Clinical characteristics.

Treacher Collins syndrome (TCS) is characterized by bilateral and symmetric downslanting palpebral fissures, malar hypoplasia, micrognathia, and external ear abnormalities. Hypoplasia of the zygomatic bones and mandible can cause significant feeding and respiratory difficulties. 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. 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 about 97% of probands by detection of a heterozygous (autosomal dominant) pathogenic variant in TCOF1, POLR1D, or POLR1B or biallelic (autosomal recessive) pathogenic variants in POLR1C or POLR1D using molecular genetic testing and in about 3% of probands by clinical findings when molecular genetic testing has not been performed or does not identify pathogenic variants in one of the known genes.

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 special positioning or tracheostomy to facilitate ventilation. Hearing loss is treated with bone conduction amplification, speech therapy, and educational intervention. Craniofacial reconstruction is often necessary. Cleft palate repair (if needed) occurs at about age one year; zygomatic and orbital reconstruction at about age five to seven years; and bilateral microtia and/or narrow ear canal reconstruction after age six years. The age of maxillomandibular reconstruction varies by severity; orthognathic therapies are typically before age 16 years.

Genetic counseling.

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

• Autosomal dominant TCS. About 55%-61% of probands have the disorder as the result of a de novo TCOF1, POLR1D, or POLR1B pathogenic variant. Each child of an individual with TCS has a 50% chance of inheriting the pathogenic variant.
• Autosomal recessive TCS. The parents of a child with autosomal recessive TCS are obligate heterozygotes (i.e., carriers of one POLR1C or POLR1D pathogenic variant). At conception, each sib of an affected individual has 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.

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

Suggestive Findings

Treacher Collins syndrome (TCS) should be suspected in individuals with the following craniofacial features (see Teber et al [2004], Figure 2; Trainor et al [2009], Figure 2; Dauwerse et al [2011], Figure 1; and Vincent et al [2016], Figure 1), hearing loss, and radiographic findings.

Craniofacial features

• Midface hypoplasia with a bilaterally symmetric convex facial profile, prominent nose, and characteristic downward slant of the eyes secondary to hypoplasia of the zygomatic arch and lateral aspects of the orbits
• Micrognathia and retrognathia with variable effects on the temporomandibular joints and jaw muscles
• External ear abnormalities including absent, small, malformed, and/or rotated ears, and atresia or stenosis of the external auditory canals
• Lower eyelid abnormalities including the following:
  • Coloboma (notching)
  • Sparse, partially absent, or totally absent lashes and tear ducts

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) [Posnick & Ruiz 2000]
• Mandibular retrognathia, detected by orthopantogram [Posnick & Ruiz 2000]

Establishing the Diagnosis

The diagnosis of TCS is established in about 97% of probands by detection of a heterozygous (autosomal dominant) pathogenic (or likely pathogenic) variant in TCOF1, POLR1D, or POLR1B or biallelic (autosomal recessive) pathogenic (or likely pathogenic) variants in POLR1C or POLR1D using molecular genetic testing (Table 1) and in about 3% of probands by clinical findings when molecular genetic testing has not been performed or does not identify pathogenic variants in one of the known genes.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Clinical Description

Treacher Collins syndrome (TCS) is characterized by facial features of bilateral and symmetric downslanting palpebral fissures, malar hypoplasia, and micrognathia. The hypoplasia of the zygomatic bones and mandible can cause significant feeding and respiratory 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 in TCS [Posnick & Ruiz 2000, Teber et al 2004]. While some individuals may be so mildly affected as to go undiagnosed (Figure 1), others can have severe facial involvement and life-threatening airway compromise [Trainor & Andrews 2013].

Figure 1.

Intrafamilial variation in families with a confirmed TCOF1 pathogenic variant. a. The proband (arrow) has the characteristic facial phenotype with downward-slanting palpebral fissures, hypoplastic zygomatic complex, hypoplasia of mandible, slightly dysplastic (more...)

Classic features of TCS are bilaterally symmetric and evident at birth (Table 2). Table 3 presents a scoring system to rate the severity of clinical findings.

