Treacher Collins Syndrome

Mendelian MONDO:0002457 Pathograph 17 Show in embeddings browser Mandibulofacial dysostosis

Treacher Collins syndrome (TCS) is an autosomal dominant craniofacial disorder characterized by bilateral and symmetric hypoplasia of the zygomatic bones, maxilla, and mandible, resulting in malar flattening, micrognathia, downslanted palpebral fissures, lower eyelid colobomas, external ear anomalies, and conductive hearing loss. TCS is caused by mutations in genes involved in ribosome biogenesis (TCOF1, POLR1B, POLR1C, POLR1D), which lead to inadequate ribosome production in neural crest cells, triggering p53-dependent apoptosis during embryonic development. Incidence is approximately 1 in 50,000 live births. Intellect is typically normal.

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2
Inheritance
3
Pathophys.
12
Phenotypes
17
Pathograph
4
Genes
4
Medical Actions
4
Subtypes
1
References
1
Deep Research
👪

Inheritance

2
Autosomal dominant inheritance HP:0000006
Most TCS cases (~93%) follow autosomal dominant inheritance with variable expressivity. About 55-61% of autosomal dominant cases are de novo.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:20301704 SUPPORT Human Clinical
"Autosomal dominant inheritance accounts for most of TCS, most commonly heterozygous pathogenic variants in TCOF1 and less commonly heterozygous pathogenic variants in POLR1B or POLR1D."
GeneReviews confirms autosomal dominant inheritance as the predominant pattern for TCS.
PMID:20301704 SUPPORT Human Clinical
"About 55%-61% of individuals with autosomal dominant TCS have the disorder as the result of a de novo pathogenic variant."
High de novo rate explains sporadic cases.
Autosomal recessive inheritance HP:0000007
A minority of TCS cases are caused by biallelic pathogenic variants in POLR1C or POLR1D, following autosomal recessive inheritance.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"Autosomal recessive inheritance (biallelic pathogenic variants in POLR1C or POLR1D) accounts for a minority of TCS."
GeneReviews documents the autosomal recessive minority of TCS.
◆

Subtypes

4
Treacher Collins Syndrome 1 (TCOF1) MONDO:0007944
Most common subtype (>90% of cases), caused by heterozygous pathogenic variants in TCOF1 encoding Treacle, a nucleolar phosphoprotein essential for ribosomal DNA transcription.
Show evidence (1 reference)
PMID:34573374 SUPPORT Human Clinical
"TCS can be caused by pathogenic variants in the TCOF1, POLR1D, POLR1C and POLR1B genes. Genetically, the TCOF1 gene contains 27 exons which encodes the Treacle protein. In TCOF1, over 200 pathogenic variants have been identified"
Identifies TCOF1 as a causative gene for TCS with over 200 known pathogenic variants.
Treacher Collins Syndrome 2 (POLR1D, AD) MONDO:0013385
Caused by heterozygous pathogenic variants in POLR1D, encoding a subunit shared by RNA polymerases I and III.
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"heterozygous pathogenic variant in TCOF1, POLR1D, or POLR1B, biallelic pathogenic variants in POLR1C, or, rarely, biallelic pathogenic variants in POLR1D identified by molecular genetic testing."
GeneReviews lists POLR1D heterozygous variants as a diagnostic criterion for TCS.
Treacher Collins Syndrome 3 (POLR1C, AR) MONDO:0009558
Caused by biallelic pathogenic variants in POLR1C, encoding a subunit shared by RNA polymerases I and III. Autosomal recessive inheritance.
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"Autosomal recessive inheritance (biallelic pathogenic variants in POLR1C or POLR1D) accounts for a minority of TCS."
GeneReviews confirms biallelic POLR1C variants cause autosomal recessive TCS.
Treacher Collins Syndrome 4 (POLR1B) MONDO:0030067
Caused by heterozygous pathogenic variants in POLR1B, encoding the second largest subunit of RNA polymerase I.
Show evidence (1 reference)
PMID:34573374 SUPPORT Human Clinical
"Four subtypes of Treacher Collins syndrome exist. TCS can be caused by pathogenic variants in the TCOF1, POLR1D, POLR1C and POLR1B genes."
Identifies POLR1B as one of the four causative genes defining TCS subtypes.
⚙

