Introduction

A broad range of congenital conditions that affect the structure and development of the head and face are all encompassed under the umbrella term of craniofacial anomalies. Treacher Collins Syndrome (TCS) is a well-characterised rare disorder within this. However, effective diagnosis of TCs is vital to ensure effective treatment and genetic counselling. In this article, we will explore the TCS, its genetic aetiology, and its distinguishing clinical features.

Treacher Collins Syndrome

Named after Edward Treacher Collins, TCS is a genetic disorder that primarily affects the development of the bones and tissues of the face. It is also known as mandibulofacial dysostosis. The syndrome affects the zygomatic complex, mandible, ears, and eyes, resulting in a facial appearance characterised by downward-slanting palpebral fissures, hypoplasia of the zygomatic arches and mandible, and external ear malformations that may lead to conductive hearing loss.¹

Genetic causes of TCS

TCS is genetically heterogeneous with an incidence of approximately 1 in 50,000 live births (1). TCOF1, POLR1C and POLR1D are implicated in the syndrome, with a majority of cases occurring due to variation in the TCOF1 gene on chromosome 5q32. TCOF1 encodes for a nucleolar phosphoprotein called treacle, which plays a crucial role in ribosomal RNA gene transcription and craniofacial development.² POLR1C and POLR1D encode subunits of RNA polymerase I and III. Mutations in these genes result in impaired ribosome biogenesis and neural crest cell survival, both essential for normal craniofacial morphogenesis.²

TCS can be inherited in either an autosomal dominant (TCOF1 and POLR1D) or autosomal recessive (POLR1C) manner. Approximately 60% of TCS cases arise from de novo mutations, meaning there is no previous family history.^1,2

Clinical features of TCS

There is high phenotypic variability of TCS even within individuals carrying the same genomic variant.^1,2 Key clinical features may include:

• Facial Bone Hypoplasia: Underdevelopment of the cheekbones and jaw leads to a sunken midface and a small, receding chin
• Downward-Slanting Eyes: The palpebral fissures slant downward and may be accompanied by colobomas (notches) of the lower eyelids
• Ear Anomalies: External ears are often small (microtia), malformed, or absent. Middle ear structures may also be affected, leading to conductive hearing loss
• Cleft Palate: Up to one-third of affected individuals may have a cleft palate
• Dental and Airway Issues: Malocclusion, abnormal tooth development, and sleep apnea due to airway obstruction are also common

While cognitive development is typical in most cases, speech and language delays may occur secondary to hearing loss.

Differential diagnosis for TCS

Several craniofacial syndromes share overlapping features with TCS, complicating the diagnostic process (Table 1). These can include Nager syndrome, Miller syndrome, Goldenhar syndrome, Pierre Robin sequence and CHARGE syndrome.

Nager Syndrome

Nager syndrome, or Nager acrofacial dysostosis, presents with craniofacial features similar to TCS, such as malar and mandibular hypoplasia and downward-slanting palpebral fissures. However, what sets it apart is the presence of preaxial limb anomalies, especially affecting the thumbs and forearms. These may include hypoplastic or absent thumbs, radial hypoplasia, and limited elbow extension. Mutations in the SF3B4 gene typically cause the condition and follow an autosomal dominant inheritance pattern.³

Miller Syndrome

Also known as postaxial acrofacial dysostosis, Miller syndrome includes facial anomalies similar to TCS, such as malar hypoplasia and cleft palate, but is differentiated by postaxial limb anomalies, particularly involving the ulnae and fifth digits. It is associated with mutations in the DHODH gene and is inherited in an autosomal recessive pattern.¹

Goldenhar Syndrome

Goldenhar syndrome, part of the oculo-auriculo-vertebral (OAV) spectrum, features facial asymmetry, epibulbar dermoids (benign growths on the eyes), vertebral anomalies, and preauricular skin tags or ear anomalies. Unlike TCS, Goldenhar often affects only one side of the face and may involve spinal and cardiac defects. The aetiology is multifactorial and often sporadic.²

Pierre Robin Sequence

Pierre Robin Sequence (PRS) is not a syndrome per se but a sequence of developmental anomalies that includes micrognathia, glossoptosis, and cleft palate.³ TCS can present these features, but PRS is more commonly associated with other syndromes like Stickler syndrome. PRS primarily causes breathing and feeding difficulties due to the retracted jaw and tongue position.

CHARGE Syndrome

CHARGE syndrome is a complex genetic condition characterised by Coloboma, Heart defects, Atresia choanae, Retardation of growth and development, Genital abnormalities, and Ear anomalies. While facial asymmetry and ear defects may resemble TCS, CHARGE has a broader systemic involvement and is caused by mutations in the CHD7 gene.²

Table 1: Differential diagnosis chart of cranofacial disorders

Diagnosis

A diagnosis of TCS is based on clinical features and confirmed through genetic testing. Diagnostic steps typically include:

• Clinical Examination: Assessment of craniofacial structure, ear anomalies, and airway function
• Imaging: CT or MRI scans can reveal underdeveloped facial bones and middle ear structures
• Audiology Testing: To evaluate hearing loss and plan appropriate interventions
• Genetic Testing: Whole-exome sequencing or targeted gene panels can confirm mutations in TCOF1, POLR1C, or POLR1D. Testing for other genes may be indicated if symptoms suggest a different syndrome
• Prenatal Diagnosis: Ultrasound may detect facial anomalies; if TCS is suspected, prenatal genetic testing via amniocentesis or chorionic villus sampling can confirm the diagnosis

Treatment and Management

Management of TCS is multidisciplinary and tailored to the severity of symptoms. The primary goals are to improve breathing, hearing, speech, feeding, and facial aesthetics.

Medical and Surgical Interventions

• Craniofacial Surgery: Procedures to correct mandibular hypoplasia, zygomatic reconstruction, and orbital rim advancement
• Ear Reconstruction: Performed typically around age 6–10 if microtia is present
• Cleft Palate Repair: Usually done in the first year of life to support feeding and speech development
• Tracheostomy or Mandibular Distraction Osteogenesis: For severe airway obstruction
• Hearing Aids or Cochlear Implants: To manage conductive hearing loss

Therapies and Support

• Speech and Language Therapy: To address articulation and communication delays
• Feeding Therapy: Especially for infants with cleft palate or mandibular hypoplasia
• Psychosocial Support: This includes addressing issues such as self-esteem, bullying, and emotional health for both the patient and family
• Educational Support: Early intervention programs can assist with learning and developmental milestones

Genetic counselling and family planning

Genetic counselling is essential for families affected by TCS. Counsellors can provide information on the risk of recurrence, especially in families where one parent is affected or carries a mutation. In de novo cases, the recurrence risk is low, but germline mosaicism must be considered. Options such as preimplantation genetic diagnosis (PGD) and prenatal testing may be discussed with families planning future pregnancies.

Living with TCS and related syndromes:

Though TCS presents significant challenges, individuals often lead fulfilling lives with proper medical care and support. Advances in reconstructive surgery, assistive hearing technologies, and inclusive education have improved the quality of life for those affected. Advocacy and support groups also play a crucial role in connecting families and raising awareness.

Conclusion

Treacher Collins Syndrome is a complex condition that demands a nuanced and multidisciplinary approach to diagnosis and management. Effective treatment planning and accurate genetic counselling are essential to distinguishing it from syndromes with similar craniofacial features, such as Nager, Miller, and Goldenhar syndromes. Individuals with TCS and related conditions can achieve positive long-term outcomes with early diagnosis, coordinated care, and ongoing support.