What Is Treacher-Collins Syndrome?

Overview

Over the years, many genetic syndromes have been discovered and reported, some more prevalent than others, some more recognizable than others. Among these many conditions, Treacher-Collins syndrome (TCS) is one of them: characterised by malformations of the facial bones and structures (eyes, ears), this rare genetic syndrome can vary in severity from mild to severe.¹ In recent years, more awareness of Treacher Collins syndrome has been raised due to media content being produced, including the film adaptation of the novel “Wonder”, starring Julia Robers, Owen Wilson and Jacob Tremblay. But what exactly causes Treacher Collins syndrome? What are the signs and symptoms that it causes? Let’s understand more about this condition.

Causes

Treacher-Collins syndrome is the name given by the British ophthalmologist Edward Treacher Collins in 1900 when he discovered the condition.¹ Although he wasn’t the first one to describe it, as physicians Thomson and Berry had made note of the syndrome in 1846 and 1889, respectively, his name is what historically has been used due to his contributions to understanding TCS.¹ In 1949, two other doctors, Franceschetti and Klein, also made observations about the condition and called it Franceschetti-Klein syndrome or mandibulofacial dysostosis.¹ Even though the names are different, they all refer to the same disease.

As previously stated, Treacher-Collins is a genetic syndrome.¹ It is a heterogeneous syndrome, and current literature describes four subtypes based on which gene has been mutated.²

TCS subtype 1: caused by a mutation of the TCOF1 gene. This is an autosomal dominant mutation that causes apoptosis (cell death) of the neural crest cells during in-utero development of the foetus.²

TCS subtype 2: caused by a mutation of the POLR1D gene. This is also an autosomal dominant mutation and leads to the early apoptosis of the neural crest cells that were developing normally at first.²

TCS subtype 3: caused by a mutation of the POLR1C gene. Its mechanism is identical to the POLR1D gene, but it’s an autosomal recessive gene.²

TCS subtype 4: caused by a mutation of the POLR1B gene. This gene causes a mutation of the p53 gene that controls apoptosis, leading to early cell death. It is also an autosomal dominant gene.²

Mutations of the aforementioned genes cause early death of the cells that form the first and second branchial arches: these developmental arches are responsible for the formation of the face and cranial region, and the premature death of the cells causes malformations of these regions.²  

Signs and symptoms

Treacher-Collins syndrome has characteristic features like hypoplasia of the zygomatic region (lack of development of the cheekbone area), downward slanted eyes, mandibular hypoplasia (lack of development of the mandible), and hearing impairment.² 

Common signs and symptoms are:²

• Hypoplasia of the zygomatic complex
• Hypoplasia of the mandible (micrognathia)
• Downward slanted eyelids
• Conductive hearing loss
• Atresia of the external ear canal
• Microtia (small, malformed ear)
• Coloboma (notching) of the lower lid
• Asymmetry of the face
• Delays in speech development
• Preauricular hair displacement
• Cleft palate
• Choanal (openings that connect the nasal cavity to the nasopharynx) stenosis or choanal atresia

Other rarer manifestations of TCS include cardiac malformations, renal malformation, rachis malformation, microcephaly (a development impairment in which the head is smaller than what it is supposed to be), limb anomaly, intellectual disability and delayed motor development.² As it affects the jaws, Treacher-Collins syndrome can cause dental abnormalities.³ Some of the most common findings in patients include tooth agenesis, discolouration of the teeth, widely spaced teeth (multiple diastemas), ectopic eruption of the maxillary first molars, and malocclusion.³

Diagnosis

Clinical evaluation of the patient should be performed to diagnose features that are characteristic of Treacher-Collins syndrome.³ A detailed family history is also important because, as it is inherited, patients with a history of TCS in their families are more likely to have the syndrome.³

Complementary exams like X-rays or CT scans can be performed to assess the extent of the malformations of the facial bones and middle and inner ear structures and to plan for surgeries.³  

Genetic testing should be done to confirm the diagnosis.³  A laboratory can identify if there are mutations present and which gene has been affected: most patients, about 90-95% of them, are part of the TCS subtype 1 and possess the mutation of the TCOF1 gene.⁴ Prenatal testing can diagnose the disease early on during pregnancy.²

Diagnosis of TCS can be tricky, as the syndrome might have a similar clinical presentation to other syndromes and genetic disorders that affect the development of the first and second branchial arches.² 