Pathophysiology

3
Impaired Ribosome Biogenesis in Neural Crest Cells
Mutations in TCOF1/POLR1B/POLR1C/POLR1D impair ribosomal RNA transcription and ribosome biogenesis. Neural crest cells are uniquely sensitive to reduced ribosome output due to their high proliferative and migratory demands during embryonic craniofacial development.
neural crest cell CL:0000333
Ribosome biogenesis GO:0042254 ↓ DECREASED
pharyngeal arch UBERON:0002539
Downstream
p53-Dependent Neural Crest Cell Apoptosis Reduced ribosome biogenesis activates nucleolar stress, stabilizing p53 and triggering apoptosis in neural crest cells.
Show evidence (2 references)
PMID:24690222 SUPPORT Model Organism
"The association of the TCOF1 gene product, Treacle, and gene products of POLR1C and POLR1D with ribosome biosynthesis suggests that a loss of function mutation in these genes disrupts ribosome biosynthesis in constituent neural crest cells and neuroepithelium leading to apoptosis."
Establishes the mechanistic link between TCS gene mutations, impaired ribosome biogenesis, and neural crest cell apoptosis.
PMID:33804586 SUPPORT In Vitro
"One of the crucial proteins involved in most of the key nucleolar functions is treacle phosphoprotein encoded by the TCOF1 gene."
Identifies Treacle as a crucial nucleolar protein involved in key nucleolar functions including ribosome biogenesis.
p53-Dependent Neural Crest Cell Apoptosis
Nucleolar stress from impaired ribosome biogenesis stabilizes p53 in neural crest cells, triggering apoptosis during the critical window of craniofacial development. p53 heterozygosity is protective, confirming p53's central role in TCS pathogenesis.
neural crest cell CL:0000333
Apoptotic process GO:0006915 ↑ INCREASED
pharyngeal arch UBERON:0002539
Downstream
Craniofacial Skeletal Hypoplasia Depletion of cranial neural crest cells leads to deficient formation of first and second pharyngeal arch-derived craniofacial structures.
Show evidence (1 reference)
PMID:24690222 SUPPORT Model Organism
"P53 heterozygosity is protective against TCS, and that P53 and TCOF1 hemizygous embryos do not affect ribosomal function, implicates P53 or elements downstream of P53 as playing a role in TCS pathogenesis."
Mouse model data showing p53 heterozygosity rescues the TCS phenotype, confirming p53-dependent apoptosis as the key mechanism.
Craniofacial Skeletal Hypoplasia
Depletion of cranial neural crest cells results in bilateral symmetric hypoplasia of the zygomatic bones, maxilla, and mandible, as well as external and middle ear malformations and orbital abnormalities.
Neural crest cell migration GO:0001755 ↓ DECREASED
mandible UBERON:0001684 zygomatic bone UBERON:0001683
Downstream
Malar Flattening Zygomatic and midface hypoplasia produces malar flattening.
Micrognathia Mandibular hypoplasia produces micrognathia.
Downslanted Palpebral Fissures Orbital and periocular craniofacial maldevelopment produces downslanted palpebral fissures.
Lower Eyelid Coloboma Periocular craniofacial maldevelopment produces lower eyelid coloboma.
Microtia First and second pharyngeal arch maldevelopment produces external ear malformations including microtia.
Atresia of External Auditory Canal Ear canal maldevelopment produces atresia or stenosis of the external auditory canal.
Conductive Hearing Loss External and middle ear malformations impair sound conduction.
Cleft Palate Abnormal pharyngeal arch and palatal development can produce cleft palate.
Choanal Atresia Craniofacial maldevelopment can include choanal stenosis or atresia.
Upper Airway Obstruction Mandibular hypoplasia and glossoptosis narrow the upper airway.
Feeding Difficulties Mandibular hypoplasia and cleft palate can impair infant feeding.
Obstructive Sleep Apnea Mandibular hypoplasia and upper airway narrowing predispose to obstructive sleep apnea.
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"Treacher Collins syndrome (TCS) is characterized by lower eyelid abnormalities, malar hypoplasia, downslanted palpebral fissures, and micro- or retrognathia due to symmetric hypoplasia of the zygomatic bones, maxilla, and mandible."
GeneReviews describes the characteristic bilateral symmetric craniofacial skeletal hypoplasia.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Treacher Collins Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Digestive 1
Feeding Difficulties Feeding difficulties HP:0011968
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"Significant respiratory and feeding difficulties can be present in infancy."
GeneReviews identifies feeding difficulties as a significant neonatal concern.
Ear 2
Conductive Hearing Loss FREQUENT Conductive hearing impairment HP:0000405
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation of the ossicles and hypoplasia of the middle ear cavities."
GeneReviews specifies the frequency and mechanism of conductive hearing loss in TCS.
Atresia of External Auditory Canal Atresia of the external auditory canal HP:0000413
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"External ear anomalies include absent, small, malformed, and/or posteriorly rotated ears and atresia or stenosis of the external auditory canals."
Atresia of the external auditory canal is listed among ear anomalies.
Head and Neck 5
Malar Flattening Malar flattening HP:0000272
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"Treacher Collins syndrome (TCS) is characterized by lower eyelid abnormalities, malar hypoplasia, downslanted palpebral fissures, and micro- or retrognathia due to symmetric hypoplasia of the zygomatic bones, maxilla, and mandible."
Malar hypoplasia is listed as a defining feature of TCS.
Micrognathia Micrognathia HP:0000347
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"Treacher Collins syndrome (TCS) is characterized by lower eyelid abnormalities, malar hypoplasia, downslanted palpebral fissures, and micro- or retrognathia due to symmetric hypoplasia of the zygomatic bones, maxilla, and mandible."
Micro- or retrognathia is a core feature of TCS.
Downslanted Palpebral Fissures Downslanted palpebral fissures HP:0000494
Show evidence (1 reference)
PMID:34573374 SUPPORT Human Clinical
"Features of TCS include microtia with conductive hearing loss, slanting palpebral fissures with possibly coloboma of the lateral part of lower eyelids, midface hypoplasia, micrognathia as well as sporadically cleft palate and choanal atresia or stenosis."
Slanting palpebral fissures listed as a key TCS feature.
Cleft Palate Cleft palate HP:0000175
Show evidence (1 reference)
PMID:34573374 SUPPORT Human Clinical
"Features of TCS include microtia with conductive hearing loss, slanting palpebral fissures with possibly coloboma of the lateral part of lower eyelids, midface hypoplasia, micrognathia as well as sporadically cleft palate and choanal atresia or stenosis."
Cleft palate listed as a sporadic feature of TCS.
Choanal Atresia Choanal atresia HP:0000453
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia."
GeneReviews notes choanal atresia as a less common but recognized feature.
Nervous System 1
Obstructive Sleep Apnea Obstructive sleep apnea HP:0002870
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"assess for manifestations of obstructive sleep apnea, growth, and caloric intake at each visit"
GeneReviews surveillance recommendations include assessment for OSA at each visit.
Respiratory 1
Upper Airway Obstruction Upper airway obstruction HP:0002781
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"Neonates with airway issues may require airway management at delivery, special positioning, or tracheostomy to facilitate ventilation."
GeneReviews describes significant airway obstruction requiring intervention in some neonates.
Other 2
Microtia Microtia HP:0008551
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"External ear anomalies include absent, small, malformed, and/or posteriorly rotated ears and atresia or stenosis of the external auditory canals."
GeneReviews describes the range of external ear anomalies in TCS.
Lower Eyelid Coloboma Lower eyelid coloboma HP:0000652
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"Treacher Collins syndrome (TCS) is characterized by lower eyelid abnormalities, malar hypoplasia, downslanted palpebral fissures, and micro- or retrognathia"
Lower eyelid abnormalities are a defining clinical feature.
🧬

