Gorlin RJ, Cohen MM, Hennekam RCM Syndromes of the Head and Neck, 4th edn. New York, NY, USA: Oxford University Press; 2001
Grzanka M, Piekiełko–Witkowska A The role of TCOF1 gene in health and disease: beyond Treacher Collins syndrome. Int J Mol Sci. 2021; 22 https://doi.org/10.3390/ijms22052482
Watt KE, Macintosh J, Bernard G, Trainor PA RNA Polymerases I and III in development and disease. Semin Cell Dev Biol. 2023; 136:49-63 https://doi.org/10.1016/j.semcdb.2022.03.027
Kadakia S, Helman SN, Badhey AK Treacher Collins syndrome: the genetics of a craniofacial disease. Int J Pediatr Otorhinolaryngol. 2014; 78:893-898 https://doi.org/10.1016/j.ijporl.2014.03.006
Marszałek–Kruk BA, Wójcicki P, Dowgierd K, Śmigiel R Treacher Collins syndrome: genetics, clinical features and management. Genes (Basel). 2021; 12 https://doi.org/10.3390/genes12091392
Barbosa M, Jabs EW, Huston S Treacher Collins syndrome. In: Adam MP, Feldman J, Mirzaa GM (eds). Seattle, WA, USA: University of Washington; 2024
Edwards SJ, Fowlie A, Cust MP Prenatal diagnosis in Treacher Collins syndrome using combined linkage analysis and ultrasound imaging. J Med Genet. 1996; 33:603-606 https://doi.org/10.1136/jmg.33.7.603
Wang Y, Wang Y, Yao M Prenatal diagnosis of Treacher Collins syndrome: a case report and literature review. Int J Gynaecol Obstet. 2023; 163:778-781 https://doi.org/10.1002/ijgo.14881
Kapadia H, Shetye PR, Grayson BH, McCarthy JG Cephalometric assessment of craniofacial morphology in patients with Treacher Collins syndrome. J Craniofac Surg. 2013; 24:1141-1145 https://doi.org/10.1097/scs.0b013e3182860541
Travieso R, Chang CC, Terner JS A range of condylar hypoplasia exists in Treacher Collins syndrome. J Oral Maxillofac Surg. 2013; 71:393-397 https://doi.org/10.1016/j.joms.2012.04.031
Jermwiwatkul W, Boonsiriseth K, Viwattanatipa N Treacher Collins syndrome: orthodontic treatment with mandibular distraction osteogenesis and orthognathic surgery. Am J Orthod Dentofacial Orthop. 2021; 159:836-851 https://doi.org/10.1016/j.ajodo.2020.05.016
Golinko MS, LeBlanc EM, Hallett AM Long-term surgical and speech outcomes following palatoplasty in patients with treacher-collins syndrome. J Craniofac Surg. 2016; 27:1408-1411 https://doi.org/10.1097/scs.0000000000002821
Rooijers W, Schreuder MJ, Loudon SE Ocular and adnexal anomalies in Treacher Collins syndrome: a retrospective multicenter study. J AAPOS. 2022; 26:10.e1-10.e6 https://doi.org/10.1016/j.jaapos.2021.10.005
Beaumont CA, Dunaway DJ, Padwa BL Extracraniofacial anomalies in Treacher Collins syndrome: a multicentre study of 248 patients. Int J Oral Maxillofac Surg. 2021; 50:1471-1476 https://doi.org/10.1016/j.ijom.2021.03.001
Zanchetta R, Jost LM, Peixoto PP, Costa AP, Da Silva Dalben B Dental anomalies in individuals with Treacher Collins Syndrome – tomographic analysis. JSM Head Face Med. 2018; 3 https://doi.org/10.47739/2578-3793/1012
Østerhus IN, Skogedal N, Akre H Salivary gland pathology as a new finding in Treacher Collins syndrome. Am J Med Genet A. 2012; 158:1320-1325 https://doi.org/10.1002/ajmg.a.35331
Trainor PA, Andrews BT Facial dysostoses: etiology, pathogenesis and management. Am J Med Genet C Semin Med Genet. 2013; 163:283-294 https://doi.org/10.1002/ajmg.c.31375
Plomp RG, Bredero–Boelhouwer HH, Joosten KF Obstructive sleep apnoea in Treacher Collins syndrome: prevalence, severity and cause. Int J Oral Maxillofac Surg. 2012; 41:696-701 https://doi.org/10.1016/j.ijom.2012.01.018
