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.

Suggestive Findings

TCS should be suspected in probands with the following craniofacial features, conductive hearing loss, and radiographic features.

Craniofacial features

• Lower eyelid abnormalities including coloboma (notching) of the lower eyelid and sparse, partially absent, or totally absent eyelashes and tear ducts
• Malar hypoplasia due to hypoplasia of the zygomatic arch and lateral aspects of the orbits resulting in downward-slanted palpebral fissures, a bilaterally symmetric convex facial profile, and prominent nose
• Mandibular hypoplasia with micro- or retrognathia
• External ear abnormalities including absent, small, malformed, and/or posteriorly rotated ears and atresia or stenosis of the external auditory canals
• Preauricular hair displacement, in which hair growth extends in front of the ear to the lateral cheekbones

Conductive hearing loss is attributed most commonly to ankylosis, hypoplasia, or absence of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures are typically normal.

Radiographic features

• Hypoplasia or aplasia (discontinuity) of the zygomatic arch, detected by occipitomental radiographs (Waters view) [Marszałek-Kruk et al 2021]
• Mandibular retrognathia, detected by orthopantomogram [Marszałek-Kruk et al 2021]

Establishing the Diagnosis

Clinical Description

Treacher Collins syndrome (TCS) is characterized by bilateral and symmetric downslanted palpebral fissures, malar hypoplasia, and micro- or retrognathia. Hypoplasia of the zygomatic bones, maxilla, and mandible can cause significant respiratory and feeding difficulties. Ear abnormalities are associated with conductive hearing loss. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia.

Significant inter- and intrafamilial clinical variability is common. While some individuals may be so mildly affected as to go undiagnosed, others can have severe facial involvement and life-threatening airway compromise [Trainor & Andrews 2013]. To date, more than 5,000 individuals have been identified with a pathogenic variant in one of the genes listed in Table 1. The following description of the phenotypic features associated with this condition is based on these reports.

Ophthalmologic defects. The prevalence of ocular and adnexal anomalies was evaluated in 194 individuals with TCS [Rooijers et al 2022]. Primary ocular anomalies were described in almost all individuals, mostly consisting of downslanted palpebral fissures (93.8%), colobomata of the lower eyelids (69.6%), and (partial) absence of lower lid eyelashes (42.8%). The most prevalent secondary ocular anomalies were epiphora (24.2%) and exposure keratopathy (14.4%). Strabismus was reported in 27.3% and refractive errors in 49.5% [Rooijers et al 2022].

Ear anomalies and hearing. External ear anomalies including absent, small, malformed, and/or posteriorly rotated ears are typical. In those with atresia or stenosis of the external auditory canals, the presence and severity of external auditory canal defects correlate highly with the presence and severity of middle ear defects [Marszałek-Kruk et al 2021]. The inner ear structures are typically normal. Conductive hearing loss is usually attributed to middle ear anomalies including hypoplasia or absence of the ossicles or middle ear cavities.

Airway/respiratory issues. Choanal atresia/stenosis or severe micrognathia with glossoptosis can obstruct the airway in an infant from the time of delivery [Trainor & Andrews 2013]. Prenatal ultrasound can identify a fetus at risk of severe airway obstruction at birth by assessment for micrognathia and abnormal fetal swallowing [Wang et al 2023]. Neonatal death in infants with TCS is usually associated with obstructive sleep apnea as a result of airway malformations. Management of the airway in a severely affected neonate with TCS typically includes special positioning of the infant to facilitate ex utero intrapartum treatment (EXIT) in order to perform oral intubation or tracheostomy during birth; Appropriate airway management can result in life expectancy that approximates that of the general population.

Feeding. Micrognathia and retrognathia can have variable effects on the temporomandibular joints and jaw muscles and can lead to cleft palate (typically U-shaped in the context of Pierre Robin sequence). These findings contribute to feeding issues including problems with chewing and swallowing.

Dental anomalies, reported in 60% of individuals with TCS, include tooth agenesis (33.3%), enamel opacities (20%), and ectopic eruption of the maxillary first molars (13.3%) [da Silva Dalben et al 2006]. Angle class II anterior open-bite malocclusion has been reported.

Additional craniofacial features. Preauricular hair displacement, in which hair growth extends in front of the ear to the lateral cheekbones, is common. Although craniosynostosis is not a feature of TCS, the cranium may have an abnormal shape (brachycephaly with bitemporal narrowing) [Marszałek-Kruk et al 2021]. Less frequently observed craniofacial features in individuals with TCS include hypertelorism, nasal deformity, high-arched palate, and macrostomia [Marszałek-Kruk et al 2021].

