Mandibulofacial Dysostosis (Treacher Collins Syndrome)

Frequency

United States and international

Prevalence of Treacher Collins syndrome is in the range 1 per 25,000 to 1 in 50,000 live births.[2]

Race

Treacher Collins syndrome has no race predilection.

Sex

Males and females are equally affected.

Age

In the vast majority of cases, Treacher Collins syndrome is clearly diagnosed at birth. Because of typical facial dysmorphology in severe cases, it may also be diagnosed prenatally by ultrasonography. In mild cases, with minimal expression of facial features, the syndrome may be undiagnosed at birth.

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.

• 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.

  • 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.

See the list below:

• Midtrimester ultrasonography can detect facial dysmorphology and, because of its noninvasive quality, is preferred to fetoscopy, which greatly aided prenatal diagnoses in the 1980s.[8, 9] The images below are examples of fetal findings.

  Anteroposterior view of 19-week-old fetus with Treacher Collins syndrome. Diagnosis was confirmed based on fetoscopy images. Tolarova M, Zwinger A. The use of fetoscopy by inborn morphological anomalies. Acta Chir Plast. 1981;23(3):139-51.

  Lateral view of 19-week-old fetus with Treacher Collins syndrome. Diagnosis was confirmed based on fetoscopy images. Tolarova M, Zwinger A. The use of fetoscopy by inborn morphological anomalies. Acta Chir Plast. 1981;23(3):139-51.

• Mutations of the TCOF1 gene can be detected as single-nucleotide polymorphisms. Thus, prenatal diagnosis is possible but not yet clinically available. A prenatal diagnosis requires the following:

  • Blood samples from family members

  • Fetal cells obtained via chorionic villi sampling (performed at 10-11 weeks' gestation) or via amniocentesis (performed at 16-17 weeks' gestation)

• Assessment and monitoring of postnatal functions

  • Pulse oximeter monitoring of hemoglobin saturation with oxygen

  • Assessment of feeding efficiency

  • Audiologic testing

  • Neuroophthalmologic assessment

  • Full craniofacial CT scan (axial and coronal slices, from the top of the skull through the cervical spine)

  • Evaluation and genetic diagnosis by a medical geneticist

See the list below:

• The following imaging studies should be obtained to visualize craniofacial dysmorphology in detail and repeated, as needed, for surgical planning:

  • Anteroposterior and lateral cephalography

  • Full craniofacial CT scan (axial and coronal slices from the top of the skull through the cervical spine)

  • As follow-up, CT scans from orbits through mandible (usually enough for surgical planning)

  • Panoramic radiography

  • Brain MRI for inner auditory canal (IAC) study preferred (If MRI is not available, CT scan may be obtained for IAC.)

• If the clinical diagnosis of Treacher Collins syndrome is in doubt, radiological assessment can be useful. These tests are more helpful when mild expression is suspected upon clinical evaluation. The occipitomental projection of the skull (Waters view, anteroposterior with the canthomeatal line extended 45° with no inclination of the incident ray) can confirm zygomatic arch hypoplasia or aplasia. Orthopantomography should be used to demonstrate mandibular hypoplasia and changes in mandibular configuration. Temporomandibular joint abnormalities and asymmetry can be evaluated on these orthopantomograms. Roentgenography can also reveal any bony asymmetry in mild cases of Treacher Collins syndrome. If a patient needs any surgical correction or treatment, CT scan or MRI is mandatory.

Treatment of mandibulofacial dysostosis (Treacher Collins syndrome) is lengthy and requires a multidisciplinary approach focused on treatment of symptoms.[29] In newborns with mandibulofacial dysostosis, immediate attention to airway and swallowing inadequacies is critical.[30]

• In patients with severe manifestations in which airway inadequacy is the prominent feature after birth, a tracheostomy is performed (and may remain for several years, until the lower jaw has sufficiently grown or until alveolar distraction is performed to enable passage of air through the oral cavity).[10] Otherwise, special positioning of the infant may be sufficient.

• In patients with severe swallowing difficulty, introduce feeding by gavage or even through a gastrostomy tube, to ensure adequate caloric intake and hydration.

• Fit hearing aids shortly after birth if the patient has substantial conductive hearing loss. Hearing aids are important for the development of the infant's communication skills and for the normal bonding process within the family.

• Family-to-family support has proven to be of great psychological value.

Operative repair in Treacher Collins syndrome is based on the anatomic deformity, and the timing of corrections depends on physiologic need and development.

The most pressing issue at birth is airway and obstruction secondary to mandibular retrognathia. Occlusion of the oropharynx can occur in severe phenotypes, with collapse of the suprahyoid musculature and base of tongue. Emergent intubation with or without tracheostomy can be required.

