eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Mandibulofacial Dysostosis (Treacher Collins Syndrome)

Author: Marie M Tolarova, MD, PhD, DSc, Professor and Executive Director, UOP Craniofacial Team, Cleft Prevention Program, Department of Orthodontics, University of the Pacific School of Dentistry
Coauthor(s): Granger B Wong, MD, DMD, FACS, Assistant Professor of Surgery, Division of Plastic and Reconstructive Surgery, University of California Davis School of Medicine; Surendra Varma, MD, Vice-Chairman and Program Director, University Distinguished Professor, Department of Pediatrics, Texas Tech University School of Medicine
Contributor Information and Disclosures

Updated: Mar 12, 2007

Introduction

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

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.

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