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Treacher Collins Syndrome

Synonyms: Mandibulofacial Dysostosis, Treacher Collins-Franceschetti Syndrome

, MS and , MD.

Author Information

Initial Posting: ; Last Update: September 27, 2018.

Summary

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 96% of probands by detection of a heterozygous (autosomal dominant) pathogenic variant in TCOF1 or POLR1D or biallelic (autosomal recessive) pathogenic variants in POLR1C or POLR1D using molecular genetic testing and in about 4% 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 54%-60% of probands have the disorder as the result of a de novo TCOF1 or POLR1D 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 testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Diagnosis

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 96% of probands by detection of a heterozygous (autosomal dominant) pathogenic variant in TCOF1 or POLR1D or biallelic (autosomal recessive) pathogenic variants in POLR1C or POLR1D using molecular genetic testing (Table 1) and in about 4% 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.

Molecular Diagnosis of TCS

Molecular genetic testing approaches can include a combination of gene-targeted testing (concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing).

  • Serial single-gene testing. Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, whole-exon or whole-gene deletions/duplications are not detected. Perform sequence analysis of TCOF1 first, since the majority of individuals with TCS will have a pathogenic variant in this gene (Table 1). If no pathogenic variant is found in TCOF1, perform sequence analysis of POLR1C and POLR1D, and gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications for TCOF1 and POLR1D.
  • Chromosomal microarray analysis (CMA), which uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including TCOF1 as well as surrounding genes) that cannot be detected by sequence analysis, could be considered when an individual with clinical features of TCS also has intellectual disability.
  • A multigene panel that includes TCOF1, POLR1C, and POLR1D, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis or deletion/duplication analysis. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is an option when TCOF1 sequence analysis does not reveal a pathogenic variant. Exome sequencing could be considered to assess variants in POLR1C, POLR1D, and the rest of the genome. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Genome sequencing is also possible.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Treacher Collins Syndrome

Gene 1, 2Proportion of TCS Attributed to Pathogenic Variants in This GeneMOIProportion of Pathogenic Variants 3 Detectable by This Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5CMA 6
POLR1C1.2% 7AR (3/3) 73/3 7No multiexon or whole-gene deletions / duplications reportedNo whole-gene deletions / duplications reported
POLR1D6% 8AD (28/31) 928/31 9, 103/31 9
AR (3/31) 10
TCOF163%-93% 11
86% w/typical features 12
AD>97% 1114 deletions reported 132 large deletions 13
Unknown4% 8NA
1.

Genes are listed in alphabetic order.

2.
3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Vincent et al [2014]) may not be detected by these methods.

6.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including TCOF1 or POLR1D) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 5q32-q33.1 or 13q12.2 regions.

7.
8.

Individuals with typical clinical signs of TCS who do not have pathogenic variants in TCOF1, POLR1C, or POLR1D [Vincent et al 2016]

9.
10.

The same homozygous variant, c.163C>G (p.Leu55Val), was reported in three families [Schaefer et al 2014, Vincent et al 2016].

11.

The majority of individuals with TCS are heterozygous for a pathogenic variant in TCOF1. Differences in reported percentages could reflect variations in populations or clinical criteria for typical TCS. Splendore et al [2000] reported 93% sensitivity (26/28 individuals with clinical diagnosis of TCS); Teber et al [2004] reported 78% sensitivity (8/36 individuals who had unequivocal features of TCS had no pathogenic variant in TCOF1); Bowman et al [2012] identified a TCOF1 pathogenic variant in 70.6% (84/119) of unrelated individuals with a strong suspicion of TCS; Vincent et al [2016] reported 63% sensitivity among individuals (92/146) with typical and atypical clinical features of TCS.

12.

Vincent et al [2016] reported 86% (72/84) of those with typical TCS features had a TCOF1 variant.

13.

Reported deletions range from single exon to whole gene [Beygo et al 2012, Bowman et al 2012, Vincent et al 2014, Vincent et al 2016]. Although >97% of reported cases had a pathogenic variant detectable by sequencing, Bowman et al [2012] reported 5% of cases (5/92) with a large deletion; therefore, the rate of large deletions may be higher than current data suggest.

Clinical Diagnosis of TCS

TCS is generally characterized by bilaterally symmetric abnormalities of the facial and mandibular structures; downward-slanting palpebral fissures, and hypoplasia of the zygomatic complex and mandible are almost always evident (see Suggestive Findings and Clinical Description).

