AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Background

Mandibulofacial dysostosis, also known as Treacher Collins syndrome (TCS; entry 154500 in the Online Mendelian Inheritance in Man [OMIM] classification system), is an inherited developmental disorder with a prevalence estimated to range between 1 in 40,000 to 1 in 70,000 of live births (Gorlin et al. 1990; Gorlin et al. 2001; Rovin, 1964; Mares et al. 1995; Posnick 1997). Growth of craniofacial structures derived from the first and second pharyngeal arch, groove, and pouch is diminished symmetrically and bilaterally. The condition is recognizable at birth and can also be diagnosed prenatally based on ultrasonography findings. Management of this condition is lengthy and requires a multidisciplinary approach focused on treatment of symptoms.

This syndrome was named after the eminent British ophthalmologist Edward Treacher Collins (1862-1932), who described the essential features of this syndrome in a paper in 1900. However, some features of this syndrome were probably first described by Thomson and Toynbee in 1846-1847 and later by Berry (1889), who is usually given credit for its discovery (Gorlin, 2001). On the European continent, a more common name for this condition is Franceschetti-Zwahlen-Klein syndrome, based on extensive studies of mandibulofacial dysostosis published by the Swiss ophthalmologist Franceschetti and the geneticist Klein (1949).

Frequency

United States

Prevalence of Treacher Collins syndrome is in the range 1 per 25,000 to 1 in 50,000 live births (Gorlin, 2001).

International

Prevalence of Treacher Collins syndrome is in the range 1 per 25,000 to 1 in 50,000 live births (Gorlin, 2001).

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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Physical

Diagnosis 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 (Gorlin, 2001):

• 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, down-turned mouth (see Images 1-4).
• 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 (see Image 1).
• Ears
• • The pinnae are often malformed, crumpled forward, or misplaced toward the angle of the mandible (see Image 2).
  • 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.
• 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.
  • 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)
  • Impaired vision (caused by underdeveloped lateral orbit and extraocular muscles)

Causes

• 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 (Poswillo, 1975; Sulik, 1987; Wiley, 1983).
  • Treacher Collins syndrome is caused by mutations in the TCOF1 gene. 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 (The Treacher Collins Syndrome Collaborative Group, 1996; Wise, 1997).

    Dixon (1996) reviewed the clinical and molecular features of Treacher Collins syndrome. 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. Edwards et al (1997) reported 25 previously undescribed mutations throughout the TCOF1 gene in patients with Treacher Collins syndrome. 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 (2004) 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.

  • Lowry et al (1985) described a form of mandibulofacial dysostosis that resembles features of Treacher Collins syndrome but displays an autosomal recessive inheritance. This condition is considered a Treacher Collins–type autosomal recessive mandibulofacial dysostosis (OMIM 248390). In addition, Richieri-Costa et al (1993) and Splendore et al (2000) reported siblings with similar Treacher Collins syndrome born to parents without the condition. 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.

DIFFERENTIALS

Section 4 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Consider the following 3 conditions in the differential diagnoses:

• Acrofacial dysostosis, type Nager (preaxial acrofacial dysostosis) is associated with facial features nearly identical to those of Treacher Collins Syndrome. The cleft palate is more frequent, and mandibular growth is usually more severely affected. Lower-lid colobomas are rare. The radial rays are affected, and patients may present with hypoplastic or absent thumbs, radioulnar synostosis, and/or radius and 1 or more metacarpal bones that are hypoplastic or absent. Preaxial acrofacial dysostosis, also known as Nager syndrome, is genetically heterogenous. Autosomal dominant and autosomal recessive patterns have been suggested. Gorlin (2001) pointed out that apparent recessive inheritance could represent a nonpenetrance or a gonadal mosaicism.
• Oculoauriculovertebral spectrum, including Goldenhar syndrome, should not create a diagnostic problem when the full spectrum is present. The phenotype consists of epibulbar dermoids of the eye, preauricular tags, vertebral defects, and facial underdevelopment (Cohen, 1989). Closely examine minimal expression and, if possible, also examine first-degree relatives.
• X-linked dominant maxillofacial dysostosis consists of bilateral hypoplasia of malar bones, downward-slanting palpebral fissures without colobomas, maxillary hypoplasia, open bite, and relative mandibular prognathism.