Genetic Associations

4
TCOF1
Gene: TCOF1 hgnc:11654 relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (2 references)
PMID:34573374 SUPPORT Human Clinical
"the TCOF1 gene contains 27 exons which encodes the Treacle protein. In TCOF1, over 200 pathogenic variants have been identified, of which most are deletions leading to a frame-shift, that result in the formation of a termination codon."
Details the molecular genetics of TCOF1 mutations in TCS.
PMID:33804586 SUPPORT In Vitro
"One of the crucial proteins involved in most of the key nucleolar functions is treacle phosphoprotein encoded by the TCOF1 gene."
Identifies Treacle as a key nucleolar protein central to ribosome biogenesis.
POLR1D
Gene: POLR1D hgnc:20422 relationship_type: CAUSATIVE
Autosomal dominant Autosomal recessive
Show evidence (1 reference)
PMID:34573374 SUPPORT Human Clinical
"TCS can be caused by pathogenic variants in the TCOF1, POLR1D, POLR1C and POLR1B genes."
Lists POLR1D as a causative gene for TCS.
POLR1C
Gene: POLR1C hgnc:20194 relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (1 reference)
PMID:34573374 SUPPORT Human Clinical
"TCS can be caused by pathogenic variants in the TCOF1, POLR1D, POLR1C and POLR1B genes."
Lists POLR1C as a causative gene for TCS.
POLR1B
Gene: POLR1B hgnc:20454 relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"a heterozygous pathogenic variant in TCOF1, POLR1D, or POLR1B, biallelic pathogenic variants in POLR1C"
GeneReviews lists POLR1B as a TCS-causing gene.
💊

Medical Actions

4
Craniofacial Reconstruction
Action: craniofacial surgical procedure Ontology label: surgical procedure MAXO:0000004
Zygomatic, orbital, and mandibular reconstruction surgery tailored to severity. Zygomatic/orbital reconstruction typically at age 5-7 years, ear reconstruction after age 6 years, orthognathic surgery before age 16.
Show evidence (2 references)
PMID:20301704 SUPPORT Human Clinical
"Craniofacial reconstruction is often necessary: zygomatic and orbital reconstruction at about age five to seven years, and bilateral microtia and/or narrow ear canal reconstruction after age six years."
GeneReviews describes the staged surgical reconstruction approach.
PMID:20301704 SUPPORT Human Clinical
"The age of maxillomandibular reconstruction varies by severity; orthognathic therapies are typically before age 16 years."
Orthognathic surgery timing specified by GeneReviews.
Speech Therapy
Action: speech therapy MAXO:0000930
Speech therapy as part of multimodal hearing-loss support for individuals with conductive hearing impairment.
Target Phenotypes: Conductive hearing impairment HP:0000405
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"Hearing loss is treated with bone conduction amplification, speech therapy, and educational intervention."
GeneReviews explicitly includes speech therapy within the multimodal approach to conductive hearing loss.
Airway Management
Action: airway management MAXO:0000500
Neonatal airway management including special positioning, nasopharyngeal airways, or tracheostomy for infants with significant upper airway obstruction.
Target Phenotypes: Upper airway obstruction HP:0002781
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"Neonates with airway issues may require airway management at delivery, special positioning, or tracheostomy to facilitate ventilation."
GeneReviews describes airway management strategies.
Genetic Counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling for TCS families addressing inheritance patterns, de novo rates, recurrence risks, and prenatal/preimplantation testing options.
Show evidence (1 reference)
PMID:20301704 SUPPORT Human Clinical
"Once the TCS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
GeneReviews describes genetic testing and counseling options.
{ }

Source YAML

click to show 
name: Treacher Collins Syndrome
creation_date: '2026-05-28T12:00:00Z'
synonyms:
- Mandibulofacial dysostosis without limb anomalies
- Franceschetti-Klein syndrome
- TCS
description: 'Treacher Collins syndrome (TCS) is an autosomal dominant craniofacial disorder characterized by bilateral and symmetric hypoplasia of the zygomatic bones, maxilla, and mandible, resulting in malar flattening, micrognathia, downslanted palpebral fissures, lower eyelid colobomas, external ear anomalies, and conductive hearing loss. TCS is caused by mutations in genes involved in ribosome biogenesis (TCOF1, POLR1B, POLR1C, POLR1D), which lead to inadequate ribosome production in neural crest cells, triggering p53-dependent apoptosis during embryonic development. Incidence is approximately 1 in 50,000 live births. Intellect is typically normal.

