. We propose several hypotheses to be considered in explaining this developmental amplification, including some promoter effect on the gene, some position effect on the gene, a polymorphism elsewhere in the gene, a point mutation elsewhere in the gene, a polymorphism in another gene, or a point mutation in another gene, such as POLR1C (which maps to 6p21.1) or POLR1D (which maps to13q12.2). We also review the etiology and pathogenesis of Treacher Collins syndrome, and discuss several other severe cases from the past.

Clinical characteristics Treacher Collins syndrome (TCS) is characterized by bilateral and symmetric downslanting palpebral fissures, malar hypoplasia, micrognathia, and external ear abnormalities. Hypoplasia of the zygomatic bones and mandible can cause significant feeding and respiratory difficulties. About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures tend to be normal. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia. Typically intellect is normal. Diagnosis/testing The diagnosis of TCS is established in about 97% of probands by detection of a heterozygous (autosomal dominant) pathogenic variant in TCOF1, POLR1D, or POLR1B or biallelic (autosomal recessive) pathogenic variants in POLR1C or POLR1D using molecular genetic testing and in about 3% of probands by clinical findings when molecular genetic testing has not been performed or does not identify pathogenic variants in one of the known genes. Management Treatment of manifestations: Treatment should be tailored to the specific needs of each individual, preferably by a multidisciplinary craniofacial management team. Neonates with airway issues may require special positioning or tracheostomy to facilitate ventilation. Hearing loss is treated with bone conduction amplification, speech therapy, and educational intervention. Craniofacial reconstruction is often necessary. Cleft palate repair (if needed) occurs at about age one year; zygomatic and orbital reconstruction at about age five to seven years; and bilateral microtia and/or narrow ear canal reconstruction after age six years. The age of maxillomandibular reconstruction varies by severity; orthognathic therapies are typically before age 16 years. Genetic counseling Treacher Collins syndrome (TCS) can be inherited in an autosomal dominant or autosomal recessive manner. Autosomal dominant TCS. About 55%-61% of probands have the disorder as the result of a de novo TCOF1, POLR1D, or POLR1B pathogenic variant. Each child of an individual with TCS has a 50% chance of inheriting the pathogenic variant. Autosomal recessive TCS. The parents of a child with autosomal recessive TCS are obligate heterozygotes (i.e., carriers of one POLR1C or POLR1D pathogenic variant). At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the TCS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Treacher Collins syndrome (TCS), the best known form of mandibulofacial dysostosis (MFD) comprises a recognizable pattern of anomalies. In 1985, Lowry et al. reported on two Hutterite sisters born to apparently unaffected parents with TCS, raising the possibility of an autosomal recessive (AR) variant of TCS, subsequently given a unique Mendelian Inheritance of Man (MIM) number (248390). Recently, biallelic mutations in POLR1C were found in TCS patients, confirming AR TCS as a distinct entity. The Hutterites, an endogamous Anabaptist group, like other genetically isolated populations, provide a powerful resource for mapping AR disorders. We elected to study the molecular basis of TCS in the Hutterite population including the original kindred described in 1985, and another unrelated Hutterite patient. Prior to starting this study, a TCOF1 mutation had apparently been excluded in the original family at two outside institutions. We hypothesized that an AR variant of TCS was present in the three Hutterite patients, but homozygosity mapping did not show convincing evidence of shared regions between the affected individuals. TCOF1 analysis was undertaken and mutations were found in the three affected patients and an unaffected parent. These data show that the initial Hutterite family reported with AR TCS in fact has classic TCS due to a TCOF1 mutation, despite recent data confirming the existence of AR TCS in other populations. These results have significant counseling implications for the affected families in the Hutterite population and in the population at large. © 2013 Wiley Periodicals, Inc.