Jiang D, Morrison GA The influence of long-term tracheostomy on speech and language development in children. Int J Pediatr Otorhinolaryngol. 2003; 67 https://doi.org/10.1016/j.ijporl.2003.08.031
Heggie AA, Kumar R, Shand JM The role of distraction osteogenesis in the management of craniofacial syndromes. Ann Maxillofac Surg. 2013; 3:4-10 https://doi.org/10.4103/2231-0746.110063
Vandevender J, Park RB, Choudhary A Considerations in eyelid reconstruction in Treacher Collins syndrome: a scoping review. FACE. 2023; 4:306-318 https://doi.org/10.1177/27325016231174649
Hertle RW, Ziylan S, Katowitz JA Ophthalmic features and visual prognosis in the Treacher Collins syndrome. Br J Ophthalmol. 1993; 77:642-645 https://doi.org/10.1136/bjo.77.10.642
Grewcock RE, Innes NPT, Mossey PA, Robertson MD Caries in children with and without orofacial clefting: a systematic review and meta-analysis. Oral Dis. 2022; 28:1400-1411 https://doi.org/10.1111/odi.14183
Teber OA, Gillessen-Kaesbach G, Fischer S Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation. Eur J Hum Genet. 2004; 12:879-890 https://doi.org/10.1038/sj.ejhg.5201260
Vincent M, Geneviève D, Ostertag A Treacher Collins syndrome: a clinical and molecular study based on a large series of patients. Genet Med. 2016; 18:49-56 https://doi.org/10.1038/gim.2015.29
Rosa F, Coutinho MB, Ferreira JP, Sousa CA Ear malformations, hearing loss and hearing rehabilitation in children with Treacher Collins syndrome. Acta Otorrinolaringol Esp. 2016; 67:142-147 https://doi.org/10.1016/j.otorri.2015.01.005
Baluch N, Nagata S, Park C Auricular reconstruction for microtia: a review of available methods. Plast Surg (Oakv). 2014; 22:39-43
Ladani P Ear reconstruction. In: Bonanthaya K, Panneerselvam E, Manuel S (eds). : Springer; 2021
Opitz C, Ring P, Stoll C Orthodontic and surgical treatment of patients with congenital unilateral and bilateral mandibulofacial dysostosis. J Orofac Orthop. 2004; 65:150-163 https://doi.org/10.1007/s00056-004-0324-0
Nguyen PD, Caro MC, Smith DM Long-term orthognathic surgical outcomes in Treacher Collins patients. J Plast Reconstr Aesthet Surg. 2016; 69:402-408 https://doi.org/10.1016/j.bjps.2015.10.036
Tuk JG, Lindeboom JA, Tan ML, de Lange J Impact of orthognathic surgery on quality of life in patients with different dentofacial deformities: longitudinal study of the Oral Health Impact Profile (OHIP-14) with at least 1 year of follow-up. Oral Maxillofac Surg. 2022; 26:281-289 https://doi.org/10.1007/s10006-021-00992-6
Konofaos P, Arnaud E Early fat grafting for augmentation of orbitozygomatic region in Treacher Collins Syndrome. J Craniofac Surg. 2015; 26:1258-1260 https://doi.org/10.1097/scs.0000000000001722
Lim AA, Fan K, Allam KA Autologous fat transplantation in the craniofacial patient: the UCLA experience. J Craniofac Surg. 2012; 23:1061-1066 https://doi.org/10.1097/scs.0b013e31824e695b
This article provides an overview of Treacher Collins syndrome (TCS), its diagnostic features, aetiology and management. TCS is a genetic disorder that results in congenital craniofacial malformation. The facial, dental manifestations and orthodontic implications of TCS are outlined. General dental practitioners (GDPs) and orthodontists play a critical role in the multidisciplinary care of these patients.
