Mandibulofacial Dysostosis (Treacher Collins Syndrome) Clinical Presentation

Diagnosis of mandibulofacial dysostosis (Treacher Collins syndrome) is easily determined when a full expressivity of the syndrome occurs. However, diagnostic problems may be encountered when only a minimal expression of facial features is present.

Dysmorphology and symptoms are as follows: ^[2]

• Facies

  • The face of an individual with Treacher Collins syndrome is characteristic. Abnormalities are usually present bilaterally and symmetrically.

  • The nose has a normal size; however, it appears large because of hypoplastic supraorbital rims and hypoplastic zygomas.

  • The palpebral fissures are downward sloping; the cheekbones are depressed; the pinnae are malformed, with widely varying severity; and the chin recedes with a large, downturned mouth.

• Skull

  • On radiographs, the malar bones, zygomatic process of frontal bone, lateral pterygoid plates, paranasal sinuses, and mandibular condyles are hypoplastic.

  • The mastoids are not pneumatized.

  • The lateral margins of the orbits may be defective, and the orbits are hyperteloric.

  • The cranial base is progressively kyphotic.

  • The calvaria are essentially normal.

• Eyes

  • The palpebral fissures are short and slope laterally downward.

  • In the outer third of the lower lid, a coloboma is present, and the cilia (ie, eyelashes) may be deficient medially from the lower lid, as is seen in the image below.

    Anteroposterior view of 2-month-old boy with Treacher Collins syndrome.

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• Ears

  • The pinnae are often malformed, crumpled forward, or misplaced toward the angle of the mandible, as is seen in the image below.

    Lateral view of 2-month-old boy with Treacher Collins syndrome.

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  • Frequently, meatal atresia, external auditory canal stenosis or atresia, hypoplasia or agenesis of the malleus and the incus, monopodal stapes, ankylosis of stapes in the oval window, and absence of the middle ear and tympanic spaces are present, resulting in a conductive hearing loss.

  • The inner ears are normal.

  • Extra ear tags and blind fistulas may develop anywhere between the tragus and the angle of the mouth.

• Nose: The nose appears large because of the lack of malar development and hypoplastic supraorbital ridges. A study by Ma et al found a 38.6% reduction in nasal airway volume in patients with Treacher Collins syndrome compared with controls. This reduction was reportedly associated with reduced maxillary projection and transverse maxillary deficiency. The study included 30 individuals with Treacher Collins syndrome and 35 controls. ^[11]

• Mouth and throat

  • A cleft palate is found in one third of patients with Treacher Collins syndrome, and congenital palatopharyngeal incompetence (foreshortened, immobile, or absent soft palate; submucous cleft palate) is found in an additional one third of patients. ^[7]

  • The parotid glands are missing or hypoplastic.

  • Pharyngeal hypoplasia is a constant finding.

  • Radiographically, the mandibular angle is more obtuse than normal and the ramus is deficient. The coronoid and condyloid processes are flat or aplastic.

• Mental status

  • Intelligence is usually normal.

  • Developmental delay may be secondary to undiagnosed hearing loss.

• Dysfunctional symptoms

  • Hypoplasia and a retropositioned tongue

  • Difficulties with swallowing and feeding (caused by musculoskeletal underdevelopment and a cleft palate)

  • Conductive hearing loss (caused by maldevelopment of the auditory canal and middle ear ossicles) ^[12]

  • Impaired vision (caused by underdeveloped lateral orbit and extraocular muscles)

With regard to eyesight, however, a retrospective study by Rooijers et al of patients with Treacher Collins syndrome reported that ocular anomalies in these individuals were not associated with visual impairment. The study included 194 patients, with 49.5% of them being examined by an ophthalmologist or optometrist. The first and last visual acuity measurements were made at the mean ages of 6.96 years and 11.55 years, respectively. While the rate of primary ocular anomalies was 98.5%, and of secondary anomalies, 34.5%, the visual impairment rate was 4.6%. The severity of the syndrome also appeared not to impact the occurrence of visual impairment. ^[13]

Embryology

Failure of neural crest cells to migrate into the first and second branchial arches leads to dysplasia, hypoplasia, or aplasia of the musculoskeletal derivatives of these arches. Therefore, the abnormalities are bilateral and symmetrical.

The critical period occurs approximately between the sixth and seventh week of embryonal development.

Genetic

Inheritance of Treacher Collins syndrome is autosomal dominant, with complete penetrance and variable expressivity. Nonpenetrance is rare. Approximately 60% of cases represent fresh mutations. Administration of a teratogenic dose of vitamin A or isotretinoin in mice, rats, and hamsters produced malformations of the craniofacial skeleton that resembled features of mandibulofacial dysostosis. ^{[14, 15, 16]}

Treacher Collins syndrome results from mutations in the TCOF1, POLR1C, or POLR1D gene. Each of these genes appears to be influential early in the development of the bones and other tissues of the face, although TCOF1 mutations are responsible for most cases of Treacher Collins syndrome (81-93%). ^{[17, 18]}

TCOF1 was mapped to chromosome bands 5q31.3-33.3. The TCOF1 gene codes for the treacle protein, which may be involved in nucleolar trafficking and is required for normal craniofacial development. Single mutations in the gene result in the premature termination of the protein product. ^{[19, 20]}

Dixon reviewed the clinical and molecular features of Treacher Collins syndrome. ^[21] A total of 20 mutations in the TCOF1 gene had been identified, of which 2 were nonsense mutations, 5 were insertions, 11 were deletions, and 2 were splicing mutations. All of the mutations observed resulted in introduction of premature termination codons into the reading frame, suggesting haploinsufficiency as the molecular mechanism underlying the disorder. ^[22]

Edwards et al reported 25 previously undescribed mutations throughout the TCOF1 gene in patients with Treacher Collins syndrome. ^[23] This brought the total reported mutations to 35, which represented a detection rate of 60%. All but one of the mutations resulted in the introduction of a premature termination codon into the predicted protein. The mutational spectrum supported the hypothesis that Treacher Collins syndrome results from haploinsufficiency.

Horiuchi et al identified a de novo truncating mutation in exon 17 of the TCOF1 gene in a 5-year-old girl with classic findings of Treacher Collins syndrome and craniosynostosis, choanal atresia, and esophageal regurgitation. ^[24]

Lowry et al described a form of mandibulofacial dysostosis that resembles features of Treacher Collins syndrome but displays an autosomal recessive inheritance. ^[25] This condition is considered a Treacher Collins–type autosomal recessive mandibulofacial dysostosis (OMIM 248390). In addition, Richieri-Costa et al and Splendore et al reported siblings with similar Treacher Collins syndrome born to parents without the condition. ^{[26, 27]} Similarly, as in any genetic condition that shows autosomal dominant inheritance in the vast majority of cases, an autosomal recessive–like pattern could represent, in fact, a gonadal mosaicism in some cases.