Treacher Collins syndrome (TCS)

Rare congenital disorder of craniofacial morphogenesis that arises as the result of mutations in the TCOF1 gene (encodes a nucleolar phosphoprotein, Treacle).

• Also known as mandibulofacial dysostosis and Franceschetti-Zwahlen-Klein syndrome
• Autosomal dominant inheritance with variable penetrance

History

TCS was first described in 1889 as a congenital neonatal deformity with the colobomata of the lower eyelids by George Andreas Berry. In 1900, an ophthalmologist named Edward Treacher Collins presented two patients with these ocular and periorbital sequelae at a meeting in London and subsequently published one of earliest case reports describing his findings. In the 1940s, Adolphe Franceschetti of Switzerland further characterized the disorder and published extensive reviews with his colleague David Klein. They further characterized the facial features and coined the description, mandibulofacial dysostosis. Today, there are several eponyms for this syndrome as it is known in the United States and United Kingdom as Treacher Collins syndrome, in Europe as Franceschetti-Klein syndrome, and otherwise as mandibulofacial dysostosis.

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Etiopathogenesis

TCOF1 mutations:

Neural crest cells are a migratory cell population derived from the neuroepithelium during early embryogenesis that ultimately give rise to the majority of the cartilage, bone, and connective tissue of the head and face. Thus, most craniofacial anomalies, such as those associated with TCS, are thought to arise due to defects in neural crest cell formation, proliferation, migration and/or differentiation. Interestingly, the Tcof1 gene is spatiotemporally expressed in the neuroepithelium and in the neural crest-derived facial mesenchyme during early mouse embryogenesis, implying it plays a role in the development of these tissues.

• Affects structures of the 1st and 2nd pharyngeal arches

• Spontaneous mutation (60% cases)
• Familial/hereditary (40% cases)

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Presentation

• Facial asymmetry
• Coloboma of lower eyelids
• External ear defects

Facial bone malformation:

• Mandibular hypoplasia (78% cases)
  • Mandibular micrognathia and a retro-positioned tongue obstructing the oropharyngeal and hypopharyngeal spaces
• Zygomatic complex hypoplasia (81% cases)
• Maxillary hypoplasia (constrict the nasal passages) → Choanal stenosis/atresia
• Bird-like appearance (prominent nose and midface with a retruded lower third of the face)
  • Due to shortened mandible + normal anterior maxillary height

Oral/dental abnormalities:

• Facial bone hypoplasia → Dental malocclusion, with anterior open bite
• Cleft palate (33% cases)
• Retropositioned tongue
• Steep occlusal plane

Ophthalmic abnormalities:

• Abnormal palpebral fissures:
  • Downward slanting (89% cases) with notching of the lower eyelids (69% cases)
• Coloboma of lower eyelid (paucity of lid lashes medial to the defect) (69% cases)

Auricular abnormalities:

• Bilateral microtia (85% cases): Malformed pinna, low set
• Conductive hearing loss

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Diagnosis

Genetic testing:

• Direct sequencing of the coding and flanking intronic regions of TCOF1 defects mutations (90-95% cases)

X-ray skull:

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Orthopantomograph (OPG):

3D CT analysis:

Differential diagnosis:

• Nager’s acrofacial dysostosis
• Miller acrofacial dysostosis
• Oculoauriculovertebral spectrum

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Management

The care of individuals affected by TCS requires a multidisciplinary approach and may involve intervention from a number of health-care professionals both pre-and post-operatively

Mandible:

Microretrognathic TCS mandible is a priority for surgical evaluation because it can be markedly hypoplastic and can lead to glossoptosis and upper airway obstruction.

Oral surgery/dentition:

Ear reconstruction:

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Summary