Distraction osteogenesis, an orthopedic method of lengthening bone, has been used to lengthen the neonatal mandible. In this operation, the infant is intubated at birth, and, within a few days, a cut is made in both sides of the jaw and distraction hardware is placed. The jaw is stretched at 1-2 mm/d, and extubation is usually performed when 10 mm of lengthening is achieved. However, a study by Ali-Khan et al indicated that in patients with Treacher Collins syndrome who undergo bilateral mandibular distraction osteogenesis, airway function outcomes are poorer than in patients with Pierre Robin sequence who are treated with the procedure. Surgery in the study was deemed successful if imminent tracheostomy was prevented or the patient was successfully decannulated within 1 year subsequent to primary distraction. Such success was achieved in 21% of patients with Treacher Collins syndrome and 65% of patients with Pierre Robin sequence, with repeated distraction required in 46% and 7.7% of patients, respectively.[31]

Tracheostomy is still the standard approach to severe airway management, but alternatives may be applicable in certain cases.

For more minor obstructions that can be corrected with positioning, a tongue-lip adhesion is considered. Surgical adhesion is performed between the tongue, lip, and anterior mandible. This pulls the tongue forward, correcting the base of tongue obstruction, and pulls the tongue out of the nasopharynx in the presence of cleft palate. If tracheostomy has been performed for emergent airway concerns, mandibular distraction can be used in infancy to expedite decannulation, as demonstrated in the images below.

Right-lateral cranial radiograph of an 18-month-old infant with Treacher Collins syndrome. Note the mandibular osteotomies and internal distraction hardware.

Left-lateral cranial radiograph showing mandibular osteotomy and distraction osteogeneses for micrognathia.

Lateral radiograph of same patient as in Media files 7 and 8. Completion of distraction; note increased mandibular length.

As mentioned above, the tongue and suprahyoid musculature are advanced anteriorly with the lengthened mandible.

After the airway is controlled, soft tissue deficiencies are addressed, usually within the first year of life. Infant scars tend to be more minor and less noticeable, although this should not be confused with scarless fetal wound healing.

The lateral coloboma of the lower eyelid has traditionally been corrected with a skin-muscle flap from the upper lid or brow. This adds vertical height to the lateral lid, correcting the notch and downturned lateral palpebral fissure.

Macrostomia, if present, can be repaired at the same time with Z-plasty or straight-line skin repair; however, restoration of continuity in the oral musculature is important, as it restores the function of the oral sphincter and limits scar contracture.

Cleft palate, present in one third of cases, is repaired at approximately age 10-12 months but can be delayed if airway concerns exist. Extra time before cleft palate repair allows for some mandibular growth to occur prior to the surgical narrowing of the airway with repair of the palate.

Microtia is addressed at age 5-7 years, which is when the external ear is approximately 80-90% of adult size and rib cartilage is of sufficient volume to use as graft material. The ear is constructed in 3 stages; the first stage is the most involved. Autologous costochondral grafts are usually harvested from the fifth, sixth, and seventh rib. The cartilage is carved into a framework that simulates the helix and is then placed into a subcutaneous pocket at the absent ear site. This is allowed to heal; the remnant lobule is then rotated into anatomic position on the helix or created if it is not present. Finally, the framework is released from the side of the head; this step requires a skin graft.

Addressing the hard tissues is usually deferred until skeletal maturity. Osteotomies and bone grafts address the long midface, short mandible, and lateral facial clefts. The Le Fort osteotomy II is performed to derotate the middle face with the nasofrontal junction as the fulcrum. The maxilla and nasal bones are disjoined from the cranium to shorten the anterior midface while lengthening the posterior facial height. A compensatory mandibular osteotomy is performed to both vertically and horizontally lengthen the jaw and equilibrate the dental occlusion.[32] Bone grafts fill in the congenital defects at the lateral orbital rim, zygoma, and malar prominence. This stage of reconstruction is the most invasive and physically taxing on the patient. Additional procedures such as rhinoplasty and genioplasty (chin advancement) can be performed after the major osteotomies.

Mitsukawa et al a devised the following a three-stage surgical correction of hard and soft tissue deformities of the upper half of the face in patients with Treacher Collins syndrome[33] :

• Dermal fat from the lower eyelid is grafted to the malar subcutaneous area

• A graft is performed with a custom-made, synthetic zygomatic bone

• A Z-plasty flap is transposed from the upper eyelid to the lower one, and a Mitek anchor system is used for superior repositioning and fixation of the lateral canthal tendon

The study’s authors reported good results for four Treacher Collins syndrome patients with moderate to severe hypoplasia of the lower eyelids and zygomas.[33]

See the list below:

• Referral of the family of an infant diagnosed with Treacher Collins syndrome to a clinical geneticist or genetic counselor is important for informing the parents about the autosomal dominant inheritance of the disorder.

• Because more than half of cases represent new mutations, most families do not have a risk of recurrence in future pregnancies, although their affected child has a 50% chance of passing the trait to his or her own offspring.

Drug therapy is not currently a component of the standard of care for this syndrome. See Treatment.