Lecture 19 Part I: Treacher Collins

What is Treacher Collins Syndrome (TCS) and what are its alternative names?

• Craniofacial disorder caused by malformation of the 1st and 2nd pharyngeal arches.

• Also known as Franceschetti-Zwahlen-Klein syndrome or Mandibulofacial Dysostosis (MFD1).

• Named after Edward Treacher Collins (1900); dominant inheritance recognized by 1950-1960.

What is the incidence and epidemiology of TCS?

• Occurs in ~1/50,000 births; prevalence 0.2–1 per 10,000.

• No sex or ethnic predilection.

• ~60% of cases are de novo mutations.

What are the recurrence risks for TCS?

• 50% recurrence for autosomal dominant forms.

• 25% recurrence for autosomal recessive forms.

What are the key phenotypic features of TCS?

• Malar and mandibular hypoplasia; downward-slanting palpebral fissures.

• Coloboma; external ear anomalies; cleft palate.

• Conductive hearing loss; respiratory issues.

What are the newborn complications and adult outcomes in TCS?

• Newborns: airway obstruction (small jaw), feeding difficulties.

• Adults: normal intelligence, normal life expectancy.

• May require multiple reconstructive surgeries throughout life.

What is the developmental basis of TCS?

• Malformation of 1st and 2nd pharyngeal arches due to insufficient neural crest cells (NCCs).

• 1st arch → mandible, maxilla, malleus, incus.

• 2nd arch → stapes, parts of external ear.

What is the cellular/tissue basis of TCS?

• TCS is a neurocristopathy → caused by abnormalities in neural crest cells (NCCs) during embryonic development.

• NCCs are migratory, multipotent cells derived from the neuroepithelium that form the craniofacial skeleton.

• When NCCs are insufficient, pharyngeal arch-derived structures are stunted or absent.

What are the four genes involved in TCS and their inheritance patterns?

• TCOF1 (Type 1): autosomal dominant, majority of cases.

• POLR1D & POLR1C (Types 2 & 3): autosomal recessive.

• POLR1B (Type 4): haploinsufficient.

What is TCOF1, what does it encode, and what mutations cause TCS?

• Located on chromosome 5q32-33.1; encodes Treacle, a shuttling nucleolar phosphoprotein.

• Treacle interacts with Upstream Binding Factor (UBF) to initiate RNA Pol I transcription of rDNA → essential for ribosome biogenesis.

• Most mutations create a Premature Termination Codon (PTC): frameshift (63%), nonsense substitutions, and deletions.

What is the molecular mechanism and p53 pathway in TCS?

• TCOF1 mutations → reduced 47S pre-rRNA synthesis (specifically impaired A' site cleavage in 18S rRNA processing) → ribosome deficiency in NCC precursors.

• Ribosomal/nucleolar stress → MDM2 can no longer suppress p53 → p53 activates → Caspase-3 → apoptosis of NCCs.

• Normal state: Treacle supports rRNA transcription → MDM2 degrades p53 → normal cell proliferation → normal craniofacial features; TCS state: opposite cascade → craniofacial malformations.

How is TCS diagnosed?

• Primarily clinical: symmetrical underdevelopment of cheekbones and jaw.

• Prenatal: ultrasound and genetic testing.

• Key radiographic marker: absent or discontinuous zygomatic arch on Waters view X-ray.

How is TCS treated and what is the surgical timeline?

• No cure; multidisciplinary management (pediatrics, audiology, otolaryngology, plastic surgery).

• Ages 1–2: cleft palate repair; Ages 5–7: zygomatic/orbital reconstruction.

• Ages 6+: microtia/ear canal reconstruction; Before 16: orthognathic therapies.

• Hearing aids, speech therapy, and mental health support also used.

What environmental/external factors influence TCS severity?

• Maternal nutrition, oxidative stress, and hypoxia during pregnancy have been linked to TCS severity.

• Disease severity influenced by both primary mutation AND environmental factors.

• Earlier hypothesis (abnormal NCC migration, ECM problems) was insufficient alone.

What is morpholino knockdown and what did zebrafish results show for POLR1B?

• Morpholino: molecule that binds mRNA at start codon or splice sites, blocking translation into protein.

• Zebrafish with reduced POLR1B showed craniofacial defects from 20 hpf: underdeveloped skull/facial bones, small/malformed ears, small eyes.

• By 72 hours: smaller body, fluid around heart, abnormal pigment cells, underdeveloped pectoral fins; some died from cardiovascular defects.

What are future directions for TCS treatment?

• Mouse models show p53 inhibition during development can prevent TCS.

• Maternal antioxidant supplementation reduced NCC death and improved outcomes in mice.

• Goal: shift from supportive reconstructive surgery to molecular prevention.

Why is intelligence preserved in TCS despite severe facial features?

• TCS only affects craniofacial structures derived from NCCs → brain development is not disrupted.

• Severe facial disfigurement can mislead observers into assuming cognitive impairment, but intelligence and life expectancy are normal.

• Analogy: nucleolus is the ribosome "factory," Treacle is the supervisor → the shutdown only affects the craniofacial "branch," not the brain.