Clinical Characteristics

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].

Figure1. . Intrafamilial variation in families with a confirmed TCOF1 pathogenic variant.

Figure1.

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.

Table 2.

Classic Features of Treacher Collins Syndrome

Classic Feature% (n) of Affected Individuals with the Feature
Vincent et al [2016]Teber et al [2004]Splendore et al [2000]
Very
frequent
Downward-slanting palpebral fissures99% (76/77)100% (35/35)89%
Malar hypoplasia / hypoplasia of zygomatic complex97% (76/78)97% (34/35)81%
Conductive hearing loss92% (69/75)83% (25/30)
Mandibular hypoplasia / micrognathia88% (69/78)91% (32/35)78%
FrequentAtresia of external ear canal70% (46/65)68% (23/34)
Microtia70% (55/79)71% (25/35)77%
Coloboma (notching) of the lower lid63% (46/73)54% (19/35)69%
Delayed speech development57% (16/28)
Asymmetry52% (34/65)
Preauricular hair displacement49% (25/51)24% (8/33)
RareNasogastric tube or gastrostomy in neonates28% (17/60)
Cleft palate21% (15/70)33% (11/33)28%
Intubation or tracheostomy in neonates18% (12/65)12% (4/34)
Choanal stenosis/atresia13% (8/64)25% (8/32)
Cardiac malformation11% (7/65)
Very rareRachis malformation7% (3/42)
Renal malformation4% (2/50)
Microcephaly3% (2/66)
Intellectual disability / delayed motor development1.7% (1/58)10% (3/30)
Limb anomaly1.5% (1/67)

Table 3.

Scoring Systems to Rate Severity of Clinical Findings

FeaturePoints Assigned 1
Teber et al [2004]Vincent et al [2016]
Downward-slanting palpebral fissures21
Malar hypoplasia / hypoplasia of zygomatic complex21
Conductive hearing loss12
Mandibular hypoplasia / micrognathia21
Atresia of external ear canal11
Microtia21
Coloboma (notching) of the lower lid21
Delayed speech developmentNot assignedNot assigned
AsymmetryNot assigned1
Preauricular hair displacement11
Nasogastric tube or gastrostomy in neonatesNot assigned2
Cleft palate11
Intubation or tracheostomy in neonates12
Choanal stenosis/atresia12
Cardiac malformationNot assignedNot assigned
Rachis malformationNot assignedNot assigned
Renal malformationNot assignedAtypical
MicrocephalyNot assignedAtypical
Intellectual disability / delayed motor development1Atypical
Limb anomalyNot assignedAtypical
Total Points
1.

Maximum score is 17 for both systems. Scores ≤8 = mildly affected; scores ≥9 = severely affected.

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:

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].

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].

Differential Diagnosis

Table 4.

Disorders with Mandibulofacial Dysostosis to Consider in the Differential Diagnosis of Treacher Collins Syndrome

DisorderGeneMOIDistinguishing Clinical Features
Mandibulofacial dysostosis with microcephalyEFTUD2AD
  • Microcephaly
  • ID
  • Asymmetry of facial features
  • Esophageal atresia
  • Thumb abnormalities
Nager syndrome
(OMIM 154400)
SF3B4ADLimb deformities, preaxial abnormalities (e.g., small or absent thumbs, triphalangeal thumbs, radial hypoplasia or aplasia, radioulnar synostosis)
Miller syndrome
(OMIM 263750)
DHODHARLimb deformities, postaxial abnormalities (e.g., small or absent 5th digit incl 5th metacarpal, ulnar hypoplasia, absent 5th toe)
Toriello-Carey syndrome
(OMIM 217980)
AR
  • Failure to grow
  • Microcephaly
  • Agenesis of the corpus callosum
  • ID
  • Urogenital anomalies in affected males
  • Facial dysmorphisms (hypertelorism, flattened nasal bridge, anteverted nares)
  • Short neck
Branchial arch syndrome
(OMIM 301950)
XL
  • Microcephaly
  • ID
  • High-arched palate
  • Webbed neck
Bauru syndrome
(OMIM 604830)
AD
  • Upslanting palpebral fissures
  • Hypoplastic tragus & ear lobes
Hedera-Toriello-Petty syndrome
(OMIM 608257)
ADPtosis
Hemifacial macrosomia, Goldenhar syndrome, Oculoauriculovertebral spectrum
(OMIM 164210)
UnknownAD
  • Asymmetric
  • Preauricular tags & pits
  • Ocular epibulbar dermoid cyst
  • Cleft lip & palate
  • Vertebral anomalies, Kippel-Feil syndrome
Pierre Robin sequence
(OMIM 261800)
Cases of disruption of long-range cis-regulatory element → misregulation of SOX9ARMicrognathia, glossoptosis, & airway obstruction w/cleft palate deformity may self-correct w/growth & w/out intervention. 1
Nonsyndromic mandibular hypoplasia
  • Severe mandibular deficiencies (e.g., temporomandibular joint, ankylosis, aglossia/microglossia, rare craniofacial cleft)
  • Progressive micrognathia or retrognathia 1, 2