Internal carotid artery aplasia or hypoplasia above the cervical bifurcation is rare, occurring in less than 0.01% of the general population. Unilateral neurocristopathy complicated by unilateral internal carotid artery agenesis or hypogenesis has been reported, but bilateral internal carotid artery hypoplasia is rare and scarcely reported. Herein, we report a novel case of Treacher Collins syndrome complicated by bilateral internal carotid artery hypoplasia. A 94-year-old woman presented with complaints of headache and vomiting. Computed tomography revealed a subarachnoid hemorrhage and dysplasia of the bilateral zygoma, mandible, and external auditory meatus. The patient had severe hearing loss and visual impairment. Computed tomography angiography revealed bilateral internal carotid artery hypoplasia and multiple aneurysmal changes in the intracranial arteries. We diagnosed the patient with a ruptured anterior inferior cerebellar artery aneurysm and performed coil embolization. The patient's unique facial features were consistent with neurocristopathy, especially Treacher Collins syndrome. Developmental anomalies of neural crest cells can present as vascular abnormalities and craniofacial malformations. Special care is required for endovascular treatment and airway management in cases of neurocristopathy because of the specific craniofacial anomalies.

Treacher Collins Ι syndrome (TCS1, OMIM:154500) is an autosomal dominant disease with a series of clinical manifestations such as craniofacial dysplasia including eye and ear abnormalities, small jaw deformity, cleft lip, as well as repeated respiratory tract infection and conductive hearing loss. Two cases of Treacher Collins syndrome with TCOF1(OMIM:606847) gene variations were reported in the article, with clinical characteristics, gene variants and the etiology. The clinical data of two patients with Treacher Collins syndrome caused by TCOF1 gene variation were retrospectively analyzed. The whole exome sequencing (WES) was performed to detect the pathogenic variants of TCOF1 gene in the patients, and the verification of variants were confirmed by Sanger sequencing. Proband 1 presented with bilateral craniofacial deformities, conductive hearing loss and recurrent respiratory tract infection. Proband 2 showed bilateral craniofacial malformations with cleft palate, which harbored similar manifestations in her family. She died soon after birth due to dyspnea and feeding difficulties. WES identified two novel pathogenic variants of TCOF1 gene in two probands, each with one variant. According to the American College of Medical Genetics and Genomics, the heterozygous variation NM_001371623.1: c.877del (p. Ala293Profs*34) of TCOF1 gene was detected in Proband 1, which was evaluated as a likely pathogenic (LP) and de novo variant. Another variant found in Proband 2 was NM_001135243.1: c.1660_1661del (p. D554Qfs*3) heterozygous variation, which was evaluated as a pathogenic variation and the variant inherited from the mother. To date, the two variants have not been reported before. Our study found two novel pathogenic variants of TCOF1 gene and clarified the etiology of Treacher Collins syndrome. We also enriched the phenotypic spectrum of Treacher Collins syndrome and TCOF1 gene variation spectrum in the Chinese population, and provided the basis for clinical diagnosis, treatment and genetic counseling.

Introduction Treacher Collins Syndrome is a rare disorder of craniofacial development characterised by maxillary, zygomatic, and mandibular dysplasia.1 Anaesthesia in patients with Treacher Collins Syndrome is a challenge, in view of difficult mask ventilation and difficult intubation. Aim To review different airway management techniques in children with Treacher Collins Syndrome. To determine the difficulty of intubation with increasing age. Methods A retrospective review of airway management in children with Treacher Collins Syndrome reported in the difficult airway database from 2010 to 2017. There were 435 difficult airway cases reported, out of these, 26 cases were Treacher Collins Syndrome. The information collected included age, predicted difficult airway, intubation technique, ease of bag mask ventilation, grade of intubation, time taken for intubation and number of attempts. Results There were 26 cases of Treacher Collins Syndrome reported in the difficult airway database during the period 2010 to 2017. Out of these, 50% were difficult bag mask ventilation. We specifically looked into different intubation techniques used. Fibreoptic intubation was used in 8 (30.7%) cases, Airtraq used in 9 (34.6%), GlideScope in 4 (15.38%), fibreoptic intubation via LMA and GlideScope was used in 2 (7.69%) cases each. Discussion and conclusion All the children we analysed had undergone previous anaesthetics with documented previous difficult intubation. Specialised intubation techniques were the preferred option for airway management in these children. We found it difficult to conclude whether the difficulty of intubation increases with age. We acknowledge that our study was very limited. To get more accurate data, we are conducting a prospective study. Reference 1. Hosking J1, Zoanetti D, Carlyle A, et al. Anesthesia for treacher collins syndrome: A review of airway management in 240 pediatric cases. Paediatr Anaesth 2012 August;22(8):752–8. doi:10.1111/j.1460–9592.2012.03829.x [Epub 2012 Mar 7].

Autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA is responsible for Treacher Collins syndrome

To compare craniofacial structural characteristic of individuals with different types of cleft palate and to lay a foundation for better treatment protocol for patients with cleft palate, we chose a sample consisting of 12 patients with Treacher Collin syndrome, 15 patients with Pierre Robin sequence, 40 patients with unilateral complete cleft lip and palate, and 40 patients with isolated cleft palate who met certain criteria. Lateral cephalometric radiographs were obtained from each subject. A total of 22 variables, comprising 11 angular, 9 linear, and 2 ratio measurements, were studied. The z-scores were analyzed during paired Student t test. The data showed us that there seems to be no difference in craniofacial structures between patients with isolated cleft palate and normal persons. Patients with unilateral complete cleft lip and palate who had only cleft lip repaired exhibit such characteristics as midface retrusion, relatively excessive lower facial height, and more obtuse gonial angle. The cranial base areas of individuals with Treacher Collin syndrome and Pierre Robin sequence are similar to those of normal persons. Mandibular hypoplasia in both vertical and horizontal dimensions and maxillary retrusion can be found in patients with Treacher Collin syndrome, while only mandibular hypoplasia in the horizontal dimension can be found in patients with Pierre Robin sequence. The developmental deficiency of craniofacial structures seems to be a separate deformity, not the direct outcome of cleft palate defect.

Mandibulofacial dysostosis is part of a clinically and genetically heterogeneous group of disorders of craniofacial development, which lead to malar and mandibular hypoplasia. Treacher Collins syndrome is the major cause of mandibulofacial dysostosis and is due to mutations in the TCOF1 gene. Usually patients with Treacher Collins syndrome do not present with intellectual disability. Recently, the EFTUD2 gene was identified in patients with mandibulofacial dysostosis associated with microcephaly, intellectual disability and esophageal atresia. We report on two patients presenting with mandibulofacial dysostosis characteristic of Treacher Collins syndrome, but associated with unexpected intellectual disability, due to a large deletion encompassing several genes including the TCOF1 gene. We discuss the involvement of the other deleted genes such as CAMK2A or SLC6A7 in the cognitive development delay of the patients reported, and we propose the systematic investigation for 5q32 deletion when intellectual disability is associated with Treacher Collins syndrome.

Introduction: Treacher Collins Syndrome (TCS) is a condition affecting the development of facial structures. TCS presents with variable clinical manifestations and can impact the quality of life of those affected. Early identification and diagnosis are crucial management planning and intervention. Objective: To understand the embryology, genetic abnormalities, and manifestations of TCS which would facilitate the diagnosis. Methods: A narrative review of the literature published between 2010 and 2024. The literature search was conducted using the keywords "Treacher Collins Syndrome" and related terms (embryology, epidemiology, diagnosis) across academic databases such as PubMed, Google Scholar, and ScienceDirect. Result: From the 116 articles identified, a review was conducted on 23 publications deemed relevant and appropriate to the topic. Treacher Collins Syndrome (TCS), also known as Mandibulofacial Dysostosis, is a genetic disorder affecting facial structures, characterized by variable clinical manifestations. TCS has impact on the quality of life of those affected. It is inherited in an autosomal dominant manner and involves mutations in the TCOF1, POLR1D, POLR1C or POLR1B genes, which disrupts the development of the pharyngeal arches during embryogenesis. Microtia and conductive hearing loss are otology manifestations of TCS. TCS is diagnosed based on clinical manifestations, along with genetic confirmation. Conclusion: Identification and diagnosis of Treacher Collins Syndrome (TCS) are crucial for planning management and interventions that can improve the patient's quality of life. Keywords: microtia, Treacher Collins syndrome, mandibulofacial dysostosis, conductive hearing los

Treacher Collins Syndrome, also known as mandibulofacial dysostosis is a rare autosomal dominant disorder characterized by craniofacial abnormalities and dysmorphic facies. The estimated incidence varies about 1 in 40,000 to 1 in 70,000 live births. It is associated with difficult mask ventilation and intubation because of facial abnormalities. Hence, recognition of this syndrome is of prime importance for us as anaesthesiologists to prevent potential airway problems under anaesthesia. Here, we report a case of Treacher Collins Syndrome posted for pseudopterygium excision, who was successfully managed with general anaesthesia.