WORKUP

Section 5 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Lab Studies

• Midtrimester ultrasonography can detect facial dysmorphology and, because of its noninvasive quality, is preferred to fetoscopy (see Images 5-6), which greatly aided prenatal diagnoses in the 1980s (Nicolaides, 1984; Tolarova, 1981).
• 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 wk of fetal development) or via amniocentesis (performed at 16-17 wk of fetal development)
• 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

Imaging Studies

• 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

Section 6 of 10  

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• Differentials
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• Medication
• Miscellaneous
• Multimedia
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Medical Care

Treatment of this condition is lengthy and requires a multidisciplinary approach focused on treatment of symptoms. In newborns with mandibulofacial dysostosis, immediate attention to airway and swallowing inadequacies is critical.

• 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). 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.

Surgical Care

Operative repair of Treacher Collins syndrome is based upon the anatomic deformity and timing of correction is done according to 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.
• • A new management technique has been performed in selected cases. Distraction osteogenesis, an orthopedic method of lengthening bone, has been used to lengthen the neonatal mandible. 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. Tracheostomy is still the standard management for 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 (see Images 7-9). 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 down-turned 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. 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.

Consultations

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.

MEDICATION

Section 7 of 10  

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• Miscellaneous
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• References

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

MISCELLANEOUS

Section 8 of 10  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• A child affected with Treacher Collins syndrome needs multidisciplinary care starting from birth and throughout most of his or her life. As in any multidisciplinary treatment that involves many specialists, one center or team must coordinate a treatment plan. Therefore, each child should always be referred to a craniofacial center or a multidisciplinary craniofacial team as soon as possible. The team will develop and present a treatment plan for the child to the family. If a child is not referred to such a center or team, existing or potential problems may be overlooked.

  All craniofacial centers in the country are staffed with or have the ability to consult with a specialist for each discipline that is involved in the care for a child with Treacher Collins syndrome. A geneticist should be involved from the beginning, and a careful genetic examination should involve all first-degree relatives in order to specify a risk of recurrence. The team should also have a neonatologist, a pediatrician, a craniofacial or plastic surgeon, an otorhinolaryngologist, an ophthalmologist, a pediatric dentist and orthodontist, a speech pathologist, and a psychologist.

• A treatment plan should be presented to the family as early as possible and should include a timeline for each planned procedure, its benefits and risks, and its anticipated costs. Informed consent should be a part of every step of the treatment. If legal issues arise, a physician's defense must include detailed records of each discussion with the family, including all of the many potential risks and benefits.

MULTIMEDIA

Section 9 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Media file 1:  Anteroposterior view of 2-month-old boy with Treacher Collins syndrome.
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Media file 2:  Lateral view of 2-month-old boy with Treacher Collins syndrome.
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Media file 3:  Anteroposterior view of 2-year-old boy with Treacher Collins syndrome.
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Media file 4:  Lateral views of 2-year-old boy with Treacher Collins syndrome.
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Media file 5:  Anteroposterior view of 19-week-old fetus with Treacher Collins syndrome. Diagnosis was confirmed based on fetoscopy images (Tolarova, 1981).
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Media file 6:  Lateral view of 19-week-old fetus with Treacher Collins syndrome. Diagnosis was confirmed based on fetoscopy images (Tolarova, 1981).
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Media file 7:  Right-lateral cranial radiograph of an 18-month-old infant with Treacher Collins syndrome. Note the mandibular osteotomies and internal distraction hardware.
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Media file 8:  Left-lateral cranial radiograph showing mandibular osteotomy and distraction osteogeneses for micrognathia.
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Media file 9:  Lateral radiograph of same patient as in Pictures 7 and 8. Completion of distraction; note increased mandibular length.
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REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