ID = intellectual disability

1.
2.

In one study, 52 of 266 individuals with congenital mandibular hypoplasia had TCS [Singh & Bartlett 2005]. Molecular diagnosis was not confirmed on these individuals.

Management

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 www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 POLR1D [Dauwerse et al 2011].
  • 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].

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a 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 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 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].
  • 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

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, his or her family members may at risk.

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

Sibs of a proband

  • 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.
  • 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 (Heterozygote) 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 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the TCS-related pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis 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, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Children's Craniofacial Association
    13140 Coit Road, Suite 517
    Dallas TX 75240
    Phone: 800-535-3643; 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • FACES: The National Craniofacial Association
    P.O. Box 11082
    Chattanooga TN 37401
    Phone: 800-332-2373 ; 423-266-1632
    Fax: 800-332-2373
    Email: faces@faces-cranio.org
  • Foundation for Faces of Children
    258 Harvard Street, #367
    Brookline MA 02446-2904
    Phone: 617-355-8299
    Email: info@facesofchildren.org
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • BabyHearing.org
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Treacher Collins Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Treacher Collins Syndrome (View All in OMIM)

154500TREACHER COLLINS SYNDROME 1; TCS1
248390TREACHER COLLINS SYNDROME 3; TCS3
606847TCOF1 GENE; TCOF1
610060POLYMERASE I, RNA, SUBUNIT C; POLR1C
613715POLYMERASE I, RNA, SUBUNIT D; POLR1D
613717TREACHER COLLINS SYNDROME 2; TCS2

Molecular Genetic 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, 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].

POLR1C

Gene structure. POLR1C comprises nine coding exons, with two isoforms. The longest transcript contains an open reading frame of 1,355 nucleotides with an 88-bp 5' UTR and a 226-bp 3' UTR. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. To date, six compound heterozygous POLR1C pathogenic variants have been identified in three affected individuals without a TCOF1 pathogenic variant [Dauwerse et al 2011]. These variants included three missense, one splice site, one nonsense, and one frameshift.

Normal gene product. POLR1C encodes the 16-kd (133-amino-acid) subunit that comprises both RNA polymerase I and RNA polymerase III complexes. RNA polymerase I and RNA polymerase III are involved in ribosomal RNA transcription [Dauwerse et al 2011].

Abnormal gene product. Compound heterozygous pathogenic variants in POLR1C lead to functional depletion of POLR1C at a critical time during embryogenesis [Dauwerse et al 2011, Noack Watt et al 2016].

POLR1D

Gene structure. POLR1D comprises three exons, with two isoforms. The longest transcript contains an open reading frame of 1,945 nucleotides with a 118-bp 5' UTR and a 1,458-bp 3' UTR. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 30 heterozygous POLR1D pathogenic variants have been identified in individuals with TCS without a TCOF1 pathogenic variant [Dauwerse et al 2011, Vincent et al 2016]. These include loss-of-function (e.g., nonsense) variants, splice site and missense variants, and small deletions and duplications. Whole-gene deletions have also been described [Dauwerse et al 2011, Vincent et al 2016].

Table 5.

POLR1D Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.163C>Gp.Leu55ValNM_015972​.3
NP_057056​.1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. POLR1D encodes the 39 kd (346 amino acids) subunit that comprises both RNA polymerase I and RNA polymerase III complexes. RNA polymerase I and RNA polymerase III are involved in ribosomal RNA transcription [Dauwerse et al 2011].

