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Treacher Collins Syndrome

Synonyms: Mandibulofacial Dysostosis, Treacher Collins-Franceschetti Syndrome

, MS and , MD.

Author Information
, MS
Duke Institute for Genome Sciences & Policy
Durham, North Carolina
, MD
Department of Genetics and Genomic Sciences
Mount Sinai School of Medicine
New York, New York

Initial Posting: ; Last Revision: August 30, 2012.

Summary

Disease characteristics. Treacher Collins syndrome (TCS) is characterized by hypoplasia of the zygomatic bones and mandible, external ear abnormalities, coloboma (notching) of the lower eyelid, absence of the lower eyelashes, and preauricular hair displacement onto the cheeks. About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation (including ankylosis, hypoplasia, or absence) of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures tend to be normal. Other less common abnormalities include cleft palate with or without cleft lip and unilateral or bilateral choanal stenosis or atresia.

Diagnosis/testing. The diagnosis of TCS relies on clinical and radiographic findings. Mutation of one of three genes is known to be causative: TCOF1 (78%-93% of individuals with TCS) and POLR1C or POLR1D (8%).

Management. Treatment of manifestations: Treatment should be tailored to the specific needs of each individual, preferably by a multidisciplinary craniofacial management team. Neonates may require special positioning or tracheostomy to manage the airway. 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 age one to two years, zygomatic and orbital reconstruction at about age five to seven years, and external ear reconstruction after age six years. The age of maxillomandibular reconstruction varies by severity; orthognathic procedures are typically before age 16 years. Bilateral microtia and/or narrow ear canals require reconstruction.

Therapies under investigation: Surgical outcome may be improved with incorporation of stem cells in the treatment of craniofacial abnormalities; however, such surgery is experimental and controversial. Suppression of p53 during embryogenesis may prevent neurocristopathies.

Genetic counseling. Most TCS is inherited in an autosomal dominant manner; a small portion (~1%) is inherited in an autosomal recessive manner.

Autosomal dominant TCS: About 60% of individuals have the disorder as the result of a de novo mutation. Each child of an individual with TCS has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk for TCS is possible if the disease-causing mutation has been identified in the family.

Diagnosis

Clinical Diagnosis

The diagnosis of Treacher Collins syndrome (TCS) relies on clinical and radiographic findings.

Distinguishing clinical features [Hertle et al 1993, Posnick & Ruiz 2000, Marszalek et al 2002, Teber et al 2004, Trainor et al 2009]

  • Photographs of individuals with TCS who have an identified TCOF1 mutation; see Figure 1. For additional photos and further details on the individuals in Figure 1, see Figure 2.
  • Three of eight individuals with a clinically unequivocal diagnosis of TCS without a detected TCOF1 mutation; see Figure 3.
  • Intrafamilial variation of TCS features; see Figure 4.
Figure 1

Figure

Figure 1. Individuals with TCS and a detected TCOF1 mutation

Reprinted by permission from Nature Publishing Group [Teber et al 2004]

Figure 2

Figure

Figure 2. Individuals with TCS and a detected TCOF1 mutation (a-k). Photographs are arranged according to the location of the mutation in TCOF1.
a. Patient M17639 ; mutation Met1Ile
b. Patient M17807; 121Ter
c. Patient M20194; (more...)

Figure 3

Figure

Figure 3. Three of the eight individuals with a clinically unequivocal diagnosis of TCS without a detected TCOF1 mutation
a. Patient M17739
b. Patient M18662
c. Patient M17652

Reprinted by permission from Nature (more...)

Figure 4

Figure

Figure 4. Intrafamilial variation
a. Pedigree of family M17629. The proband shows the characteristic facial phenotype with downward slanting palpebral fissures, hypoplastic zygomatic complex, slightly dysplastic ears, conductive hearing loss, (more...)

