Saethre-Chotzen Syndrome

Mendelian MONDO:0007042 Pathograph 9 Show in embeddings browser TWIST1-related disorder Craniosynostosis syndrome

Saethre-Chotzen syndrome (acrocephalosyndactyly type III) is one of the most common autosomal dominant craniosynostosis syndromes, caused by haploinsufficiency of TWIST1, a basic helix-loop-helix (bHLH) transcription factor. Unlike the FGFR gain-of-function craniosynostoses, which fuse sutures by excess pro-osteogenic signalling, Saethre-Chotzen exemplifies the boundary/niche-loss route to premature suture fusion: loss of one TWIST1 allele removes the anti-osteogenic restraint that maintains suture patency (TWIST1 inhibition of RUNX2, the TWIST1-EphA4 osteogenic boundary between the neural-crest frontal bone and the mesodermal parietal bone, and the Gli1+/Axin2+ suture mesenchymal stem-cell niche). The result is typically bilateral coronal craniosynostosis with ptosis, low frontal hairline, facial asymmetry, prominent ear crura, and limb anomalies (brachydactyly, cutaneous syndactyly).

Ask OpenScientist

Ask a research question about Saethre-Chotzen Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
4
Pathophys.
7
Phenotypes
9
Pathograph
2
Genes
2
Medical Actions
👪

Inheritance

1
Autosomal dominant HP:0000006
Saethre-Chotzen syndrome is inherited in an autosomal dominant manner and results from haploinsufficiency of TWIST1.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:8988166 SUPPORT Human Clinical
"Saethre-Chotzen syndrome is one of the most common autosomal dominant disorders of craniosynostosis in humans and is characterized by craniofacial and limb anomalies."
Establishes autosomal dominant inheritance and the craniofacial-plus-limb phenotype of Saethre-Chotzen syndrome.
⚙