CPD/Clinical Relevance: Clinicians should be aware of the challenges in treating this cohort of patients.
Article
Treacher Collins syndrome (TCS), also known as mandibulofacial dysostosis, is a congenital condition that affects the structures derived from the first and second pharyngeal arch. TCS may occur as a result of sporadic mutation or familial inheritance. In familial cases of TCS, autosomal dominant inheritance is most common. The incidence of TCS is one in 50,000 live births.1
The clinical presentation of TCS varies among affected individuals, ranging from mild to severe facial involvement, and in severe cases, life-threatening airway compromise can occur. The phenotypic characteristics of TCS are typically bilateral. TCS is characterized by significant hypoplasia of the midface structures, which leads to shorter lateral and lower orbital walls, resulting in a narrowed and flattened facial bone structure. This often occurs with hypoplasia of the maxilla, and a skeletal Class II relationship with severe hyper-divergence and mandibular retrognathia is often observed.
Additional anomalies may include visual impairment, cleft palate, dental abnormalities leading to anterior open bite, spacing or hypodontia. The facial features of TCS can cause difficulty with speech, breathing, feeding and hearing. Treatment is multidisciplinary in nature and depends on the individual presentation and severity of the syndrome as well as the severity of symptoms.
Aetiology
TCS is caused by gene mutations involved in the development of the craniofacial region during embryonic development. It is primarily associated with mutations in the TCOF1 (treacle ribosome biogenesis factor 1) gene, which encodes the protein, treacle. Treacle plays a crucial role in ribosomal production.2 Mutations in treacle lead to apoptosis of neural crest cells, which are essential for craniofacial development. Pathogenic variants in TCOF1 are responsible for approximately 80% of TCS cases, while POLR1B, POLR1C and POLR1D have been shown to contribute to most of the remaining cases. Approximately 60% of cases result from de novo mutations. Inheritance from an affected parent accounts for the remaining 40% of cases.3,4
Diagnosis
Diagnosis is typically based on clinical assessment of the characteristic facial features, which are discussed in detail in the next section. There can be significant overlap in the clinical features of TCS and other syndromes such as hemifacial microsomia, Goldenhar syndrome, Miller and Nager syndrome, as well as mandibulofacial dysostosis with microcephaly. However, TCS is usually bilateral and symmetrical and there are no limb anomalies, in contrast to other syndromes.5
Hypoplasia or aplasia of the zygomatic arch can be detected on an occipito-mental radiograph. Mandibular retrognathia can be seen on an orthopantomogram and cephalometric radiograph, although CT scans are now commonly conducted to determine the severity of the dysmorphology.
Prenatal genetic testing and ultrasound can also detect associated craniofacial abnormalities, such as micrognathia and microtia.6,7 Molecular genetic testing is necessary to confirm the definitive diagnosis by identifying genetic mutations within TCOF1, POLR1B, POLR1C and POLR1D. It is also useful to guide genetic counselling for prenatal diagnosis and provide options for families to use pre-implantation genetic diagnosis.8
Clinical manifestations
TCS presents with a distinctive array of craniofacial abnormalities that are apparent at birth and can vary in severity among affected individuals.
Facial features
Characteristic facial features of TCS include (Figures 1 and 2):
Hypoplasia or absence of the zygomatic bones;
Hypoplasia of mandible and maxilla;
Downward-slanting palpebral fissures with colobomas of the lower eyelids and sparse eyelashes;
Microtia with conductive hearing loss owing to middle ear malformations.
Figure 1. (a,b) Characteristic facial features of TCS include midface and zygomatic hypoplasia, microtia, and mandibular retrognathia. Patients can be fitted with a bone-anchored hearing aid to help conductive hearing loss.Figure 2. (a,b) A 3D reconstitution of a patient with TCS demonstrating the characteristic facial features of TCS, including downward-slanting palpebral fissures, hypoplasia of zygomatic bones and mandibular retrognathia. Condylar hypoplasia is a common feature. The facial features of TCS commonly result in a skeletal open bite.