Major clinical features

  • Hypoplasia of the zygomatic bones and mandible [Posnick 1997] resulting in the following:
    • Midface hypoplasia (89%) with a bilaterally symmetric convex facial profile, prominent nose, and characteristic downward slant of the eyes secondary to hypoplasia of the lateral aspects of the orbits
    • Micrognathia and retrognathia (78%) with variable effects on the temporomandibular joints and jaw muscles
  • External ear abnormalities (77%) including absent, small, and malformed ears (microtia) or rotated ears
  • Lower eyelid abnormalities including the following:
    • Coloboma (notching) (69%)
    • Sparse, partially absent, or totally absent lashes (53%)
  • Family history consistent with autosomal dominant inheritance (40%)

Minor clinical features

  • External ear abnormalities including atresia or stenosis of the external auditory canals (36%)
  • Conductive hearing loss (40%-50%) attributed most commonly to ankylosis, hypoplasia, or absence of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures tend to be normal.
  • Ophthalmologic defects
    • Vision loss (37%)
    • Amblyopia (33%)
    • Refractive errors (58%)
    • Anisometropia (17%)
    • Strabismus (37%)
  • Cleft palate with or without cleft lip (28%)
  • Preauricular hair displacement (26%), in which hair growth extends in front of the ear to the lateral cheekbones
  • Airway abnormalities including the following:
    • Tracheostoma
    • Uni- or bilateral choanal stenosis or atresia
  • Delayed motor or speech development
  • Family history consistent with autosomal recessive inheritance (1%)

Distinguishing radiographic features

  • Hypoplasia or aplasia (discontinuity) of the zygomatic arch detected by occipitomental radiographs. These radiographs include an occipitomental projection of the skull (Waters' view) and orthopantogram to identify mandibular hypoplasia or other abnormalities.
  • Malar hypoplasia confirmed by intraorbital measurements by CT that are at the mean, with zygomatic measurements less than normal [Posnick & Ruiz 2000]
  • Mandibular retrognathia caused by facial convexity, the extent of which is established by cephalometric radiographic measurements [Posnick & Ruiz 2000]

Molecular Genetic Testing

Genes. The three genes in which mutations are known to cause TCS are TCOF1, POLR1C, and POLR1D (see Table 1).

Evidence for further locus heterogeneity. Some individuals with typical clinical signs of TCS do not have mutations in TCOF1, POLR1C, or POLR1D.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Treacher Collins Syndrome

Gene 1Proportion of TCS Attributed to Mutations in This GeneTest MethodMutations Detected 2
TCOF171%-93% 3Sequence analysis 4Sequence variants
Deletion/duplication analysis 5(Multi)exonic or whole-gene deletions 6
POLR1D8% of individuals with TCS without a detectable TCOF1 mutation 7Deletion/duplication analysis 5(Multi)exonic or whole-gene deletions 7
Sequence analysis 4Sequence variants
POLR1CSequence analysis 4Sequence variants
Deletion/duplication analysis 5(Multi)exonic or whole-gene deletions 8

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The majority of individuals with TCS are heterozygous for a mutation in TCOF1 [Treacher Collins Syndrome Collaborative Group 1996]. Splendore et al [2000] reported a 93% sensitivity; Teber et al [2004] reported a 78% clinical sensitivity with 8/36 individuals who had unequivocal features of TCS and no mutation in TCOF1; Bowman et al [2012] identified a TCOF1 pathogenic mutation in 84/119 (70.6%) of unrelated individuals with a strong suspicion of TCS.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. Beygo et al [2012], Bowman et al [2012]

7. Dauwerse et al [2011]

8. No deletions or duplications of POLR1C have been reported to cause Treacher Collins syndrome. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Testing Strategy

To confirm/establish the diagnosis in a proband. For any individual with at least two major features or three minor features of TCS, molecular genetic testing should be considered:

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Significant inter- and intrafamilial clinical variability is common in Treacher Collins syndrome (TCS) [Posnick & Ruiz 2000, Teber et al 2004]. While some individuals may be so mildly affected as to go undiagnosed, others can have severe facial involvement and life-threatening airway compromise [Edwards et al 1996].

Classic features of TCS are bilaterally symmetric and evident at birth.

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, 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.

Conductive hearing loss in individuals with TCS is usually attributed to middle ear anomalies including hypoplasia or absence of the ossicles or middle ear cavities. The inner ear structures are typically normal. External ear anomalies including absent, small or rotated ears are typical of individuals with TCS, and some may also present with atresia or stenosis of the external auditory canals.

Ophthalmologic defects, including coloboma of the lower eyelid, are present in the majority of individuals with TCS and should be addressed to protect the cornea. Vision loss can occur and may be associated with refractive errors, anisometropia, and/or strabismus.

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

Da Silva Dalben et al [2006] found dental anomalies in 60% of individuals with TCS, with one to eight anomalies per individual. Anomalies identified included tooth agenesis (33.3%), enamel opacities (20%), and ectopic eruption of the maxillary first molars (13.3%).

