DiagnosisClinical DiagnosisThe 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.FigureFigure 1. Individuals with TCS and a detected TCOF1 mutation
Reprinted by permission from Nature Publishing Group [Teber et al 2004] FigureFigure 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; 121X
c. Patient M20194; 209X
d. (more...)FigureFigure 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...)FigureFigure 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 orbitsMicrognathia and retrognathia (78%) with variable effects on the temporomandibular joints and jaw musclesExternal ear abnormalities (77%) including absent, small, and malformed ears (microtia) or rotated earsLower 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 defectsVision 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 cheekbonesAirway abnormalities including the following:Tracheostoma Uni- or bilateral choanal stenosis or atresiaDelayed motor or speech developmentFamily 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 TestingGenes. 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 SyndromeView in own windowGene SymbolProportion of TCS Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityTCOF171%-93% ^{1Sequence analysisSequence variants 2Clinical Deletion / duplication analysis 3Exonic, multiexonic, or whole-gene deletions 4 POLR1D8% of individuals with TCS without a detectable TCOF1 mutation 5Deletion / duplication analysis 3Exonic, multiexonic, or whole-gene deletions 5-Clinical Sequence analysisSequence variants 2POLR1CSequence analysisSequence variants 2Clinical Deletion / duplication analysis 3Exonic, multiexonic, or whole-gene deletions 6 1. 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.2. 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.3. 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.4. Beygo et al [2012], Bowman et al [2012]5. Dauwerse et al [2011]6. 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.) Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo 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: Sequence analysis and deletion/duplication analysis of TCOF1 is performed first for: Those with a family history of TCS consistent with autosomal dominant inheritance;
and Those who represent simplex cases (i.e., a single occurrence in a family). If a mutation or deletion in TCOF1 is not identified, POLR1D sequence analysis should be considered next.POLR1C sequence analysis should be considered:In families with multiple affected sibs and/or consanguinity;
or In those who represent simplex cases who do not have a TCOF1 or POLR1D mutation.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersMutations in TCOF1, POLR1D, or POLR1C have not been associated with any other phenotypes.}

Natural HistorySignificant 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 deformityHigh-arched palateAngle class II anterior open-bite malocclusionVision loss (37%)Abnormalities occasionally observed in individuals with TCS:Coloboma of the upper lid [Marszalek et al 2002]Ocular hypertelorism [Marszalek et al 2002] Choanal atresia Macrostomia 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 CorrelationsThe 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.Ser264Glnfs*7) indicate that variable expressivity in individuals with TCOF1 mutations is likely modified by a combination of genetic, environmental and stochastic factors [Schlump 2012].

Differential DiagnosisOther mandibulofacial dysostoses include Toriello syndrome (OMIM 301950), Bauru syndrome (OMIM 604830), Hedera-Toriello-Petty syndrome (OMIM 608257), and Guion-Almeida syndrome (OMIM 610536) [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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 cleftsSwallowing functionHearing through formal audiologic examination (see Deafness and Hereditary Hearing Loss Overview)Ophthalmologic evaluation with attention to extraocular movement, corneal exposure, and visual acuityIf 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 ManifestationsTreatment 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 system13 years to 18 years: orthognathic surgeryProcedures 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 yearsType IIB (moderate to severe malformation): at skeletal maturityType 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 InvestigationSurgical 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTCOF15q32Treacle proteinDeafness Gene Mutation Database
TCOF1 mutation database
TCOF1 homepage - Mendelian genesTCOF1POLR1C6p21​.1DNA-directed RNA polymerases I and III subunit RPAC1POLR1C @ LOVDPOLR1CPOLR1D13q12​.2DNA-directed RNA polymerases I and III subunit RPAC2POLR1D @ LOVDPOLR1DData 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) View in own window 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; TCS2TCOF1Normal allelic variants. 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]. 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]. Pathologic 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 mis-splicing 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 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide Change
(Alias ¹) Protein Amino Acid ChangeReference Sequencesc.790_791delAGp.Ser264Glnfs*7NM_001135243​.1
NP_001128715​.1c.2490delAp.Val831Xc.2853dupT
(2853_2854insT)p.Ala952Cysfs*5c.4369_4373delAAGAAp.Lys1457Glufs*12See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal 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]. POLR1CNormal allelic variants. 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. Pathologic 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].POLR1DNormal allelic variants. 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.Pathologic 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].