Potential differential diagnosis hypotheses are:²

• Goldenhar syndrome (oculoauriculovertebral spectrum): although also a genetic syndrome, its specific causing gene is still unknown
• Nager syndrome: caused by mutations of the SF3B4 gene in chromosome 1. Aside from the facial abnormalities shared with TCS, Nager syndrome also causes radial limb defects (like absent or underdeveloped thumbs) and forearm abnormalities (hypoplasia of the radius with radioulnar synostosis)
• Miller syndrome: this condition is caused by a mutation in the DHODH in chromosome 16, and while it possesses facial anomalies similar to TCS, it also causes distinctive limb defects like forearm abnormalities and absent or incomplete development of the 5th digital ray of arms and legs
• Mandibulofacial dysostosis with microcephaly (MFDM): mutations of the EFTUD2 can result in MFDM, a condition characterised by facial abnormalities with significant impact on intellectual and physical development due to the microcephaly

Management and treatment

There is no cure for Treacher-Collins syndrome, but there are plenty of available treatments to aid each patient’s specific needs.⁴ A team of professionals should accompany a patient to help improve their outcome in many aspects: paediatric doctors, paediatric dentists, orthodontists, psychologists, otolaryngologists, and surgeons are some of the components of a team.²

Treatment can be divided into phases according to age:²

• Birth to 2 years old: consists of procedures that help facilitate living functions, such as tracheostomy (to improve breathing) and feeding tubes (to improve nutrition)
• 3 to 12 years old: speech therapy, orthodontics and ophthalmological support, as well as surgeries to reconstruct the mandible, can be performed to improve aesthetics and function and to mitigate the progression of the defects
• 13 to 18 years old: patients in this age group can undergo bigger surgeries for facial reconstruction, such as orthognathic surgery, periorbital reconstruction, chin osteotomy and nasal reconstruction

Treatment has greater chances of success the earlier it starts for TCS patients, as many consequences can be mitigated, implying less invasive surgeries in adulthood, with proper measures taken to correct abnormalities at a younger age.² Furthermore, there is also a significant improvement in quality of life: as these patients have short mandibles and tongues that fall back, upper airway obstruction is a common finding, and it can be improved with surgery.² Likewise, the coloboma (cleft) of the eyelids can result in dry eyes, and surgery to correct the issue can be done to improve hydration and eye protection. Cleft palate correction is another surgery performed early on to improve feeding, breathing and speech.²

Hearing loss is a common symptom of TCS, and, unfortunately, surgery isn’t always efficient in correcting this problem, with only a minority of patients being positively impacted by surgery.⁴ However, hearing aids can and should be used by patients, as they can significantly improve not only their hearing but also their concentration, learning and development.⁴

Psychological treatment is extremely important for patients and family members. Dissatisfaction with one’s physical appearance and self-esteem issues, stress and avoidant behaviours are not uncommon in patients with congenital facial abnormalities due to social stigma.⁴

There are currently no strict guidelines to be followed: treatment is individual and planned with the patient, the family and a team of health professionals to improve the specific needs of each patient.⁴

Epidemiology

It is estimated that the incidence of Treacher-Collins syndrome is about 1 in every 50.000 live births. About 40% of the cases have a previous familial history of the syndrome, while the other 60% occur from de novo mutations - meaning that the patient didn’t inherit the trait but rather developed a mutation spontaneously.²

Summary

Treacher-Collins syndrome is a genetic disorder that causes malformation of the facial bones and results in underdevelopment of the zygomatic (cheekbone) and mandibular bones, cleft palate, hearing loss and impairment, dental anomalies (tooth agenesis, malocclusion), asymmetry of the face, ear malformations (microtia, atresia of the ear canal), and problems in speech development. It is considered rare, affecting one in every 50.000 newborns each year. It is caused by mutations of the TCOF1, POLR1B, POLR1C, or POLR1D genes, and those mutations cause early cell death of the cells responsible for the formation of facial structures, resulting in incomplete development. Diagnosis can be made through clinical evaluation, family history, image exams (X-ray and CT scan), and confirmed through genetic testing to search for mutated genes. Treatment is tailored to each individual and consists of a multidisciplinary approach: reconstructive surgeries of the mandible, zygomatic bone, periorbital area, chin and nose, as well as orthognathic surgery, can be performed to mitigate or correct developmental defects; orthodontic treatment to correct malocclusion, eye surgery to correct coloboma, and plastic surgery to improve facial aesthetics are treatment options as well. Regardless, psychological treatment is just as important to aid in self-esteem issues and avoidant behaviours that stem from the social stigma of having a facial abnormality disease.