  '
category: Mendelian
parents:
- Mandibulofacial dysostosis
disease_term:
  preferred_term: Treacher Collins syndrome
  term:
    id: MONDO:0002457
    label: Treacher-Collins syndrome
has_subtypes:
- name: TCS1
  display_name: Treacher Collins Syndrome 1 (TCOF1)
  description: Most common subtype (>90% of cases), caused by heterozygous pathogenic variants in TCOF1 encoding Treacle, a nucleolar phosphoprotein essential for ribosomal DNA transcription.
  subtype_term:
    preferred_term: Treacher Collins syndrome 1
    term:
      id: MONDO:0007944
      label: Treacher Collins syndrome 1
  evidence:
  - reference: PMID:34573374
    reference_title: 'Treacher Collins Syndrome: Genetics, Clinical Features and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: TCS can be caused by pathogenic variants in the TCOF1, POLR1D, POLR1C and POLR1B genes. Genetically, the TCOF1 gene contains 27 exons which encodes the Treacle protein. In TCOF1, over 200 pathogenic variants have been identified
    explanation: Identifies TCOF1 as a causative gene for TCS with over 200 known pathogenic variants.
- name: TCS2
  display_name: Treacher Collins Syndrome 2 (POLR1D, AD)
  description: Caused by heterozygous pathogenic variants in POLR1D, encoding a subunit shared by RNA polymerases I and III.
  subtype_term:
    preferred_term: Treacher Collins syndrome 2
    term:
      id: MONDO:0013385
      label: Treacher Collins syndrome 2
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: heterozygous pathogenic variant in TCOF1, POLR1D, or POLR1B, biallelic pathogenic variants in POLR1C, or, rarely, biallelic pathogenic variants in POLR1D identified by molecular genetic testing.
    explanation: GeneReviews lists POLR1D heterozygous variants as a diagnostic criterion for TCS.
- name: TCS3
  display_name: Treacher Collins Syndrome 3 (POLR1C, AR)
  description: Caused by biallelic pathogenic variants in POLR1C, encoding a subunit shared by RNA polymerases I and III. Autosomal recessive inheritance.
  subtype_term:
    preferred_term: Treacher Collins syndrome 3
    term:
      id: MONDO:0009558
      label: Treacher Collins syndrome 3
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Autosomal recessive inheritance (biallelic pathogenic variants in POLR1C or POLR1D) accounts for a minority of TCS.
    explanation: GeneReviews confirms biallelic POLR1C variants cause autosomal recessive TCS.
- name: TCS4
  display_name: Treacher Collins Syndrome 4 (POLR1B)
  description: Caused by heterozygous pathogenic variants in POLR1B, encoding the second largest subunit of RNA polymerase I.
  subtype_term:
    preferred_term: Treacher Collins syndrome 4
    term:
      id: MONDO:0030067
      label: Treacher Collins syndrome 4
  evidence:
  - reference: PMID:34573374
    reference_title: 'Treacher Collins Syndrome: Genetics, Clinical Features and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four subtypes of Treacher Collins syndrome exist. TCS can be caused by pathogenic variants in the TCOF1, POLR1D, POLR1C and POLR1B genes.
    explanation: Identifies POLR1B as one of the four causative genes defining TCS subtypes.
inheritance:
- name: Autosomal dominant inheritance
  description: Most TCS cases (~93%) follow autosomal dominant inheritance with variable expressivity. About 55-61% of autosomal dominant cases are de novo.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Autosomal dominant inheritance accounts for most of TCS, most commonly heterozygous pathogenic variants in TCOF1 and less commonly heterozygous pathogenic variants in POLR1B or POLR1D.
    explanation: GeneReviews confirms autosomal dominant inheritance as the predominant pattern for TCS.
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: About 55%-61% of individuals with autosomal dominant TCS have the disorder as the result of a de novo pathogenic variant.
    explanation: High de novo rate explains sporadic cases.
- name: Autosomal recessive inheritance
  description: A minority of TCS cases are caused by biallelic pathogenic variants in POLR1C or POLR1D, following autosomal recessive inheritance.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Autosomal recessive inheritance (biallelic pathogenic variants in POLR1C or POLR1D) accounts for a minority of TCS.
    explanation: GeneReviews documents the autosomal recessive minority of TCS.
prevalence:
- population: Worldwide
  percentage: 0.002
  notes: Incidence approximately 1 in 50,000 live births.
  evidence:
  - reference: PMID:34573374
    reference_title: 'Treacher Collins Syndrome: Genetics, Clinical Features and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: TCS occurs in the general population at a frequency of 1 in 50,000 live births.
    explanation: Directly states the prevalence of TCS.
pathophysiology:
- name: Impaired Ribosome Biogenesis in Neural Crest Cells
  conforms_to: "pharyngeal_arch_patterning_serial_homology#Cranial Neural Crest and Pharyngeal Arch Program Perturbation"
  description: 'Mutations in TCOF1/POLR1B/POLR1C/POLR1D impair ribosomal RNA transcription and ribosome biogenesis. Neural crest cells are uniquely sensitive to reduced ribosome output due to their high proliferative and migratory demands during embryonic craniofacial development.