Cardiac manifestations are reported in some individuals with TCOF1- or POLR1D-related TCS. Congenital heart anomalies described to date include atrial septal defect, ventricular septal defect, patent ductus arteriosus, and patent foramen ovale; hypertrophic cardiomyopathy has also been rarely reported [Vincent et al 2016, Beaumont et al 2021].

Gastrointestinal manifestations. Altered function of the upper digestive tract including pyloric stenosis and esophageal atresia have also been reported [Beaumont et al 2021]. Abnormality of the lower digestive tract can include chronic intestinal pseudo-obstruction with abnormal innervation (enlarged ganglionic myenteric plexus has been histologically confirmed on a surgical rectal biopsy) [Giabicani et al 2017].

Musculoskeletal manifestations. Spine anomalies are observed in ~10% of individuals. Scoliosis is the most common; spina bifida occulta has also been reported. Other musculoskeletal manifestations include pectus excavatum or carinatum and pes planus [Beaumont et al 2021]. Congenital limb anomalies are rare but have been reported, including toe syndactyly, absent or hypoplastic thumbs, and carpal bone fusion [Beaumont et al 2021].

Renal malformations are rare but have been described, including congenital bilateral hydronephrosis and duplicated collecting system. One individual had a non-functioning left kidney [Beaumont et al 2021].

Development. Although intellectual disability and delayed motor development have been reported [Vincent et al 2014, Marszałek-Kruk et al 2021], intelligence is usually normal.

Phenotype Correlations by Gene

Individuals with TCOF1-related TCS may have more severe clinical features than individuals with POLR1B-, POLR1C-, and POLR1D-related TCS [Ulhaq et al 2023], although data is limited. Atresia of the external ear canal, downslanted palpebral fissures, and lower lid coloboma are more common in individuals with TCOF1-related TCS [Ulhaq et al 2023].

Genotype-Phenotype Correlations

TCOF1

• Individuals with TCOF1 duplications tend to have a milder presentation than individuals with other TCOF1 pathogenic variants [Ulhaq et al 2023].
• The most common 5-bp deletion in exon 24 (c.4369_4373delAAGAA) has been reported to have a higher severity than other exon 24 pathogenic variants [Teber et al 2004, Ulhaq et al 2023].
• Individuals with pathogenic variants in exon 15 have a significantly lower frequency of microtia, conductive deafness, and atresia of the external ear canal [Ulhaq et al 2023].

Penetrance

While the penetrance of pathogenic variants associated with TCS is high, reduced penetrance in TCOF1 [Dixon et al 2004, Vincent et al 2016] and POLR1D [Dauwerse et al 2011, Vincent et al 2016] has also been reported.

Nomenclature

Autosomal dominant TCS has variably been termed Fransceschetti-Zwahlen-Klein syndrome and zygoauromandibular dysplasia.

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], Treacher Collins syndrome is included in the craniofacial dysostoses group and referred to by the following gene-specific designations:

• POLR1B-related mandibulofacial dysostosis (Treacher-Collins, Franceschetti-Klein)
• POLR1C-related mandibulofacial dysostosis (Treacher-Collins, Franceschetti-Klein)
• POLR1D-related mandibulofacial dysostosis (Treacher-Collins, Franceschetti-Klein)
• TCOF1-related mandibulofacial dysostosis (Treacher-Collins, Franceschetti-Klein)

Prevalence

The prevalence of TCS is estimated at 1:80,000 [Reid & Carroll 2021].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TCS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment should be tailored to the specific needs of each individual, preferably by a multidisciplinary craniofacial management team that typically comprises a clinical geneticist, plastic surgeon, head and neck surgeon, otolaryngologist, oral surgeon, orthodontist, audiologist, speech-language pathologist, and psychologist.

Major management issues can be stratified by three age groups and graded for severity [Thompson et al 2009, Trainor & Andrews 2013].

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Treacher Collins syndrome (TCS) can be inherited in an autosomal dominant or autosomal recessive manner.