• Berry GA. Note on a congenital defect (coloboma?) of the lower lid. R Lond Ophthalmol Hosp Rep. 1889;12:255-257.
• Cohen MM Jr, Rollnick BR, Kaye CI. Oculoauriculovertebral spectrum: an updated critique. Cleft Palate J. Oct 1989;26(4):276-86. [Medline].
• Collins ET. Cases of symmetrical congenital notches in the outer part of each lower lid and defective development of the malar bones. Trans Ophthal Soc UK. 1900;20:190-192.
• Dixon, M. J. Treacher Collins syndrome. Hum. Molec. Genet. 1996;1391-1396.
• Edwards, S. J, Gladwin, A. J, Dixon, M. J. The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon. Am. J. Hum. Genet. 1997.;60:515-524.
• Franceschetti A, Klein D. Mandibulo-facial dysostosis: New hereditary syndrome. Acta Ophthalmol (Kbh). 1949;27:143-224.
• Gorlin RJ, Cohen MM Jr, Hennekam RCM. Syndromes of the head and neck, 4th ed. Oxford University Press. 2001.
• Horiuchi, K, Ariga, T, Fujioka, H. Treacher Collins syndrome with craniosynostosis, choanal atresia, and esophageal regurgitation caused by a novel nonsense mutation in TCOF1. Am. J. Med. Genet. 2004;128A:173-175.
• Lowry RB, Morgan K, Holmes TM, et al. Mandibulofacial dysostosis in Hutterite sibs: a possible recessive trait. Am J Med Genet. Nov 1985;22(3):501-12. [Medline].
• Marres HA, Cremers CW, Dixon MJ, et al. The Treacher Collins syndrome. A clinical, radiological, and genetic linkage study on two pedigrees. Arch Otolaryngol Head Neck Surg. May 1995;121(5):509-14. [Medline].
• Marres HAM, Cremers CWRJ, Dixon MJ et al. The Treacher Collins syndrome: a clinical, radiological, and genetic linkage study on two pedigrees. Arch Otolaryngol Head Neck Surg. 1995;121:509-14.
• Moore MH, Guzman-Stein G, Proudman TW, et al. Mandibular lengthening by distraction for airway obstruction in Treacher-Collins syndrome. J Craniofac Surg. Feb 1994;5(1):22-5. [Medline].
• Nicolaides KH, Johansson D, Donnai D, Rodeck CH. Prenatal diagnosis of mandibulofacial dysostosis. Prenat Diagn. May-Jun 1984;4(3):201-5. [Medline].
• Posnick JC, Ruiz RL. Treacher Collins syndrome: current evaluation, treatment, and future directions. Cleft Palate Craniofac J. Sep 2000;37(5):434. [Medline]. [Full Text].
• Posnick JC. Treacher Collins syndrome: perspectives in evaluation and treatment. J Oral Maxilofac Surg. 1997;55:1120-33.
• Poswillo D. The pathogenesis of the Treacher Collins syndrome (mandibulofacial dysostosis). Br J Oral Surg. Jul 1975;13(1):1-26. [Medline].
• Richieri-Costa A, Bortolozo MA, Lauris JR, et al. Mandibulofacial dysostosis: report on two Brazilian families suggesting autosomal recessive inheritance. Am J Med Genet. Jul 1 1993;46(6):659-64. [Medline].
• Rovin S et al. Mandibulofacial dysostosis: A familial study of five generations. J Pediatrics. 1964;65:215-221.
• Splendore A, Silva EO, Alonso LG, et al. High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes. Hum Mutat. Oct 2000;16(4):315-22. [Medline].
• Sulik KK, Johnston MC, Smiley SJ, et al. Mandibulofacial dysostosis (Treacher Collins syndrome): a new proposal for its pathogenesis. Am J Med Genet. Jun 1987;27(2):359-72. [Medline].
• The Treacher Collins Syndrome Collaborative Group. Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. Nat Genet. Feb 1996;12(2):130-6. [Medline].
• Tolarova M, Zwinger A. The use of fetoscopy by inborn morphological anomalies. Acta Chir Plast. 1981;23(3):139-51. [Medline].
• Wiley MJ, Cauwenbergs P, Taylor IM. Effects of retinoic acid on the development of the facial skeleton in hamsters: early changes involving cranial neural crest cells. Acta Anat (Basel). 1983;116(2):180-92. [Medline].
• Williams JK, Maull D, Grayson BH, et al. Early decannulation with bilateral mandibular distraction for tracheostomy-dependent patients. Plast Reconstr Surg. Jan 1999;103(1):48-57; discussion 58-9. [Medline].
• Wise CA, Chiang LC, Paznekas WA, et al. TCOF1 gene encodes a putative nucleolar phosphoprotein that exhibits mutations in Treacher Collins Syndrome throughout its coding region. Proc Natl Acad Sci U S A. Apr 1 1997;94(7):3110-5. [Medline]. [Full Text].

Article Last Updated: Mar 12, 2007