What is Treacher-Collins Syndrome?

Treacher Collins Syndrome (TCS) is an autosomal dominant disorder, that affects the development of bones and other tissues in the face. It owes its name to the British surgeon and ophthalmologist Edward Treacher Collins, who was the first to describe the characteristics of TCS in 1900.¹

In 1949, Franceschetti and Klein provided a comprehensive overview by classifying it as a mandibulofacial dysostosis, which is why the syndrome is also known as Franceschetti–Klein syndrome.^2,1

The most common clinical features include lower eyelid abnormalities, downward slanting eye openings (palpebral fissures), malar hypoplasia (underdeveloped cheekbones) and mandibular hypoplasia or micrognathia (a small jaw), dental anomalies, unusual ear shape or size.

About 40%-50% of individuals with TCS experience hearing loss, usually because the middle ear structures (ossicles) do not form properly. he inner ear, however, is usually normal. In infancy, individuals can experience respiratory and feeding difficulties. The intellect is generally normal.^3,4

TCS has an incidence of 1 in every 50,000 births. Most of the time (around 60%), the condition happens due to a new genetic mutation in a family with no history of the syndrome, while the rest of the cases depend on specific genetic mutations present in family antecedents. Furthermore, it is supposed that the parental age may represent a risk factor for genetic mutations.

TCS follows an autosomal dominant inheritance pattern, which means that only one copy of the faulty gene is needed to pass the condition on to a child.

The main gene involved is TCOF1, and it is responsible for most cases (63%-93%), but other less common genes are involved, such as POLR1D (6%) and POLR1C (1.2%).¹

Role of Genes in Treacher-Collins Syndrome

TCS is genetically heterogeneous, divided into 4 clinical subtypes:

• Treacher Collins syndrome 1 (TCS1), caused by variants of the TCOF1 gene
• Treacher Collins syndrome 2 (TCS2), caused by variants in the POLR1D gene
• Treacher Collins syndrome 3 (TCS3), caused by variants in the POLR1C gene
• Treacher Collins syndrome 4 (TCS4), recently identified and is caused by variants in the POLR1B gene

So far, there is no strong link between specific gene mutations and how severe the physical features of TCS will be.⁵

The TCOF1 gene encodes a protein involved in various cellular functions called Treacle, and mutations in this gene are the main cause of Treacher Collins Syndrome. They interfere with the normal growth and development of facial structures.⁶

Over 200 mutations have been reported in the TCOF1 gene, including deletions, insertions, and substitutions.⁵

Other involved genes, POLR1B, POLR1C, and POLR1D, are responsible for helping the cell make RNA, a molecule involved in protein production and cell development. These genes play an essential role in guiding how cells grow and specialise during early development.

Scientists have identified 20 variations in the POLR1C and POLR1D genes, and three new mutations in the POLR1B gene, that can lead to TCS.⁶

TCOF1 Gene and Its Role in TCS

The TCOF1 gene provides instructions for making a protein called treacle, which plays a role in several essential cell functions. Treacle contributes to the development of the facial skeleton and the central and enteric nervous systems. It helps with processes such as in cell division (mitosis), cell growth and ribosome production, which are responsible for protein synthesis. It also helps protect cells from a type of damage-induced cell death, called apoptosis. Being involved in so many activities, it seems evident that TCOF1 dysfunction can cause developmental disorders.

More than 200 mutations in the TCOF1 gene have been identified, and many of them are pathogenic. The majority of these mutations result in a shortened, non-functional version of the treacle protein. During normal embryonic development, TCOF1 is strongly expressed in the neural crest cells, from which the craniofacial skeleton is derived. When TCOF1 doesn't function properly, these neural crest cells are reduced in number, leading to the facial differences seen in people with TCS.Although, the connection between TCOF1 mutations and TCS has been well studied, recent studies suggests that treacle may also play a role in other conditions, including cancer.⁷

POLR1C and POLR1D Genes and Their Role in TCS

POLR1C and POLR1D genes provide instructions for making parts of RNA polymerases I and III—enzymes that help produce ribosomal RNA (rRNA), a key ingredient in building ribosomes.^8,9 Ribosomes are essential for making proteins, and their production is especially important during embryonic development, when cells are growing and dividing rapidly.  If there is a deficiency of Pol I and Pol III due to mutations in POLR1C or POLR1D genes, the number of mature ribosomes in neural crest cells during embryonic development is reduced, causing the typical facial differences of TCS.^5,10