Patients with TCS often have a dramatically convex facial profile owing to hypoplasia of zygomatic bones, maxilla and mandibular hypoplasia. Lateral cephalometric analysis of 20 patients with TCS demonstrated that the maxilla was deficient and positioned posteriorly with respect to the cranial base.9 Patients with TCS tend to have a retrognathic mandible with a short mandibular ramus and a body with a deficient symphysis. These patients have a backward mandibular rotation, which results in a steep mandibular plane. Condylar hypoplasia is a common feature of TCS.10 Lower facial height is increased, while total facial height is decreased. The maxillary and occlusal plane is typically tipped upwards posteriorly. These features often result in a skeletal open bite, reduced posterior facial height, increased gonial angle, antegonial notching and posterior rotation of the occlusal plane. An anterior open bite malocclusion with lip incompetence is common in TCS.9,11,12 Cleft palate is a common finding, affecting 33–66% of patients with TCS.13 Even in patients without a cleft palate, the palate is often highly arched. This can lead to difficulty breathing and feeding.14
Ocular anomalies are a hallmark feature of TCS, mostly consisting of downward-slanting palpebral fissures with colobomas of the lower eyelids and partial absence of eyelashes on the lower eyelid. In a study of 194 patients, refractive errors occurred in 50% of patients with TCS, while visual impairment occurred in 5%. Less common ocular features include epiphora, exposure keratopathy and strabismus.15
Patients with TCS usually present with microtia or sometimes anotia. External ear canal abnormalities tend to be symmetric. The middle ear cavity is usually hypoplastic and dysmorphic with ankylosis or absence of the ossicles. Most patients experience conductive hearing loss owing to their middle ear malformations. The inner ear tends to be unaffected.16
Extracranial anomalies are less prevalent, but have been reported in the literature. In a 2021 study of 248 patients with TCS, vertebral anomalies were most prevalent (34%), followed by cardiac (14%), reproductive system (12%), central nervous system (7%), limb (7%), pulmonary (6%), renal (3%) and GI (3%) anomalies.17
Dental anomalies are common in patients with TCS (Figure 3). Hypodontia has been reported in 23–33% of patients with TCS,13,18 most commonly affecting the second premolars and maxillary lateral incisors. Dysplasia/atresia of salivary glands and reduced salivary secretion rates have been reported in the literature.19 This can lead to xerostomia and an increased risk of dental caries for patients with TCS. Other dental anomalies include impacted supernumerary teeth in the maxillary anterior region, hypoplasia, position alterations of the maxillary central incisors, T-shaped teeth, enamel opacities, enamel hypoplasia, microdontia, tooth rotations and ectopic tooth positioning.13
Figure 3. Orthopantomogram of a patient with TCS demonstrating the common dental anomalies in TCS, such as hypodontia and ectopic teeth.
Management
The management of TCS requires a comprehensive life-long multidisciplinary approach involving plastic surgeons, oral and maxillofacial surgeons, orthodontists, prosthodontists, GDPs, otolaryngologists, ophthalmologists, speech and language therapists and clinical psychologists. The approach and timing of any intervention depends on the individual presentation, severity of the case, functional limitations, patient concerns and psychosocial factors.
In the early years, the priority is the maintenance of a patent airway and ensuring adequate development of feeding, hearing, speech development and vision.