Pathophysiology

4
TWIST1 haploinsufficiency and loss of suture osteogenic restraint
Heterozygous loss-of-function of TWIST1 (nonsense, missense within the bHLH domain, insertions/deletions, or whole-gene deletions) reduces functional TWIST1 dosage. TWIST1 is a bHLH transcription factor required in head mesenchyme; its haploinsufficiency removes the anti-osteogenic restraint that keeps the coronal suture patent, disrupting the TWIST1-EphA4 osteogenic boundary between the neural-crest-derived frontal bone and the mesoderm-derived parietal bone and depleting the suture stem-cell niche. This is the boundary/niche-loss route into the conserved cranial-suture premature-fusion endpoint, mechanistically distinct from the FGFR/BMP pro-osteogenic-drive routes.
migratory cranial neural crest cell CL:0000008 mesenchymal stem cell CL:0000134
TWIST1 hgnc:12428 ↓ DECREASED
negative regulation of osteoblast differentiation GO:0045668 ↓ DECREASED
coronal suture UBERON:0002489
Downstream
De-repressed osteoblast differentiation in coronal suture Loss of TWIST1-mediated inhibition of RUNX2 de-represses osteoblast differentiation in coronal suture mesenchyme.
Show evidence (4 references)
PMID:8988166 SUPPORT Human Clinical
"mutational analysis reveals nonsense, missense, insertion and deletion mutations in patients. These mutations occur within the basic DNA binding, helix I and loop domains, or result in premature termination of the protein."
Documents the loss-of-function TWIST1 mutation spectrum causing haploinsufficiency in Saethre-Chotzen syndrome.
PMID:8988167 SUPPORT Human Clinical
"The Twist gene product is a transcription factor containing a basic helix-loop-helix (b-HLH) domain, required in head mesenchyme for cranial neural tube morphogenesis in mice."
Establishes TWIST1 as a bHLH transcription factor required in head mesenchyme, the anti-osteogenic regulator lost in this disorder.
PMID:16540516 SUPPORT Model Organism
"In Twist1(+/-) mice with coronal synostosis, we found that the frontal-parietal boundary is defective. Specifically, neural crest cells invade the undifferentiated mesoderm of the Twist1(+/-) mutant coronal suture."
Demonstrates that TWIST1 haploinsufficiency disrupts the neural-crest/mesoderm osteogenic boundary that maintains coronal suture patency.
+ 1 more reference
De-repressed osteoblast differentiation in coronal suture
With TWIST1 restraint removed, RUNX2-driven osteoblast differentiation is de-repressed in coronal suture mesenchyme, the convergent osteogenic-acceleration state shared with the FGFR and BMP routes but reached here by loss of anti-osteogenic restraint rather than by increased signalling drive.
osteoblast CL:0000062
osteoblast differentiation GO:0001649 ↑ INCREASED
coronal suture UBERON:0002489
Downstream
Premature coronal suture fusion De-repressed osteogenesis prematurely fuses the coronal suture.
Show evidence (2 references)
PMID:15030764 SUPPORT Model Organism
"Twist-1 or -2 deficiency leads to premature osteoblast differentiation."
Directly shows that loss of TWIST restraint accelerates osteoblast differentiation, the convergent effector of premature suture fusion.
PMID:15030764 SUPPORT Model Organism
"Thus, relief of inhibition by Twist proteins is a mandatory event precluding osteoblast differentiation."
Establishes TWIST inhibition of RUNX2 as the gate whose loss drives osteoblast differentiation in the suture.
Premature coronal suture fusion
De-repressed osteogenesis at the coronal suture causes premature bony fusion, typically bilateral, producing the coronal craniosynostosis that defines the cranial phenotype of Saethre-Chotzen syndrome.
cranial suture morphogenesis GO:0060363 ↕ DYSREGULATED osteoblast differentiation GO:0001649 ↑ INCREASED
coronal suture UBERON:0002489
Downstream
Coronal Craniosynostosis Premature coronal suture fusion manifests clinically as coronal craniosynostosis.
Craniofacial dysmorphism Premature coronal suture fusion and disturbed head-mesenchyme development produce the characteristic facial dysmorphism.
Show evidence (1 reference)
PMID:16540516 SUPPORT Human Clinical
"Known causes of coronal synostosis include haploinsufficiency of TWIST1 and a gain of function mutation in MSX2."
Establishes TWIST1 haploinsufficiency as a cause of coronal synostosis, the premature-fusion endpoint of the disorder.
Craniofacial dysmorphism
Disturbed head-mesenchyme development and premature coronal fusion produce facial asymmetry, ptosis, a low frontal hairline, and prominent ear crura.
Downstream
Ptosis Drooping of the upper eyelid, a hallmark facial feature.
Facial asymmetry Asymmetry of the face, often reflecting asymmetric coronal fusion.
Prominent ear crura Prominent crus of the helix, a characteristic ear anomaly.
Show evidence (1 reference)
PMID:8988167 SUPPORT Human Clinical
"Saethre-Chotzen syndrome (acrocephalo-syndactyly type III, ACS III) is an autosomal dominant craniosynostosis with brachydactyly, soft tissue syndactyly and facial dysmorphism including ptosis, facial asymmetry and prominent ear crura."
Documents the characteristic facial dysmorphism (ptosis, facial asymmetry, prominent ear crura) of Saethre-Chotzen syndrome.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Saethre-Chotzen 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

7
Eye 1
Ptosis Ptosis HP:0000508
Show evidence (1 reference)
PMID:8988167 SUPPORT Human Clinical
"facial dysmorphism including ptosis, facial asymmetry and prominent ear crura."
Lists ptosis as a defining facial feature.
Head and Neck 2
Coronal Craniosynostosis Coronal craniosynostosis HP:0004440
Show evidence (1 reference)
PMID:16540516 SUPPORT Human Clinical
"Known causes of coronal synostosis include haploinsufficiency of TWIST1 and a gain of function mutation in MSX2."
Identifies TWIST1 haploinsufficiency as a cause of coronal synostosis.
Facial asymmetry Facial asymmetry HP:0000324
Show evidence (1 reference)
PMID:8988167 SUPPORT Human Clinical
"facial dysmorphism including ptosis, facial asymmetry and prominent ear crura."
Lists facial asymmetry as a defining facial feature.
Limbs 2
Brachydactyly Brachydactyly HP:0001156
Show evidence (1 reference)
PMID:8988167 SUPPORT Human Clinical
"is an autosomal dominant craniosynostosis with brachydactyly, soft tissue syndactyly and facial dysmorphism"
Lists brachydactyly as a limb feature.
Cutaneous syndactyly Cutaneous finger syndactyly HP:0010554
Show evidence (1 reference)
PMID:8988167 SUPPORT Human Clinical
"is an autosomal dominant craniosynostosis with brachydactyly, soft tissue syndactyly and facial dysmorphism"
Lists soft-tissue (cutaneous) syndactyly as a limb feature.
Other 2
Prominent ear crura Prominent crus of helix HP:0009899
Show evidence (1 reference)
PMID:8988167 SUPPORT Human Clinical
"facial dysmorphism including ptosis, facial asymmetry and prominent ear crura."
Lists prominent ear crura as a defining ear feature.
Low frontal hairline Low anterior hairline HP:0000294
🧬