Abnormal gene product. Pathogenic variants in POLR1D lead to haploinsufficiency of POLR1D [Dauwerse et al 2011, Noack Watt et al 2016].

TCOF1

Gene structure. TCOF1 comprises 27 coding exons, three of which are alternatively spliced in-frame (6A, 16A, and 19) [Splendore et al 2005], and an additional exon containing the 3' UTR [So et al 2004]. The longest transcript (NM_001135243.1) contains an open reading frame of 4,467 nucleotides starting in the first exon. The open reading frame is preceded by a 93-bp 5' untranslated region (UTR) and followed by a 507-bp 3' UTR [Dixon et al 1997a]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Hundreds of pathogenic variants in TCOF1 have been reported in individuals with TCS, with novel variants being identified in a significant proportion of families [Gladwin et al 1996, Treacher Collins Syndrome Collaborative Group 1996, Edwards et al 1997, Wise et al 1997, Splendore et al 2000, Ellis et al 2002, Splendore et al 2002, Dixon et al 2004, Horiuchi et al 2005, Trainor et al 2009, Bowman et al 2012, Vincent et al 2016]. The majority of pathogenic variants found to date are frameshift variants leading to a premature termination of the transcript. Pathogenic variants have been found throughout the gene.

Of TCOF1 sequencing variants, 57%-60% are small deletions or insertions, 9%-16% are splice site variants, 19%-23% nonsense variants, and 3%-4% missense variants [Bowman et al 2012, Vincent et al 2016]. Large deletions of one or more exons have also been identified in up to 5% of individuals with TCS [Beygo et al 2012, Bowman et al 2012, Vincent et al 2016]. In one case, a synonymous pathogenic TCOF1 variant led to missplicing of a constitutive exon [Macaya et al 2009].

While several pathogenic variants have occurred more than once, only one variant in TCOF1, c.4369_4373delAAGAA, has been identified as commonly recurrent. This variant is present in 16% of individuals with an identifiable pathogenic variant.

Table 6.

TCOF1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Predicted Protein Change
(Alias 1)
Reference Sequences
c.1021_1022delAG
(790_791delAG)
p.Ser341GlnfsTer7
(Ser264GlnfsTer7)
NM_001135243​.1
NP_001128715​.1
c.2490delAp.Val831Ter
c.2853dupT
(2853_2854insT)
p.Ala952CysfsTer5
c.4369_4373delAAGAAp.Lys1457GlufsTer12

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. The 144-kd treacle protein comprises 1,488 amino acids. Treacle is a low-complexity, three-domain nucleolar protein having unique N and C termini that is structurally related to the nucleolar phosphoprotein Nopp140 [Isaac et al 2000]. A central ten-repeat motif contains protein kinase C and casein kinase 2 phosphorylation sites [Dixon et al 1997b, Winokur & Shiang 1998]. The protein has at least two functional nuclear localization signals and a nucleolar localization signal in the C terminus. Both Nopp140 and treacle contain LIS1 motifs, leading to speculation of involvement in microtubule dynamics [Emes & Ponting 2001].

Treacle interacts with the small nucleolar ribonucleoprotein hNop56p, suggesting that it is involved in ribosomal biogenesis [Hayano et al 2003]. Treacle is involved in rDNA transcription, nucleologenesis, or trafficking of proteins or ribosomal subunits between the nucleolus and cytoplasm [Winokur & Shiang 1998, Dauwerse et al 2011]; and perhaps neural crest cell migration [Sakai & Trainor 2009, Trainor & Andrews 2013, Calo et al 2018].

Abnormal gene product. Pathogenic variants in TCOF1 lead to haploinsufficiency of the treacle protein [Isaac et al 2000]. Missense variants that allow production of an abnormal protein can disrupt either the N- or C-terminus nuclear localization signals and affect the protein's ability to transport into the nucleus during first and second branchial arch development, causing cephalic neural crest cells to undergo apoptosis during embryogenesis [Dixon et al 2000, Isaac et al 2000, Trainor & Andrews 2013]. Downregulation of TCOF1 and POLR1D leads to relocalization of DDX21, a nucleolar protein involved in ribosome biogenesis [Calo et al 2018].

References

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Chapter Notes

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

  • 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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