Less frequently observed features in individuals with TCS:

  • Nasal deformity
  • High-arched palate
  • Angle class II anterior open-bite malocclusion
  • Vision loss (37%)

Abnormalities occasionally observed in individuals with TCS:

The presence and severity of external auditory canal defects correlates highly with the presence and severity of middle ear defects [Posnick 1997].

Although mild developmental delay has been reported, intelligence is usually normal.

Fertility is normal.

Genotype-Phenotype Correlations

The phenotype cannot be predicted by the genotype [Edwards et al 1997, Splendore et al 2000, Teber et al 2004, Schlump et al 2012].

Data presented by Teber et al [2004] suggest preliminary evidence that conductive hearing loss is significantly less common in individuals with mutations in the 3' ORF of TCOF1. Comparisons of phenotypic variation in four individuals with the same mutation (c.790_791delAG, p.Ser264GlnfsTer7) indicate that variable expressivity in individuals with TCOF1 mutations is likely modified by a combination of genetic, environmental and stochastic factors [Schlump 2012].

Penetrance

Penetrance of mutations associated with TCS is high, but cases of non-penetrance have been reported.

  • Reduced penetrance (i.e., absence of clinical or radiographic findings of TCS in individuals with a pathogenic TCOF1 mutation), suspected in mapping studies, was confirmed by Marres et al [1995], who detected on the basis of by clinical findings and linkage analysis the first convincing case of an individual who was determined to have the gene mutation but did not express the phenotype.
  • Katsanis et al [2003] identified the recurrent TCOF1 c.4369_4373delAAGAA mutation in an affected mother and son; prenatal testing confirmed the mutation in a subsequent pregnancy, which resulted in the birth of a child who at birth did not have the clinical features of TCS present in the mother or half-sibling, including downward-slanting eyes with lower-eyelid coloboma, mandibular hypoplasia, and microtia. It is now evident that, although incomplete penetrance is rare, both variable expressivity and reduced penetrance must be considered, particularly in the prenatal setting.
  • Incomplete penetrance in parents of an affected child has since been reported by Dixon et al [2004] for TCOF1 mutations c.2490delA (exon 15) and c.2853dupT (exon 16).
  • In four families with POLR1D mutations in the proband, the mutation was non-penetrant in another family member [Dauwerse et al 2011].

Anticipation

An apparent increased severity in successive generations is attributed to ascertainment bias: Splendore et al [2002] noted that probands were more likely to have ear malformations than their parents and concluded that ear abnormalities seemed to be an important factor in seeking medical evaluation.

Nomenclature

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

Prevalence

The prevalence of TCS is estimated at between 1:10,000 and 1:50,000 [Fazen et al 1967, Argenta & Iacobucci 1989, Gorlin et al 2001, Trainor et al 2009].

Differential Diagnosis

Other mandibulofacial dysostoses include Toriello syndrome (OMIM 301950), Bauru syndrome (OMIM 604830), Hedera-Toriello-Petty syndrome (OMIM 608257), and Guion-Almeida syndrome [Wieczorek et al 2009].

Features of Treacher Collins syndrome (TCS) are also associated with Nager syndrome (OMIM 154400), Miller syndrome (OMIM 263750), Goldenhar syndrome (OMIM 164210), Pierre Robin sequence (OMIM 261800), and nonsyndromic mandibular hypoplasia.

In Nager syndrome and Miller syndrome, individuals have limb deformities in addition to mandibular dysostosis.

In TCS, colobomas occur in the lower eyelid and are typically symmetric, while in Goldenhar syndrome colobomas are present in the upper eyelid and may be asymmetric.

Unlike the features of TCS, the features associated with Pierre Robin sequence (including micrognathia, glossoptosis, and airway obstruction with or without cleft palate deformity) tend to self-correct without intervention [Singh & Bartlett 2005].

Individuals with nonsyndromic mandibular hypoplasia have severe mandibular deficiencies (including TMJ ankylosis, aglossia/microglossia, and rare craniofacial cleft) and progressive micrognathia or retrognathia [Singh & Bartlett 2005]. In one study, 52 of 266 individuals with congenital mandibular hypoplasia had TCS [Singh & Bartlett 2005]. Molecular diagnosis was not confirmed on these individuals.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an infant diagnosed with Treacher Collins syndrome, the following assessments 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 Deafness and Hereditary Hearing Loss Overview)
  • Ophthalmologic evaluation with attention to extraocular movement, corneal exposure, and visual acuity

If 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.