In newborns with TCS, airway management may be required to address narrowing of the airway or extreme shortening of the mandible with severe micrognathia. Choanal atresia or stenosis, or severe micrognathia with glossoptosis can also obstruct the airway in an infant. Neonatal death is usually associated with obstructive sleep apnea as a result of these malformations.

External ear anomalies including absent, small, or rotated ears are typical. Conductive hearing loss is usually attributed to middle ear anomalies including hypoplasia or absence of the ossicles or middle ear cavities.

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 [Posnick 1997]. The inner ear structures are typically normal.

Ophthalmologic defects, including coloboma of the lower eyelid, can result in corneal exposure. Other possible causes of vision impairment include refractive errors, anisometropia, and strabismus [Hertle et al 1993].

Dental anomalies, found in 60% of individuals with TCS reported, include tooth agenesis (33.3%), enamel opacities (20%), and ectopic eruption of the maxillary first molars (13.3%) [da Silva Dalben et al 2006]. One to eight anomalies per individual have been identified.

Although craniosynostosis is not a feature of TCS, the cranium may have an abnormal shape (brachycephaly with bitemporal narrowing) [Posnick 1997].

Cardiac malformations are reported in some individuals with typical TCS caused by pathogenic variants in either TCOF1 or POLR1D.

Altered function of the upper digestive tract has been reported [Giabicani et al 2017].

Although mild developmental delay has been reported [Teber et al 2004, Vincent et al 2014], intelligence is usually normal.

Fertility is normal.

Less frequently observed features in individuals with TCS:

• Nasal deformity
• High-arched palate
• Angle class II anterior open-bite malocclusion
• Macrostomia

Abnormalities occasionally observed in individuals with TCS:

• Coloboma of the upper lid [Marszałek et al 2002]
• Ocular hypertelorism [Marszałek et al 2002]

Genotype-Phenotype Correlations

In most cases, the phenotype cannot be predicted by the genotype [Splendore et al 2000, Teber et al 2004, Vincent et al 2016, Sanchez et al 2020].

Penetrance

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

Nomenclature

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

Prevalence

The prevalence of TCS is estimated at 1:50,000 [Fazen et al 1967, Trainor et al 2009].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an infant diagnosed with Treacher Collins syndrome, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• The airway for evidence of choanal atresia/stenosis and/or micrognathia and glossoptosis predisposing to obstruction of the oropharynx
• The palate for clefts
• Swallowing function
• Hearing through formal audiologic examination (see Hereditary Hearing Loss and Deafness Overview). If conductive hearing loss is documented during the first six months of life, a craniofacial CT scan (axial and coronal slices) can be performed to document the anatomy of the head and neck and the external auditory canal, middle ear, and inner ear.
• Ophthalmologic evaluation with attention to extraocular movement, corneal exposure, and visual acuity
• Assessment for dental anomalies when teeth have erupted
• Cardiology and echocardiogram evaluation for structural heart defects
• Consultation with a clinical geneticist and/or genetic counselor

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 pathologist, and psychologist.

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

Birth to age two years. Major management issues are airway and feeding difficulties.

• If a diagnosis of TCS is suspected prenatally, a detailed ("level II") fetal ultrasound examination and consultation(s) with a high-risk obstetrician and/or neonatologist should be considered. The delivering team should be aware of the potential for life-threatening neonatal airway compromise [Trainor & Andrews 2013]. Management of the airway in neonates typically includes special positioning of the infant called an EXIT (ex-utero intrapartum treatment), in which the neonate's head and neck are partially delivered by cesarean section in order to perform an oral intubation or tracheostomy during birth. With proper management, life expectancy approximates that of the general population.
• Procedures for surgical intervention for the airway, if needed, are standard, primarily for improving respiratory function or restoring patency of the nostrils and distraction of the mandible. Intubation techniques other than direct laryngoscopy may be required during surgeries [Hosking et al 2012].
• Repair of cleft palate (if present) at age one to two years is recommended [Kobus & Wojcicki 2006].
• Assess nutrition and feeding to determine if gastrostomy or tracheostomy is needed to assure adequate caloric intake while protecting the airway [Trainor & Andrews 2013].
• Bone conduction amplification, speech therapy, and educational intervention are indicated for treatment of hearing loss. The bone-anchored hearing aid (BAHA) is an alternative for individuals with ear anomalies [Trainor & Andrews 2013].
• Ophthalmologic evaluation is indicated to assess eye movement, vision, lower eyelid coloboma, and diminished tearing. When present, corneal exposure keratitis should be medically treated [Hertle et al 1993].
• Structural heart defects (e.g., patent ductus arteriosus, atrial septal defects, hypertrophic myopathy) are managed as per standard practice.