Early management
At birth, the priority is airway management. In severe cases where the airway is compromised, a tracheostomy may be needed to overcome obstruction secondary to glossoptosis and mandibular retrognathia.20 The tracheostomy may need to remain in place until there is sufficient mandibular growth or until distraction osteogenesis is performed to enable the passage of air through the oral cavity. Tracheostomies have been reported in up to 41% of patients with TCS.21,22 If tracheostomy serves as the primary treatment for upper airway obstruction, it becomes a necessary commitment lasting 1–2 years, which can significantly impact the psychological health of the patient as well as increase care needs for carers. Moreover, this crucial stage for speech and language development may be compromised.23 Hypoplasia of facial bones can also cause obstructive sleep apnoea syndrome (OSAS), which is seen in up to 46% of patients with TCS.12
Other options are continuous positive airway pressure or mandibular distraction osteogenesis. Distraction osteogenesis (DO) is a procedure that lengthens the bone by inducing new bone formation from the gradual separation of two surgically separated parts of the bone. The advantages of DO include addressing the root cause by extending the mandible, raising the hyoid bone, and moving the base of the tongue forward from the back of the throat to eliminate obstruction.24 In certain cases, DO can eliminate the need for a tracheostomy or aid in decannulation.24 In a group of 35 syndromic patients who received DO for upper airway obstruction, none needed a tracheostomy following the procedure.24 Those who already had one were able to be decannulated successfully.24
An internal distractor device is placed using a submandibular approach, with bilateral osteotomies carried out as posteriorly as feasible, starting from the retromolar region to the angle of the mandible to fit the device. The activation arms come out below the auricles, and the distraction process progresses at a rate of 1.5 mm per day over 10 days. This is followed by a consolidation period lasting 6–8 weeks. Typically, most infants are successfully extubated on days 4–5 after the operation, experiencing full resolution of the obstruction.25
The oral-facial features of TCS can cause feeding difficulties and put infants with TCS at risk for growth failure and sometimes aspiration. Therefore, feeding difficulties must be addressed early on in patients with TCS. An interdisciplinary approach to address feeding challenges is essential. Positional changes, latching manoeuvres, specialized feeder nipples, squeezable bottles, and cup feeding can all help. Surgical intervention, including gastrostomy tube placement, tongue lip adhesion, mandibular distraction osteogenesis, and tracheostomy may be required in more severe cases to ensure adequate caloric intake.26
Ocular management
TCS eyelid abnormalities most commonly present as pseudo-colobomas, true colobomas, and lateral canthal dystopia. Surgical management of ocular abnormalities must consider previous craniofacial reconstruction and current mid-face development. Orbital growth is typically complete at 4 years of age. Possible surgical procedures may involve eyelid reconstruction, coloboma/pseudo-coloboma repair and lateral canthal dystopia repair. In a study of 144 patients with TCS, the average age of first eyelid reconstruction was approximately 13 years (range 1–36 years).27
Conducting an early ophthalmic examination to identify and address refractive errors and strabismus can help identify preventable causes of visual impairment, which are mainly due to untreated amblyopia. While vision can improve with treatment, achieving normal visual acuity in the affected eyes is challenging. It is crucial to implement intensive, early amblyopia therapy, optimise optical correction, provide ongoing support and ensure follow-up visits to monitor compliance.28
Cleft management
Approximately one-third of patients with TCS present with a cleft palate and it is essential that patients are linked with the cleft care pathway. The type of treatment depends on the classification and severity of the cleft. In the UK, the aim is to close the palate before the age of 1 year, improving anatomy and providing better functioning muscles before speech starts to fully develop.29 When a cleft is present, there is typically a shortage of tissue along with displacement of associated structures and muscles. The goal of surgery is to close the cleft with minimal scarring, while also realigning these structures, especially muscles, to ensure optimal function.29 Modern surgical approaches aim for palate closure in multiple stages rather than one operation with extensive relieving incisions.