Assessment for dental anomalies should be made when teeth have erupted.

Treatment of Manifestations

Treatment should be tailored to the specific needs of each individual and preferably done by a multidisciplinary craniofacial management team that typically comprises a medical 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 [Hayashi et al 2007, Thompson et al 2009]:

  • Birth to 2 years: airway and feeding difficulties
  • 3 years to 12 years: speech therapy and integration into education system
  • 13 years to 18 years: orthognathic surgery

Procedures for surgical intervention for the airway, if needed, are standard, primarily for improving the respiratory function or restoring patency of the nostrils and distraction of the mandible [Kobus & Wojcicki 2006, Jayasekera 2007]. If a diagnosis of TCS is suspected prenatally, airway management at birth should be considered [Morillas et al 2007]. Management of the airway in neonates typically includes special positioning of the infant or tracheostomy. With proper management, life expectancy approximates that of the general population.

Gastrostomy may be needed to assure adequate caloric intake while protecting the airway [Marszalek et al 2002].

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 [Marres 2002].

Craniofacial reconstruction is often necessary [Posnick 1997, Zhang et al 2009]. Generally, bone reconstruction precedes soft tissue corrections. Reconstruction can prevent the progression of facial asymmetry. Recommendations by Posnick [1997] for reconstruction include the following:

  • Repair of cleft palate, if present, at age one to two years [Kobus & Wojcicki 2006]
  • Zygomatic and orbital reconstruction when the cranio-orbitozygomatic bony development is complete (~age 5 to 7 years)
  • Maxillomandibular reconstruction
    • Type I (mild) and type IIA (moderate) malformation: age 13 to 16 years
    • Type IIB (moderate to severe malformation): at skeletal maturity
    • Type III (severe malformation): age six to ten years

Orthognathic procedures are typically indicated before age 16 years.

Misaligned teeth often require orthodonture.

Nasal reconstruction, if needed, should follow orthognathic surgeries.

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 affected individuals with bilateral microtia and/or narrow ear canals.

Coloboma of the lower eyelid may be treated with botulinum toxin and subsequent surgery, if necessary [Warner et al 2008].

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Surgical outcome may be improved with incorporation of stem cells in therapeutic treatment of craniofacial abnormalities, particularly in bone and cartilage; however, such surgery is experimental and controversial [Trainor et al 2009].

Suppression of p53 during embryogenesis, also controversial, may prevent neurocristopathies [Jones et al 2008, Trainor et al 2009]

Search ClinicalTrials.gov for access to 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

Treacher Collins syndrome (TCS) caused by heterozygous mutation in TCOF1 (or less commonly, POLR1D) is inherited in an autosomal dominant manner. AD inheritance accounts for most of TCS.

TCS caused by compound heterozygous mutations in POLR1C is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband –Autosomal Dominant Inheritance

Note: Although 40% of individuals diagnosed with autosomal dominant TCS have an affected parent, the family history may appear to be negative because of failure to recognize the mild expression of the disorder in family members or the rare occurrence of incomplete penetrance in a parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%. The specific malformations or their severity cannot be predicted.
  • When the parents are clinically unaffected, the risk to the sibs of a proband is usually low.
  • If a pathogenic mutation cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.
  • Suspected germline mosaicism of the TCOF1 mutation 1639_1640delAG was reported by Shoo et al [2004], whereby the mutation was detected in the peripheral blood but not in skin fibroblasts of an unaffected mother of a child diagnosed with TCS.
  • It is unknown if the previous reports of two affected individuals born of unaffected parents represent genetic heterogeneity, germline mosaicism, or an undetected alteration in TCOF1 [Splendore et al 2000].

Offspring of a proband

  • Each child of an individual with autosomal dominant TCS has a 50% chance of inheriting the mutation.
  • The specific malformations or their severity cannot be predicted.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected or has a TCS-causing mutation, his or her family members are at risk.

Parents of a proband –Autosomal Recessive Inheritance

Parents of a proband

  • The parents of a child with autosomal recessive TCS are obligate heterozygotes (i.e., carriers of one POLR1C mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive TCS are obligate heterozygotes (carriers) for a POLR1C disease-causing mutation.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the POLR1C disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or 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

Molecular genetic testing. If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: (1) The presence of a TCS-causing mutation detected by prenatal testing does not predict the specific malformation(s) or their severity. (2) The possibility of incomplete penetrance of the common TCOF1 4369_4373delAAGAA mutation must be considered in providing counseling and interpretation of prenatal diagnostic test results to parents.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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 (slanting forehead, microphthalmos, micrognathia), and abnormal fetal swallowing is possible [Rotten et al 2002, Tanaka et al 2002]. Diagnostic features in a mildly affected fetus are likely to be missed.

