Introduction

Treacher Collins syndrome (TCS) is a rare genetic disorder which affects craniofacial (the skull and the face) development.^1,2 This congenital syndrome affects approximately 1 in 50,000 live births and is due to both autosomal dominant (AD) and autosomal recessive (AR) genetic mutations.^1,3 

TCS has been linked to mutations in the TCOF1, POLR1B, POLR1C, and POLR1D genes, leading to four clinical subtypes of the condition. These are:³ 

• Treacher Collins syndromes 1: TCS1 – due to pathogenic variants of the TCOF1 gene
• Treacher Collins syndromes 2: TCS2 – due to pathogenic variants of the POLR1D gene 
• Treacher Collins syndromes 3: TCS3 – due to pathogenic variants of the POLR1C gene
• Treacher Collins syndromes 4: TCS4 – due to pathogenic variants of the POLR1B gene

Genetic basis and inheritance

Gene mutations

As previously stated, TCS is associated with mutations in four genes (TCOF1, POLR1B, POLR1C, and POLR1D).^3,4 

• TCOF1 – this gene is found on chromosome 5 and codes for the treacle protein, which regulates ribosome synthesis and mitosis. Treacle also plays a part in DNA repair and protection from oxidative stress^5,8
  POLR1C and POLR1D – these genes are crucial in transcribing ribosomal RNAs and maintaining ribosome biogenesis, which is needed for cellular growth and proliferation⁶
• POLR1B is a gene that was the last discovered to have an association with TCS. It is also important in ribosomal RNA (rRNA) synthesis⁷ 

Inheritance patterns

TCS follows two specific inheritance patterns based on the gene involved:^3,4 

Autosomal dominant inheritance 

• Only a single copy of the mutated gene found on the non-sex chromosome, i.e. inherited from one parent, is sufficient for the child to have the condition
• Most commonly seen in TCOF1 and POLR1D mutations, but also linked to POLR1B 
• Each child of a parent with autosomal dominant TCS has a 50% chance of inheriting the condition

Autosomal recessive inheritance

• Both copies of the mutated gene found on the non-sex chromosomes, i.e. inherited from both parents, are needed for the child to have the condition
• observed in POLR1C mutations
• Each child of parents with autosomal recessive TCS (both carriers) has a 25% chance of having the condition

From the table below, it is evident that AD inheritance is mainly responsible for TCS, while AR inheritance accounts for the minority of TCS.³

Table 1. Subtypes and genes of Treacher Collins syndrome (TCS)

De novo mutations

Notably, the majority (60%) of TCS cases are caused by de novo mutations, which means they are not due to inheritance and instead occur spontaneously during foetal development.^1,3 The other 40% are linked to family history.³ 

Key craniofacial features and symptoms

The common, frequent and rare clinical features of TCS include:^1,3,4

• Hypoplasia or underdevelopment of the facial bones, especially the lower jaw (mandible) 
• Widely spaced, ill-positioned or less-than-normal teeth
• Zygomatic complex
• Displacement of the outer corner of the eye and downward-slanting eye openings (palpebral fissures)
• Coloboma of the lower eyelids with a lack of or sparse eyelashes and tear duct defects
• Abnormalities of the external ears’ shape, size and position (microtia) and the middle ear, leading to malformation of the ossicles and conductive hearing loss
• Hypertrophy of the tongue 
• Cleft palate or high arched palate 
• Forward protruding nose and unilateral or bilateral choanal stenosis or atresia
• Hair displacement, where the hair growth extends in front of the ear to the cheekbones
• Delayed speech development 
• Cardiac malformation (rare)
• Spine malformation (rare)
• Kidney malformation (rare)
• Microcephaly (rare)
• Limb anomaly (rare)
• Impaired intelligence and cognitive function (rare)

The presentation can vary widely among individuals, where some may have mild facial asymmetry, while others experience extremely significant craniofacial differences.¹

Diagnosis and medical evaluation

Clinical examination

A physical examination will provide suggestive findings that can later be confirmed through other tests. TCS should be suspected in individuals displaying the typical craniofacial features and conductive hearing loss mentioned earlier, as well as radiographic features (hypoplasia or aplasia of the zygomatic arch and retrognathia).⁴

Genetic testing

Molecular genetic testing can confirm mutations in the TCOF1, POLR1C, POLR1D, or POLR1B genes through DNA sequencing.⁴

Prenatal and preimplantation genetic testing and diagnosis

Once a parent is confirmed to possess a TCS-related pathogenic variant, testing via chorionic villus sampling, amniocentesis or periumbilical blood sampling (PUBS), along with imaging, can determine if the foetus carries the mutation.⁴

