Clinical characteristics: Treacher Collins syndrome (TCS) is characterized by lower eyelid abnormalities, malar hypoplasia, downslanted palpebral fissures, and micro- or retrognathia due to symmetric hypoplasia of the zygomatic bones, maxilla, and mandible. External ear anomalies include absent, small, malformed, and/or posteriorly rotated ears and atresia or stenosis of the external auditory canals. About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures tend to be normal. Significant respiratory and feeding difficulties can be present in infancy. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia. Typically, intellect is normal.

Diagnosis/testing: The diagnosis of TCS is established in a proband with characteristic clinical features and/or a heterozygous pathogenic variant in TCOF1, POLR1D, or POLR1B, biallelic pathogenic variants in POLR1C, or, rarely, biallelic pathogenic variants in POLR1D identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment should be tailored to the specific needs of each individual, preferably by a multidisciplinary craniofacial management team. Neonates with airway issues may require airway management at delivery, special positioning, or tracheostomy to facilitate ventilation. Tube feeding may be needed for adequate caloric intake. Cleft palate repair (if needed) occurs at about age one year. Hearing loss is treated with bone conduction amplification, speech therapy, and educational intervention. Management of ocular issues is per ophthalmologist. Standard management for cardiac, gastrointestinal, renal, and limb anomalies. Craniofacial reconstruction is often necessary: zygomatic and orbital reconstruction at about age five to seven years, and bilateral microtia and/or narrow ear canal reconstruction after age six years. Botulinum toxin and subsequent surgery for coloboma of the lower eyelid. Eyelid reconstruction as needed for downslanted palpebral fissures. Orthodonture for misaligned teeth. The age of maxillomandibular reconstruction varies by severity; orthognathic therapies are typically before age 16 years.

Surveillance: Annual ophthalmology and audiology evaluations; assess for manifestations of obstructive sleep apnea, growth, and caloric intake at each visit; dental exams every six months with orthodontia exams as needed; assess speech development and educational progress annually or as needed.

Genetic counseling: TCS can be inherited in an autosomal dominant or autosomal recessive manner. Autosomal dominant inheritance accounts for most of TCS, most commonly heterozygous pathogenic variants in TCOF1 and less commonly heterozygous pathogenic variants in POLR1B or POLR1D. Autosomal recessive inheritance (biallelic pathogenic variants in POLR1C or POLR1D) accounts for a minority of TCS. Significant intrafamilial clinical variability is common.

Autosomal dominant TCS: About 55%-61% of individuals with autosomal dominant TCS have the disorder as the result of a de novo pathogenic variant. Each child of an individual with autosomal dominant TCS has a 50% chance of inheriting the pathogenic variant.

Autosomal recessive TCS: The parents of a child with autosomal recessive TCS are presumed to be heterozygous for a POLR1C or POLR1D pathogenic variant. If both parents are known to be heterozygous for a TCS-causing pathogenic variant, each sib of an individual with autosomal recessive TCS has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives requires prior identification of the TCS-related pathogenic variants in the family.

Once the TCS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.