Requests for prenatal testing for conditions which (like TCS) do not affect intellect and have treatment available are not common. 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. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation(s) have been identified.

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.

  • National Library of Medicine Genetics Home Reference
  • Treacher Collins Foundation
    PO Box 683
    Norwich VT 05055-0683
  • 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
  • my baby's hearing
    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 symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) 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

TCOF1

Gene structure. TCOF1 comprises 27 coding exons, three of which are alternatively spliced in-frame (6A, 16A, and 19), 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 Symbol.

Benign allelic variants. A number of apparently non-pathogenic polymorphisms (≥18) and rare variants (≥17) have been identified [Splendore et al 2000, Ellis et al 2002, Splendore et al 2002, Dixon et al 2004, Su et al 2007]. See TCOF1 Mutation Database [Splendore et al 2005].

Pathogenic allelic variants. Hundreds of disease-causing mutations in TCOF1 have been documented in individuals with Treacher Collins syndrome (TCS) with novel mutations 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]. The majority of mutations found to date are frameshift mutations leading to a premature termination of the transcript caused by an insertion or deletion. Mutations span the entire gene.

Of TCOF1 sequencing variants, 57% are small deletions or insertions, 16% are splice site mutations, 23% nonsense mutations, and 4% missense mutations [Bowman et al 2012]. Large deletions of one or more exon have also been identified in up to 5% of TCS patients [Beygo et al 2012, Bowman et al 2012]. In one case, a synonymous mutation in TCOF1 led to missplicing of a constitutive exon [Macaya et al 2009]. However, the number of nucleotide substitutions may be underestimated as a result of the methodology of detecting the known mutations.

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

Table 2. TCOF1 Pathogenic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.790_791delAGp.Ser264GlnfsTer7NM_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 (www​.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 1488 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].

Abnormal gene product. Mutations in TCOF1 lead to haploinsufficiency of the treacle protein [Isaac et al 2000]. Because the majority of mutations lead to the introduction of a premature termination codon, it is likely that RNA transcripts from the abnormal gene are lost as a result of nonsense-mediated RNA degradation leading to loss of protein from the abnormal gene and haploinsufficiency in tissues of the affected individual. Missense mutations 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 [Marsh et al 1998, Jones et al 1999, Dixon et al 2000, Isaac et al 2000].

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 Symbol.

Pathogenic allelic variants. Six compound heterozygous POLR1C mutations were identified in three affected individuals without a TCOF1 mutation [Dauwerse et al 2011]. Mutations included nonsense, missense, and splice site mutations, duplications, insertions, and deletions [Dauwerse et al 2011].

Normal gene product. The RNA polymerase 1 polypeptides D and C are 16 kd (133 amino acids) and 39 kd (346 amino acids), respectively. These subunits are present in RNA polymerase I and RNA polymerase III, and both are involved in ribosomal RNA transcription [Dauwerse et al 2011].

Abnormal gene product. Compound heterozygous mutations in POLR1C lead to functional depletion of POLR1C [Dauwerse et al 2011].

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 Symbol.

Pathogenic allelic variants. In people without a TCOF1 mutation, 20 heterozygous POLR1D mutations have been identified [Dauwerse et al 2011]. Mutations found include nonsense, missense, and splice site mutations, duplications, insertions, and deletions [Dauwerse et al 2011].

Normal gene product. The RNA polymerase 1 polypeptides D and C are 16 kd (133 amino acids) and 39 kd (346 amino acids), respectively. These subunits are present in RNA polymerase I and RNA polymerase III, and both are involved in ribosomal RNA transcription [Dauwerse et al 2011].

Abnormal gene product. Mutations in POLR1D also lead to haploinsufficiency of RNA polymerase 1 polypeptide D [Dauwerse et al 2011].

References

Literature Cited

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Chapter Notes

Acknowledgments

We acknowledge Barbara Karczeski, MS, CGC of the DNA Diagnostic Laboratory at Johns Hopkins University for her guidance on clinical testing strategies.

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

  • 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 to live Web site
  • 20 July 2004 (me) Review posted to live Web site
  • 1 March 2004 (shk,gc) Original submission
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