• Autosomal dominant inheritance accounts for most of TCS, most commonly caused by heterozygous pathogenic variants in TCOF1 and less commonly by heterozygous pathogenic variants in POLR1B or POLR1D [Dauwerse et al 2011, Sanchez et al 2020].
• Autosomal recessive inheritance accounts for a minority of TCS, caused by biallelic pathogenic variants in POLR1C [Dauwerse et al 2011] and biallelic pathogenic variants in POLR1D [Schaefer et al 2014].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• About 55%-61% of probands with autosomal dominant TCS have the disorder as the result of a de novo pathogenic variant [Trainor et al 2009, Vincent et al 2016, Sanchez et al 2020].
• About 40% of individuals diagnosed with autosomal dominant TCS have an affected parent.
• If the proband appears to be the only affected family member (i.e., a simplex case), recommended evaluations for both parents of a proband include:
  • Molecular genetic testing if a molecular diagnosis has been established in the proband;
  • If a molecular diagnosis has not been established in the proband, audiologic evaluation and occipitomental radiographic examination (Waters view). Radiographic examination may reveal mild zygomatic arch hypoplasia or even aplasia [Marres 2002].
• If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Maternal and paternal somatic and germline mosaicism have been reported [Shoo et al 2004, Vincent et al 2016, Sanchez et al 2020]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be unaffected or mildly/minimally affected [Shoo et al 2004, Sanchez et al 2020].
• The family history of some individuals diagnosed with TCS may appear to be negative because of failure to recognize the mild expression of the disorder in family members or the rare occurrence of reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and molecular genetic testing if a molecular diagnosis has been established in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. The specific malformations and their severity cannot be predicted in sibs who inherit a pathogenic variant because significant intrafamilial clinical variability is common in autosomal dominant forms of TCS [Posnick & Ruiz 2000, Teber et al 2004]. Reduced penetrance has also been reported.
• If the proband has a known TCOF1, POLR1B, or POLR1D pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Shoo et al 2004, Vincent et al 2016, Sanchez et al 2020].
• If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for TCS because of the possibility of reduced penetrance in a parent or parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant TCS has a 50% chance of inheriting the pathogenic variant; the specific malformations and their severity cannot be predicted in offspring who inherit a TCS-related pathogenic variant.

Other family members. The risk to other family members depends on the clinical/genetic status of the proband's parents: if a parent is affected or has a TCS-related pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with autosomal recessive TCS are presumed to be heterozygous for a POLR1C or POLR1D pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a TCS-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• 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.
• The specific malformations and their severity cannot be predicted in offspring who inherit biallelic TCS-related pathogenic variants.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive TCS are obligate heterozygotes (carriers) for a TCS-related pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an autosomal recessive TCS-related pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the autosomal recessive TCS-related pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

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

Note: (1) The presence of a TCS-causing pathogenic variant detected by prenatal testing does not predict the specific malformation(s) or their severity. (2) The possibility of reduced penetrance (particularly of the common TCOF1 c.4369_4373delAAGAA pathogenic variant) in the fetus needs to be considered (see Penetrance).

Ultrasound examination. In pregnancies known to be at risk for TCS, prenatal diagnosis using ultrasound examination to detect anomalies such as polyhydramnios, microcephaly, abnormal fetal facial features (micrognathia), and abnormal fetal swallowing is possible [Wang et al 2023]. Diagnostic features in a mildly affected fetus are likely to be missed. Three-dimensional imaging can assist with differential diagnosis prior to birth [Pereira et al 2013].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Cartilage and bone making up the craniofacial complex is primarily derived from neural crest cells [Trainor & Andrews 2013]. Thus, Treacher Collins syndrome (TCS) features can be explained by disturbances in neural crest cell development during embryogenesis. These disturbances can be attributed to pathogenic variants in the genetic pathway activating cell development.

TCOF1, POLR1B, POLR1C, and POLR1D are all expressed in neural crest cells, and their gene products (treacle protein; RNA polymerase I subunit 2; RNA polymerases I and III subunit AC1; protein POLR1D, isoform 2) colocalize to the nucleolus and are involved in ribogenesis. It is hypothesized that the variants in the three key proteins disrupt cell division by triggering p53-directed apoptosis of neuroepithelial cells [Gonzales et al 2005]. Variants affecting RNA polymerase I and/or III result in a deficiency of ribosomal RNA and/or transfer RNA [Dauwerse et al 2011], potentially leading to an insufficient number of mature ribosomes in the neuroepithelium and neural crest cells during embryogenesis [Dixon et al 2000, Dauwerse et al 2011].

Mechanism of disease causation. Loss of function

Gene-specific laboratory technical considerations. To date, only one POLR1D pathogenic variant, c.163C>G (p.Leu55Val), is associated with autosomal recessive inheritance and lack of clinical findings in heterozygous individuals [Schaefer et al 2014, Vincent et al 2016].

Acknowledgments

We acknowledge Mac Hays for his background research.

Author History

Mafalda Barbosa, MD, PhD, FACMG (2024-present)
Garry R Cutting, MD; Johns Hopkins University (2004-2011)
Sara Huston, MS (2004-present)
Ethylin Wang Jabs, MD (2011-present)

Revision History

• 20 June 2024 (sw) Comprehensive update posted live
• 27 September 2018 (bp) Comprehensive update posted live
• 27 October 2011 (me) Comprehensive update posted live
• 27 October 2006 (me) Comprehensive update posted live
• 20 July 2004 (me) Review posted live
• 1 March 2004 (shk,gc) Original submission

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