    '
  cell_types:
  - preferred_term: neural crest cell
    term:
      id: CL:0000333
      label: migratory neural crest cell
  biological_processes:
  - preferred_term: Ribosome biogenesis
    term:
      id: GO:0042254
      label: ribosome biogenesis
    modifier: DECREASED
  locations:
  - preferred_term: pharyngeal arch
    term:
      id: UBERON:0002539
      label: pharyngeal arch
  evidence:
  - reference: PMID:24690222
    reference_title: 'Treacher Collins Syndrome: the genetics of a craniofacial disease.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The association of the TCOF1 gene product, Treacle, and gene products of POLR1C and POLR1D with ribosome biosynthesis suggests that a loss of function mutation in these genes disrupts ribosome biosynthesis in constituent neural crest cells and neuroepithelium leading to apoptosis.
    explanation: Establishes the mechanistic link between TCS gene mutations, impaired ribosome biogenesis, and neural crest cell apoptosis.
  - reference: PMID:33804586
    reference_title: 'The Role of TCOF1 Gene in Health and Disease: Beyond Treacher Collins Syndrome.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: One of the crucial proteins involved in most of the key nucleolar functions is treacle phosphoprotein encoded by the TCOF1 gene.
    explanation: Identifies Treacle as a crucial nucleolar protein involved in key nucleolar functions including ribosome biogenesis.
  downstream:
  - target: p53-Dependent Neural Crest Cell Apoptosis
    causal_link_type: DIRECT
    description: Reduced ribosome biogenesis activates nucleolar stress, stabilizing p53 and triggering apoptosis in neural crest cells.
    evidence:
    - reference: PMID:24690222
      reference_title: 'Treacher Collins Syndrome: the genetics of a craniofacial disease.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: a loss of function mutation in these genes disrupts ribosome biosynthesis in constituent neural crest cells and neuroepithelium leading to apoptosis.
      explanation: Describes the causal chain from ribosome disruption to apoptosis.
- name: p53-Dependent Neural Crest Cell Apoptosis
  description: 'Nucleolar stress from impaired ribosome biogenesis stabilizes p53 in neural crest cells, triggering apoptosis during the critical window of craniofacial development. p53 heterozygosity is protective, confirming p53''s central role in TCS pathogenesis.

    '
  cell_types:
  - preferred_term: neural crest cell
    term:
      id: CL:0000333
      label: migratory neural crest cell
  biological_processes:
  - preferred_term: Apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  locations:
  - preferred_term: pharyngeal arch
    term:
      id: UBERON:0002539
      label: pharyngeal arch
  evidence:
  - reference: PMID:24690222
    reference_title: 'Treacher Collins Syndrome: the genetics of a craniofacial disease.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: P53 heterozygosity is protective against TCS, and that P53 and TCOF1 hemizygous embryos do not affect ribosomal function, implicates P53 or elements downstream of P53 as playing a role in TCS pathogenesis.
    explanation: Mouse model data showing p53 heterozygosity rescues the TCS phenotype, confirming p53-dependent apoptosis as the key mechanism.
  downstream:
  - target: Craniofacial Skeletal Hypoplasia
    causal_link_type: DIRECT
    description: Depletion of cranial neural crest cells leads to deficient formation of first and second pharyngeal arch-derived craniofacial structures.
    evidence:
    - reference: PMID:34573374
      reference_title: 'Treacher Collins Syndrome: Genetics, Clinical Features and Management.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Treacher Collins syndrome (TCS) is associated with abnormal differentiation of the first and second pharyngeal arches, occurring during fetal development.
      explanation: Links neural crest deficiency to pharyngeal arch malformation.
- name: Craniofacial Skeletal Hypoplasia
  conforms_to: "pharyngeal_arch_patterning_serial_homology#Serially Homologous Craniofacial Malformation Across Arch Derivatives"
  description: 'Depletion of cranial neural crest cells results in bilateral symmetric hypoplasia of the zygomatic bones, maxilla, and mandible, as well as external and middle ear malformations and orbital abnormalities.

