Treacher Collins Syndrome

Treacher Collins Syndrome

A rare genetic mandibulofacial dysostosis characterized by

• bilateral symmetrical oto-mandibular dysplasia including underdeveloped cheekbones (malar hypoplasia)
• a very small low jaw (micrognathia) and downward-slanting palpebral fissures
• coloboma of the lower eyelids
• microtia
• hearing loss and without abnormalities of the extremities
• Intelligence is normal.

Synonyms

• Franceschetti-Klein syndrome
• Mandibulofacial dysostosis without limb anomalies

Incidence

How common is Treacher Collins Syndrome?

1-9 / 100000

Inheritance

Autosomal dominant or Autosomal recessive 

Age of Onset

Neonatal

What are the symptoms of Treacher Collins Syndrome?

• Children present with characteristic facial dysmorphism with bilateral and symmetrical hypoplasia of the malar bones and infra-orbital rim (more than 80% of cases) and of the mandible (78% to 97%) (retrognathia), which results in dental malocclusion, often characterized by a limitation of mouth opening of varying severity.
• Predominant hypoplasia of soft tissues is observed in the malar bone, inferior orbital rim and cheek. Eye manifestations include downward-slanting palpebral fissures (89%-100%), lower eyelid colobomas between the external and middle thirds (54% to 69%), with absence of eyelashes on the outer third of the lower eyelid. Bilateral conductive hearing loss is frequent (83% to 96%).
• External ear abnormalities, such as microtia or anotia (77%) are often associated with atresia of the external auditory canals and anomalies of the middle ear ossicles (60%).
• Breathing and nutrition difficulties may arise during the early years because of the narrowness of the upper respiratory tract and limited mouth opening.
• Occasionally, there is high palate, cleft palate with or without cleft lip (21% to 33%) and unilateral or bilateral choanal stenosis or atresia (13%-25%).
• Less common manifestations include salivary gland abnormalities with subsequent dry mucosa, enchondromas and/or pretragal fistulas, spinal and cardiac anomalies. Intellect is typically normal, and disability or delayed motor development has been rarely reported.

Very Common Symptoms

• Abnormal facial shape
• Abnormality of bone mineral density
• Downslanted palpebral fissures
• Hypoplasia of the maxilla
• Hypoplasia of the zygomatic bone
• Malar flattening
• Micrognathia
• Midface retrusion
• Open bite
• Retrognathia
• Short face
• Skeletal dysplasia

Common Symptoms

• Abnormality of the dentition
• Abnormality of the middle ear
• Absent eyelashes
• Conductive hearing impairment
• Eyelid coloboma
• Frontal bossing
• Iris coloboma
• Low anterior hairline
• Microtia
• Narrow internal auditory canal 
• Reduced number of teeth
• Strabismus
• Visual impairment
• Wide nasal bridge

Occasional Symptoms

• Abnormality of cardiovascular system morphology
• Abnormality of dental enamel
• Abnormality of dental morphology 
• Abnormality of the adrenal glands
• Abnormality of the hair
• Abnormality of the vertebral column
• Blepharospasm
• Brachycephaly
• Branchial fistula
• Cataract
• Choanal atresia
• Cleft palate
• Cleft upper lip
• Cryptorchidism
• Dysphasia
• Encephalocele
• Facial cleft
• Failure to thrive
• Global developmental delay
• Glossoptosis
• High palate
• Hypertelorism
• Hypoplasia of penis
• Hypoplasia of the thymus 
• Microphthalmia
• Multiple enchondromatosis
• Narrow mouth
• Patent ductus arteriosus
• Preauricular skin tag
• Rectovaginal fistula
• Respiratory insufficiency
• Scrotal hypoplasia
• Thyroid hypoplasia
• Tracheoesophageal fistula
• Wide mouth

What causes this condition?

• Treacher Collins Syndrome is caused by mutations in the TCOF1 gene (5q32) encoding the nucleolar phosphoprotein, treacle, or in the POLR1C (6p21.1), POLR1D (13q12.2), POLR1B (2q14.1) genes coding for RNA polymerase I and III subunits.
• Of note, a similar phenotype of acrofacial dystosis has been associated with POLR1A.

How is this condition diagnosed?

• Diagnosis is based on clinical findings and complementary examinations. Molecular tests confirm the diagnosis.

Differential diagnosis

• Differential diagnoses include Nager syndrome (acrofacial dysostosis) distinguished by limb preaxial defects, Miller syndrome distinguished by limb postaxial defects, oculo-auriculo-vertebral spectrum in its bilateral and slightly asymmetrical form, and Burn-Mckeown syndrome.

Antenatal diagnosis

• Once a pathogenic variant is identified in a family, antenatal molecular diagnosis is possible by molecular analysis of chorionic villus samples (CVS) and amniotic fluid. Preimplantation testing is also possible. Antenatal ultrasound may show typical facial dysmorphism and bilateral ear abnormalities.

Genetic counseling

• Transmission is principally autosomal dominant with 90% penetrance and variable intra- and extra-familial expressivity.
• The mode of inheritance can be autosomal recessive in case of pathogenic variants in POLR1C and POLR1D genes.
• Genetic counseling is complicated by the variable expression of the disease and should be discussed with a multidisciplinary antenatal diagnosis team.

Management and treatment

• Management is multidisciplinary. In cases with postnatal respiratory distress, tracheostomy, non-invasive ventilation (NIV) or mandibular distraction should be discussed.
• Maxillofacial and plastic surgery can correct the soft tissue hypoplasia (facial recontouring with lipostructure), bone hypoplasia (surgical bone distraction, bone grafts), eyelid coloboma and cleft palate (surgical repair).
• The treatment of the limited opening of the mouth is very difficult. Specialist otorhinolaryngology surgery is required for the abnormalities of the middle ear (functional surgery) and the external ear (reconstruction of the auricles).
• Management of hearing impairment should be early (hearing aids and functional surgery) to aid normal development.

What is the Prognosis

• The prognosis for milder forms of the disease is favorable with adequate treatment.