Children with clefts develop more caries than those without.30 The high prevalence of dental anomalies and increased caries risk of these patients highlights the necessity of ensuring patients with TCS have a GDP and attend regular dental check-ups. Providing patients and their parents with information on the aetiology of caries and giving preventive advice is essential.30
Otologic management
Between 88% and 91% of patients with TCS experienced conductive hearing loss (CHL).31,32 Early identification of CHL enhances the potential for hearing and speech rehabilitation, with brainstem auditory evoked response playing a crucial role in this process, and which should be performed as soon as possible (before the age of 1 year). Timely hearing rehabilitation typically involves traditional prostheses via bone conduction or more modern options, such as a Softband (Oticon Medical, Hamilton, Scotland). A bone-anchored hearing aid (BAHA) stands out as a highly effective method for hearing restoration that delivers improved audiometric outcomes.33
External ear reconstruction is addressed based on the specific needs and presentation of each patient. Patients with significant ear involvement often need a prosthesis or reconstruction. The major methods of pinna reconstruction include the use of autologous costal cartilage grafts, tissue expansion, implants, osseo-integration and prostheses.34 The microtia surgeon should discuss all the options with the family at an early stage, including observation, autologous costal cartilage, alloplasts and prosthetics. Each method of management has a different timing, and repair is governed by growth and psychological consideration. Usually, by the age of 6 years, the cartilage is sufficiently developed to provide an optimal primary framework. Waiting until the child is older results in more cartilaginous graft options, but earlier reconstruction can have a positive psychological effect on the child.35
Orthodontic management
Orthodontic management differs significantly between patients. Consequently, surgical and orthodontic interventions are customized to meet the specific needs of each patient. Essential factors to consider in management are patient age, skeletal maturity, and the severity of the deformity. In general, surgical corrections are performed after growth is complete because growth is unpredictable. With TCS, mandibular retrognathia is more unpredictable. There are cases where surgery before the completion of growth may be necessary, such as airway concerns or to address aesthetic or functional concerns.
In mild cases, camouflage orthodontic treatment may be possible. However, most patients with TCS will require orthognathic surgery to correct severe facial deformities. A combined orthodontic and orthopaedic approach with orthognathic surgery is commonly required.36 The use of functional appliances during the primary and mixed dentition aims to stimulate mandibular growth. When distraction osteogenesis is used, the orthodontist must be involved in treatment planning with the craniofacial surgeons. Distraction osteogenesis requires long-term orthodontic aftercare to achieve correct alignment of the teeth and controlled closure of lateral open bites.37
Surgery may involve Le Fort I and bilateral sagittal split osteotomies, bilateral zygomatic augmentation, genioplasty and rhinoplasty.37 Pre-surgical orthodontics is often carried out to remove any dental compensations and correct any maxillary transverse discrepancies, either by using a rapid maxillary expansion in growing patients or surgically assisted rapid palatal expansion in adults. The teeth are moved into their ideal position, which may require extractions. The occlusion and facial appearance are often made worse until surgical correction occurs.38 Before commencing surgery, this must be clearly explained to the patient, as well as the risk of relapse. Studies have demonstrated that bimaxillary surgery in patients with TCS may be performed with skeletal and dental stability within the accepted relapse rate for Class II malocclusion movements.39 Le Fort I osteotomy to correct maxillary clockwise rotation has a considerable risk of relapse, while mandibular anti-clockwise rotation and bilateral sagittal split osteotomies remain stable.39 Improving the skeletal relationships can significantly contribute to improving the quality of life of these patients.40
Adjunctive procedures to improve the soft tissues can be considered both post-orthognathic surgery and as a temporary measure in adolescence.41 Fat grafting has become an increasingly popular method to improve contour and restore volume in facial soft tissues. The lower anterior abdominal wall is the first choice as a donor site, with the upper medial thigh serving as a secondary donor site. Autologous fat transfer, when performed simultaneously with orthognathic procedures, is an effective method for achieving long-term improvements in facial contour and symmetry in patients with TCS.42
Conclusion
TCS is a complex congenital condition requiring a multidisciplinary approach to manage. Patients present with severe craniofacial abnormalities requiring early intervention to prevent any potential difficulties with breathing, feeding, speech and hearing. General and specialist dental care is essential at every stage of the patient's journey. Patients with TCS must maintain excellent oral hygiene and aim to maintain a caries-free dentition to facilitate complex orthodontic treatment and potential orthognathic surgery. Life-long orthodontic retention is essential to maintain the stability of the outcome. Early engagement with all members of the dental team can aid in fostering a positive dental relationship and achieving a successful outcome. These patients should be treated in craniofacial centres to facilitate collaborative care from service specialists.