    '
  locations:
  - preferred_term: mandible
    term:
      id: UBERON:0001684
      label: mandible
  - preferred_term: zygomatic bone
    term:
      id: UBERON:0001683
      label: jugal bone
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treacher Collins syndrome (TCS) is characterized by lower eyelid abnormalities, malar hypoplasia, downslanted palpebral fissures, and micro- or retrognathia due to symmetric hypoplasia of the zygomatic bones, maxilla, and mandible.
    explanation: GeneReviews describes the characteristic bilateral symmetric craniofacial skeletal hypoplasia.
  biological_processes:
  - preferred_term: Neural crest cell migration
    term:
      id: GO:0001755
      label: neural crest cell migration
    modifier: DECREASED
  downstream:
  - target: Malar Flattening
    description: Zygomatic and midface hypoplasia produces malar flattening.
    causal_link_type: DIRECT
  - target: Micrognathia
    description: Mandibular hypoplasia produces micrognathia.
    causal_link_type: DIRECT
  - target: Downslanted Palpebral Fissures
    description: Orbital and periocular craniofacial maldevelopment produces downslanted palpebral fissures.
    causal_link_type: DIRECT
  - target: Lower Eyelid Coloboma
    description: Periocular craniofacial maldevelopment produces lower eyelid coloboma.
    causal_link_type: DIRECT
  - target: Microtia
    description: First and second pharyngeal arch maldevelopment produces external ear malformations including microtia.
    causal_link_type: DIRECT
  - target: Atresia of External Auditory Canal
    description: Ear canal maldevelopment produces atresia or stenosis of the external auditory canal.
    causal_link_type: DIRECT
  - target: Conductive Hearing Loss
    description: External and middle ear malformations impair sound conduction.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - ossicle malformation
    - middle ear cavity hypoplasia
  - target: Cleft Palate
    description: Abnormal pharyngeal arch and palatal development can produce cleft palate.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - palatal maldevelopment
  - target: Choanal Atresia
    description: Craniofacial maldevelopment can include choanal stenosis or atresia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Upper Airway Obstruction
    description: Mandibular hypoplasia and glossoptosis narrow the upper airway.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - micrognathia
    - glossoptosis
  - target: Feeding Difficulties
    description: Mandibular hypoplasia and cleft palate can impair infant feeding.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - micrognathia
    - cleft palate
  - target: Obstructive Sleep Apnea
    description: Mandibular hypoplasia and upper airway narrowing predispose to obstructive sleep apnea.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - upper airway obstruction
phenotypes:
- category: Clinical
  name: Malar Flattening
  description: Bilateral symmetric hypoplasia of the zygomatic bones causing characteristic flat midface appearance.
  phenotype_term:
    preferred_term: Malar flattening
    term:
      id: HP:0000272
      label: Malar flattening
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treacher Collins syndrome (TCS) is characterized by lower eyelid abnormalities, malar hypoplasia, downslanted palpebral fissures, and micro- or retrognathia due to symmetric hypoplasia of the zygomatic bones, maxilla, and mandible.
    explanation: Malar hypoplasia is listed as a defining feature of TCS.
- category: Clinical
  name: Micrognathia
  description: Underdevelopment of the mandible, contributing to airway and feeding difficulties.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treacher Collins syndrome (TCS) is characterized by lower eyelid abnormalities, malar hypoplasia, downslanted palpebral fissures, and micro- or retrognathia due to symmetric hypoplasia of the zygomatic bones, maxilla, and mandible.
    explanation: Micro- or retrognathia is a core feature of TCS.
- category: Clinical
  name: Downslanted Palpebral Fissures
  description: Characteristic downward slanting of the palpebral fissures.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:34573374
    reference_title: 'Treacher Collins Syndrome: Genetics, Clinical Features and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Features of TCS include microtia with conductive hearing loss, slanting palpebral fissures with possibly coloboma of the lateral part of lower eyelids, midface hypoplasia, micrognathia as well as sporadically cleft palate and choanal atresia or stenosis.
    explanation: Slanting palpebral fissures listed as a key TCS feature.
- category: Clinical
  name: Conductive Hearing Loss
  description: Conductive hearing loss affecting approximately 40-50% of individuals, due to malformation of the ossicles and hypoplasia of the middle ear cavities.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation of the ossicles and hypoplasia of the middle ear cavities.
    explanation: GeneReviews specifies the frequency and mechanism of conductive hearing loss in TCS.
  frequency: FREQUENT
- category: Clinical
  name: Microtia
  description: Absent, small, malformed, or posteriorly rotated ears.
  phenotype_term:
    preferred_term: Microtia
    term:
      id: HP:0008551
      label: Microtia
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: External ear anomalies include absent, small, malformed, and/or posteriorly rotated ears and atresia or stenosis of the external auditory canals.
    explanation: GeneReviews describes the range of external ear anomalies in TCS.
- category: Clinical
  name: Atresia of External Auditory Canal
  description: Atresia or stenosis of the external auditory canals.
  phenotype_term:
    preferred_term: Atresia of the external auditory canal
    term:
      id: HP:0000413
      label: Atresia of the external auditory canal
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: External ear anomalies include absent, small, malformed, and/or posteriorly rotated ears and atresia or stenosis of the external auditory canals.
    explanation: Atresia of the external auditory canal is listed among ear anomalies.
- category: Clinical
  name: Lower Eyelid Coloboma
  description: Coloboma of the lateral part of the lower eyelids, a distinctive feature.
  phenotype_term:
    preferred_term: Lower eyelid coloboma
    term:
      id: HP:0000652
      label: Lower eyelid coloboma
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treacher Collins syndrome (TCS) is characterized by lower eyelid abnormalities, malar hypoplasia, downslanted palpebral fissures, and micro- or retrognathia
    explanation: Lower eyelid abnormalities are a defining clinical feature.
- category: Clinical
  name: Cleft Palate
  description: Cleft palate occurs in a subset of TCS patients.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:34573374
    reference_title: 'Treacher Collins Syndrome: Genetics, Clinical Features and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Features of TCS include microtia with conductive hearing loss, slanting palpebral fissures with possibly coloboma of the lateral part of lower eyelids, midface hypoplasia, micrognathia as well as sporadically cleft palate and choanal atresia or stenosis.
    explanation: Cleft palate listed as a sporadic feature of TCS.
- category: Clinical
  name: Choanal Atresia
  description: Unilateral or bilateral choanal stenosis or atresia occurs in some patients with TCS.
  phenotype_term:
    preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia.
    explanation: GeneReviews notes choanal atresia as a less common but recognized feature.
- category: Clinical
  name: Upper Airway Obstruction
  description: Respiratory difficulties from mandibular hypoplasia and glossoptosis, which may require airway management at birth.
  phenotype_term:
    preferred_term: Upper airway obstruction
    term:
      id: HP:0002781
      label: Upper airway obstruction
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neonates with airway issues may require airway management at delivery, special positioning, or tracheostomy to facilitate ventilation.
    explanation: GeneReviews describes significant airway obstruction requiring intervention in some neonates.
- category: Clinical
  name: Feeding Difficulties
  description: Feeding difficulties in infancy due to mandibular hypoplasia and possible cleft palate.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Significant respiratory and feeding difficulties can be present in infancy.
    explanation: GeneReviews identifies feeding difficulties as a significant neonatal concern.
- category: Clinical
  name: Obstructive Sleep Apnea
  description: Obstructive sleep apnea due to mandibular hypoplasia and upper airway narrowing; annual surveillance recommended.
  phenotype_term:
    preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: assess for manifestations of obstructive sleep apnea, growth, and caloric intake at each visit
    explanation: GeneReviews surveillance recommendations include assessment for OSA at each visit.
genetic:
- name: TCOF1
  relationship_type: CAUSATIVE
  presence: Present
  subtype: TCS1
  gene_term:
    preferred_term: TCOF1
    term:
      id: hgnc:11654
      label: TCOF1
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:20301704
      reference_title: Treacher Collins Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Autosomal dominant inheritance accounts for most of TCS, most commonly heterozygous pathogenic variants in TCOF1
      explanation: Confirms AD inheritance for TCOF1.
  notes: Encodes Treacle, a nucleolar phosphoprotein. Over 200 pathogenic variants identified, most are deletions causing frameshifts. Accounts for >90% of TCS.
  evidence:
  - reference: PMID:34573374
    reference_title: 'Treacher Collins Syndrome: Genetics, Clinical Features and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the TCOF1 gene contains 27 exons which encodes the Treacle protein. In TCOF1, over 200 pathogenic variants have been identified, of which most are deletions leading to a frame-shift, that result in the formation of a termination codon.
    explanation: Details the molecular genetics of TCOF1 mutations in TCS.
  - reference: PMID:33804586
    reference_title: 'The Role of TCOF1 Gene in Health and Disease: Beyond Treacher Collins Syndrome.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: One of the crucial proteins involved in most of the key nucleolar functions is treacle phosphoprotein encoded by the TCOF1 gene.
    explanation: Identifies Treacle as a key nucleolar protein central to ribosome biogenesis.
- name: POLR1D
  relationship_type: CAUSATIVE
  presence: Present
  subtype: TCS2
  gene_term:
    preferred_term: POLR1D
    term:
      id: hgnc:20422
      label: POLR1D
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:20301704
      reference_title: Treacher Collins Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: less commonly heterozygous pathogenic variants in POLR1B or POLR1D
      explanation: Confirms AD inheritance for POLR1D heterozygous variants.
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:20301704
      reference_title: Treacher Collins Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Autosomal recessive inheritance (biallelic pathogenic variants in POLR1C or POLR1D) accounts for a minority of TCS.
      explanation: GeneReviews confirms biallelic POLR1D variants cause AR TCS.
  notes: Encodes a subunit shared by RNA polymerases I and III. Both heterozygous (AD) and biallelic (AR) pathogenic variants can cause TCS.
  evidence:
  - reference: PMID:34573374
    reference_title: 'Treacher Collins Syndrome: Genetics, Clinical Features and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: TCS can be caused by pathogenic variants in the TCOF1, POLR1D, POLR1C and POLR1B genes.
    explanation: Lists POLR1D as a causative gene for TCS.
- name: POLR1C
  relationship_type: CAUSATIVE
  presence: Present
  subtype: TCS3
  gene_term:
    preferred_term: POLR1C
    term:
      id: hgnc:20194
      label: POLR1C
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:20301704
      reference_title: Treacher Collins Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Autosomal recessive inheritance (biallelic pathogenic variants in POLR1C or POLR1D) accounts for a minority of TCS.
      explanation: Confirms AR inheritance for biallelic POLR1C variants.
  notes: Encodes a subunit shared by RNA polymerases I and III. Biallelic mutations cause the autosomal recessive form of TCS.
  evidence:
  - reference: PMID:34573374
    reference_title: 'Treacher Collins Syndrome: Genetics, Clinical Features and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: TCS can be caused by pathogenic variants in the TCOF1, POLR1D, POLR1C and POLR1B genes.
    explanation: Lists POLR1C as a causative gene for TCS.
- name: POLR1B
  relationship_type: CAUSATIVE
  presence: Present
  subtype: TCS4
  gene_term:
    preferred_term: POLR1B
    term:
      id: hgnc:20454
      label: POLR1B
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:20301704
      reference_title: Treacher Collins Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: less commonly heterozygous pathogenic variants in POLR1B or POLR1D
      explanation: Confirms AD inheritance for POLR1B variants.
  notes: Encodes the second largest subunit of RNA polymerase I. Heterozygous variants cause TCS4.
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a heterozygous pathogenic variant in TCOF1, POLR1D, or POLR1B, biallelic pathogenic variants in POLR1C
    explanation: GeneReviews lists POLR1B as a TCS-causing gene.
treatments:
- name: Craniofacial Reconstruction
  description: Zygomatic, orbital, and mandibular reconstruction surgery tailored to severity. Zygomatic/orbital reconstruction typically at age 5-7 years, ear reconstruction after age 6 years, orthognathic surgery before age 16.
  treatment_term:
    preferred_term: craniofacial surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Craniofacial reconstruction is often necessary: zygomatic and orbital reconstruction at about age five to seven years, and bilateral microtia and/or narrow ear canal reconstruction after age six years.'
    explanation: GeneReviews describes the staged surgical reconstruction approach.
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The age of maxillomandibular reconstruction varies by severity; orthognathic therapies are typically before age 16 years.
    explanation: Orthognathic surgery timing specified by GeneReviews.
- name: Speech Therapy
  description: Speech therapy as part of multimodal hearing-loss support for individuals with conductive hearing impairment.
  treatment_term:
    preferred_term: speech therapy
    term:
      id: MAXO:0000930
      label: speech therapy
  target_phenotypes:
  - preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hearing loss is treated with bone conduction amplification, speech therapy, and educational intervention.
    explanation: GeneReviews explicitly includes speech therapy within the multimodal approach to conductive hearing loss.
- name: Airway Management
  description: Neonatal airway management including special positioning, nasopharyngeal airways, or tracheostomy for infants with significant upper airway obstruction.
  treatment_term:
    preferred_term: airway management
    term:
      id: MAXO:0000500
      label: airway management
  target_phenotypes:
  - preferred_term: Upper airway obstruction
    term:
      id: HP:0002781
      label: Upper airway obstruction
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neonates with airway issues may require airway management at delivery, special positioning, or tracheostomy to facilitate ventilation.
    explanation: GeneReviews describes airway management strategies.
- name: Genetic Counseling
  description: Genetic counseling for TCS families addressing inheritance patterns, de novo rates, recurrence risks, and prenatal/preimplantation testing options.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Once the TCS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
    explanation: GeneReviews describes genetic testing and counseling options.
diagnosis:
- name: Clinical diagnosis
  description: TCS is diagnosed based on characteristic bilateral symmetric craniofacial features including malar hypoplasia, micrognathia, downslanted palpebral fissures, ear anomalies, and conductive hearing loss.
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treacher Collins syndrome (TCS) is characterized by lower eyelid abnormalities, malar hypoplasia, downslanted palpebral fissures, and micro- or retrognathia due to symmetric hypoplasia of the zygomatic bones, maxilla, and mandible.
    explanation: GeneReviews defines the clinical diagnostic criteria.
- name: Molecular genetic testing
  description: Diagnosis confirmed by identification of heterozygous pathogenic variants in TCOF1, POLR1D, or POLR1B, or biallelic pathogenic variants in POLR1C or POLR1D.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:20301704
    reference_title: Treacher Collins Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The diagnosis of TCS is established in a proband with characteristic clinical features and/or a heterozygous pathogenic variant in TCOF1, POLR1D, or POLR1B, biallelic pathogenic variants in POLR1C, or, rarely, biallelic pathogenic variants in POLR1D identified by molecular genetic testing.
    explanation: GeneReviews specifies the molecular diagnostic criteria for TCS.
references:
- reference: PMID:20301704
  title: Treacher Collins Syndrome.
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:20301704
Treacher Collins Syndrome.
No top-level findings curated for this source.