Age three to 12 years. Major management issues are speech therapy and integration into education system.

Craniofacial reconstruction is often necessary [Posnick 1997, Trainor & Andrews 2013]. Generally, bone reconstruction precedes soft tissue corrections. Reconstruction can prevent the progression of facial asymmetry:

• Zygomatic and orbital reconstruction can be undertaken once cranio-orbitozygomatic bony development is complete (age ~5-7 years).
• External ear reconstruction should be performed after age six years and should precede reconstruction of the external auditory canal or middle ear.
• External auditory canal and middle ear reconstruction should be performed for individuals with bilateral microtia and/or narrow ear canals.
• Coloboma of the lower eyelid can be treated with botulinum toxin and subsequent surgery [Warner et al 2008].
• Eyelid reconstruction to correct downward-slanting fissure can use redundant upper eyelid skin [Trainor & Andrews 2013].
• Misaligned teeth often require orthodonture.

Age 13 to 18 years. Major management issues:

• Orthognathic therapies are typically indicated before age 16 years.
• Nasal reconstruction, if needed, should follow orthognathic surgeries.
• Maxillomandibular reconstruction is recommended as follows:
  • Type I (mild) and type IIA (moderate) malformation at age 13 to 16 years
  • Type IIB (moderate to severe) malformation at skeletal maturity (~16 years)
  • Type III (severe) malformation at age six to ten years

Surveillance

The following are appropriate:

• Periodic assessment of growth and development (preferably by a pediatrician) with inquiry into symptoms of obstructive sleep apnea.
• Routine follow up by an audiologist, ophthalmologist, and dentist

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

Mode of inheritance of Treacher Collins syndrome (TCS) can be autosomal dominant or autosomal recessive (Table 1).

• 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 [Dauwerse et al 2011, Sanchez et al 2020].
• Autosomal recessive inheritance accounts for a minority of TSC – 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 TCOF1, POLR1B, or POLR1D 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.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant, or, if a pathogenic variant has not been identified in the proband, audiologic evaluation and radiographic examination by Waters' view of both parents may reveal mild zygomatic arch hypoplasia or even aplasia [Marres 2002].
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Maternal and paternal somatic and germline mosaicism have been reported [Shoo et al 2004, Vincent et al 2016, 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.
• Note: 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].

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 or their severity cannot be predicted in sibs who inherit a pathogenic variant because significant intrafamilial clinical variability and reduced penetrance have 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 TSC 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 or their severity cannot be predicted.

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 at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with autosomal recessive TCS are obligate heterozygotes (i.e., presumed to be carriers of one POLR1C or POLR1D pathogenic variant).
• If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a TCS-causing pathogenic variant and to allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• 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 affected individual 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.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive TCS are obligate heterozygotes (carriers) for a POLR1C or POLR1D pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a POLR1C or POLR1D pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the POLR1C or POLR1D pathogenic variants in the family.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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 [Rotten et al 2002, Konstantinidou et al 2013]. 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, 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; subunits C and D for RNA polymerase I and RNA polymerase III) colocalize to the nucleolus and are involved in ribogenesis. It is hypothesized that the variants in the three key proteins are disrupting 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].

Acknowledgments

We acknowledge Mac Hays for his background research.

Author History

Garry R Cutting, MD; Johns Hopkins University (2004-2011)
Sara Huston Katsanis, MS (2004-present)
Ethylin Wang Jabs, MD (2011-present)

Revision History

• 20 August 2020 (aa) Revision: added POLR1B and related citation (Sanchez et al [2020])
• 27 September 2018 (bp) Comprehensive update posted live
• 30 August 2012 (cd) Revision: TCOF1 and POLR1D deletions reported in individuals with Treacher Collins syndrome; deletion/duplication analysis available clinically for POLR1C and POLR1D
• 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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