Treacher-Collins syndrome (ORPHA:861)
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.
Clinical description
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.
Etiology
The 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.
Diagnostic methods
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.
Prognosis
The prognosis for milder forms of the disease is favorable with adequate treatment.

                            Last update: 
                            December 2020


                            - Expert reviewer(s): 
                            Dr Corinne COLLET | ITHACA*


                                * European Reference Network