Genetic counselling

This is critical for affected people and their families so that they can be educated on the necessary information related to genetic disorders, such as the modes of inheritance and implications. This allows them to make informed personal and medical decisions.⁴

Imaging 

Different imaging examinations like ultrasounds, X-rays, CT scans and 3D imaging can assess different kinds of abnormalities like microcephaly and polyhydramnios. Imaging also helps with differential diagnosis before birth.⁴

Treatment and management

Multidisciplinary care 

There is a need for a specialised, multidisciplinary team involving paediatricians, clinical geneticists, orthodontists, otolaryngologists, audiologists, psychologists and different types of surgeons to care for patients with TCS. Treatment can be linked to the age of the patient and follows these phases:^3,9

Treatment can be divided into three main phases, depending on the patient's age.

• Birth to age 2 years – facilitation of necessary living functions such as breathing via a tracheostomy, feeding and hearing, as well as visual and cardiac support if implicated
• Age 3 to 12 years – speech therapy, integration into society, bone reconstructions, visual and dental support
• Age 13 to 18 years – jaw (orthognathic) therapies, facial reconstruction, integration into society, multistage reconstructive face treatment (better to start at a younger age to get better results) 

Surgical interventions

Jaw reconstruction

An underdeveloped jaw can lead to nocturnal apnea, which can have detrimental effects like suffocation, so surgery at an early age is normal to protect the patient. The most effective type is a mandibular distraction.³

Ear reconstruction 

For patients with severe ear anomalies and conductive hearing loss, reconstruction is completed using autogenous cartilage.³ 

Cleft lip and palate repair

If a cleft lip or macrostomia is present, surgery to correct it would be performed during infancy or the first year of life. The palate is repaired between the ages of 1 and 2.³ 

Eye and coloboma surgery 

Whenever there is a coloboma of the eyelid, surgery is usually done in the first year of life to properly protect the eyeball and ensure corneal hydration. This and other eyelid defects are generally fixed by local eyelid plasty flaps. Surgery, like canthopexy, is done for misalignment of the eyelid crevices and downward-slanting eye openings.³ 

Other bone reconstruction 

Orbital wall cavity repair is typically done during eyelid reconstruction. Orbital floor malformations are fixed with allogeneic or individual orbital floor implants. Horizontal chin osteotomy and rhinoplasty may also be done if needed. Importantly, unless there are significant problems with corneal exposure, reconstruction of orbital bone and zygomatic defects should not be performed before the age of 5 years.³

Supportive therapies

Other support, such as speech therapy, feeding assistance, and psychosocial support, is necessary to improve functional outcomes and help patients cope and navigate life with their disorder.³ 

Summary

Treacher Collins syndrome (TCS) is a rare genetic disorder that affects craniofacial development. During fetal development, abnormalities lead to malformations in structures such as the ears, eyelids, cheekbones, and jaw. This congenital condition occurs in approximately 1 in 50,000 live births and is caused by mutations in the TCOF1, POLR1D, POLR1C, and POLR1B genes. The disorder follows either an autosomal dominant (AD) or autosomal recessive (AR) pattern of inheritance. However, about 60% of TCS cases arise from de novo mutations, which occur spontaneously rather than being inherited from parents.

TCS is characterised by a wide range of craniofacial anomalies, which can vary in severity. Common features include underdevelopment of facial bones, particularly the mandible, dental abnormalities, downward-slanting eyes, lower eyelid colobomas, microtia (abnormally shaped or missing external ears) and conductive hearing loss. Some individuals may also present with rare symptoms such as cardiac, renal, or limb anomalies, though intelligence and cognitive function are usually unaffected. 

Diagnosis is based on physical examination, imaging (such as X-rays or CT scans), and genetic testing, which can confirm mutations in the associated genes. Prenatal and preimplantation genetic testing can be conducted if a parent is known to carry a TCS-related mutation. Genetic counselling is essential for families to understand the inheritance risks and implications of the disorder.

The management of TCS requires a multidisciplinary approach, involving specialists such as paediatricians, geneticists, surgeons, audiologists, and speech therapists. Surgical interventions can include mandibular distraction to correct jaw underdevelopment, ear reconstruction for hearing improvement, cleft palate repair, and eyelid repair surgeries. Bone reconstruction procedures, such as orbital wall and zygomatic repairs, are typically postponed until after early childhood to optimise outcomes.

In addition to surgery, supportive therapies such as speech and psychosocial support play a crucial role in improving the quality of life for individuals with TCS. With early intervention and comprehensive care, many individuals with TCS can achieve functional improvements and lead fulfilling lives.