Deep Research

1
Treacher Collins Syndrome - Manual PubMed Research ▸

Treacher Collins Syndrome - Manual PubMed Research

Research Method

Manual literature search via PubMed E-utilities API (no deep research API keys available).

Key References

  1. PMID:20301704 - Barbosa M, Jabs EW, Huston S (2024 update). GeneReviews: Treacher Collins Syndrome.
  2. Comprehensive clinical review covering clinical characteristics, genetics, management, and genetic counseling.

  3. Key source for clinical features, diagnostic criteria, and management guidelines.

  4. PMID:34573374 - Marszałek-Kruk BA et al. (2021). Treacher Collins Syndrome: Genetics, Clinical Features and Management.

  5. Review covering genetics, phenotype, and surgical management.

  6. Source for prevalence (1 in 50,000) and four subtypes.

  7. PMID:33804586 - Grzanka M, Piekiełko-Witkowska A (2021). The Role of TCOF1 Gene in Health and Disease.

  8. Full-text review of TCOF1/Treacle function in ribosome biogenesis.

  9. Key source for molecular pathophysiology.

  10. PMID:24690222 - Kadakia S et al. (2014). Treacher Collins Syndrome: the genetics of a craniofacial disease.

  11. Review of genetics and pathophysiology.
  12. Key source for ribosome biogenesis → p53-dependent apoptosis mechanism.

Key Facts

  • MONDO:0002457
  • Incidence: ~1 in 50,000 live births
  • Inheritance: Autosomal dominant (TCOF1, POLR1B, POLR1D) or autosomal recessive (POLR1C, POLR1D biallelic)
  • 55-61% of AD cases are de novo
  • TCOF1 mutations account for >90% of cases
  • Pathomechanism: Impaired ribosome biogenesis → p53-dependent neural crest cell apoptosis → craniofacial skeletal hypoplasia
  • Core features: Malar hypoplasia, micrognathia, downslanted palpebral fissures, lower eyelid coloboma, microtia, conductive hearing loss
  • Intellect typically normal