Unlike TCOF1, mutations in POLR1C are inherited in an autosomal recessive way, meaning a person must inherit the faulty gene from both parents. POLR1D mutations can be either autosomal recessive or autosomal dominant.⁸

While researchers understand that these mutations reduce rRNA production, the exact details of how they cause TCS are still being studied.^8,11

Neural crest cells are highly sensitive to low rRNA levels due to variations in treacle, POLR1D, and POLR1C. This disruption is part of a group of conditions known as ribosomopathies, disorders caused by problems with ribosome production. Hence, TCS is classified as a ribosomopathy.¹¹

Genetic Testing and Diagnosis of TCS

The diagnosis of Treacher Collins syndrome can be difficult due to the similarity of characteristics with other disorders, such as Goldenhar syndrome, Miller syndrome and Nager syndrome, and mandibulofacial dysostosis with microcephaly⁵. 

TCS is approached by a multidisciplinary team composed of geneticists, plastic surgeons, ophthalmologists, ear–nose–throat specialists (ENTs), and many more healthcare providers.⁶

The main areas to focus on are: eye examination, by looking at the eyelids and checking vision, hearing testing, since conductive hearing loss is very common, and upper airway examination, since jaw size and position can increase the risk of sleep apnoea.⁴

When TCS is suspected, a TCOF1 gene mutation analysis is done to check for any abnormalities. If an abnormality is found, the diagnosis of TCS is confirmed, and treatment begins. If no abnormality is detected in TCOF1, other craniofacial syndromes may be considered.⁶

Based on family history or physical features, postnatal diagnosis typically involves an analysis of a blood sample from the individual and family members to analyse DNA. If a pathogenic mutation is confirmed, prenatal and preimplantation genetic testing can be offered. About 96% of TCS diagnoses are made through genetic testing, identifying a pathogenic variant in TCOF1 or POLR1D (autosomal dominant inheritance) or POLR1C or POLR1D (autosomal recessive inheritance).

The remaining 4% of patients are diagnosed based on clinical features when molecular genetic testing has not been done, or no pathogenic mutations are detected.⁴

The genetic testing that can be performed depend on the patient’s clinical situation and the available technology. They include molecular genetic testing, chromosomal microarray analysis, next-generation sequencing, targeted mutation analysis, prenatal genetic testing, and array comparative genomic hybridization.⁶

In the diagnosis of TCS, an important aspect to consider is the differential diagnosis through genetic testing, due to the similarity of clinical features with other syndromes.⁶

Summary 

Treacher Collins Syndrome (TCS) is a rare autosomal dominant genetic disorder characterized by craniofacial abnormalities, such as underdeveloped cheekbones, jaw, and ears. It is caused by genetic mutations, with the most common mutated gene called TCOF1, which encodes the protein treacle. Treacle plays roles in different cellular processes and is crucial in the development of craniofacial structures derived from neural crest cells. Mutations in TCOF1 result in a defective protein that causes deficiency in neural crest cells, undermining the normal embryonic development. This leads to the typical features seen in TCS.

While TCOF1 is the main gene involved in the pathogenesis of TCS, other genes, such as POLR1D, POLR1C, when mutated, can also contribute to the syndrome. These genes help make ribosomes—the parts of a cell that produce proteins. Variations in these genes can reduce the number of functional ribosomes in neural crest cells, further interfering with craniofacial development. The inheritance pattern of POLR1C mutations can be autosomal recessive, while POLR1D mutations can be both autosomal dominant and autosomal recessive, adding complexity to the genetic understanding of TCS.

The diagnosis of TCS is based on physical features and confirmed through genetic testing, which are performed to detect genetic mutations in individuals in whom TCS is suspected. If a pathogenic variant is identified in an affected individual, prenatal and preimplantation genetic testing can be offered. However, the diagnosis can be difficult due to the similarity of clinical features with other craniofacial disorders such as Goldenhar syndrome, Miller syndrome and Nager syndrome. This is why it is important to consider the differential diagnosis for accurate results.

Ongoing research continues to improve our understanding of how these gene mutations affect development. This is essential for improving diagnosis, treatment options, and support for individuals and families affected by TCS.