Genetic Associations

2
TWIST1 loss-of-function mutations (Causative)
Gene: TWIST1 hgnc:12428
Show evidence (1 reference)
PMID:8988167 SUPPORT Human Clinical
"Here, we report 21-bp insertions and nonsense mutations of the TWIST gene (S127X, E130X) in seven ACS III probands and describe impairment of head mesenchyme induction by TWIST as a novel pathophysiological mechanism in human craniosynostoses."
Identifies loss-of-function TWIST1 mutations in Saethre-Chotzen (ACS III) probands as causative.
EFNA4 (Modifier)
Gene: EFNA4 hgnc:3224
Show evidence (1 reference)
PMID:16540516 SUPPORT Human Clinical
"we identified heterozygous mutations in the human orthologue, EFNA4, in three of 81 patients with non-syndromic coronal synostosis."
Implicates EFNA4, the effector of the TWIST1 osteogenic boundary, in coronal synostosis.
💊

Medical Actions

2
Cranial vault reconstruction
Action: surgical procedure MAXO:0000004
Surgical expansion and remodelling of the cranial vault to relieve or prevent raised intracranial pressure and correct skull shape.
Ptosis repair
Action: surgical procedure MAXO:0000004
Oculoplastic surgical correction of eyelid ptosis to protect vision and improve the visual axis.
{ }

Source YAML

click to show 
name: Saethre-Chotzen Syndrome
creation_date: '2026-07-02T00:00:00Z'
category: Mendelian
description: >-
  Saethre-Chotzen syndrome (acrocephalosyndactyly type III) is one of the most
  common autosomal dominant craniosynostosis syndromes, caused by
  haploinsufficiency of TWIST1, a basic helix-loop-helix (bHLH) transcription
  factor. Unlike the FGFR gain-of-function craniosynostoses, which fuse sutures
  by excess pro-osteogenic signalling, Saethre-Chotzen exemplifies the
  boundary/niche-loss route to premature suture fusion: loss of one TWIST1 allele
  removes the anti-osteogenic restraint that maintains suture patency
  (TWIST1 inhibition of RUNX2, the TWIST1-EphA4 osteogenic boundary between the
  neural-crest frontal bone and the mesodermal parietal bone, and the Gli1+/Axin2+
  suture mesenchymal stem-cell niche). The result is typically bilateral coronal
  craniosynostosis with ptosis, low frontal hairline, facial asymmetry, prominent
  ear crura, and limb anomalies (brachydactyly, cutaneous syndactyly).
disease_term:
  preferred_term: Saethre-Chotzen syndrome
  term:
    id: MONDO:0007042
    label: Saethre-Chotzen syndrome
parents:
- TWIST1-related disorder
- Craniosynostosis syndrome
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Saethre-Chotzen syndrome is inherited in an autosomal dominant manner and
    results from haploinsufficiency of TWIST1.
  evidence:
  - reference: PMID:8988166
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Saethre-Chotzen syndrome is one of the most common autosomal dominant
      disorders of craniosynostosis in humans and is characterized by
      craniofacial and limb anomalies.
    explanation: >-
      Establishes autosomal dominant inheritance and the craniofacial-plus-limb
      phenotype of Saethre-Chotzen syndrome.
pathophysiology:
- name: TWIST1 haploinsufficiency and loss of suture osteogenic restraint
  conforms_to: "cranial_suture_premature_fusion#Loss of Suture Patency Restraint"
  description: >-
    Heterozygous loss-of-function of TWIST1 (nonsense, missense within the bHLH
    domain, insertions/deletions, or whole-gene deletions) reduces functional
    TWIST1 dosage. TWIST1 is a bHLH transcription factor required in head
    mesenchyme; its haploinsufficiency removes the anti-osteogenic restraint that
    keeps the coronal suture patent, disrupting the TWIST1-EphA4 osteogenic
    boundary between the neural-crest-derived frontal bone and the
    mesoderm-derived parietal bone and depleting the suture stem-cell niche. This
    is the boundary/niche-loss route into the conserved cranial-suture
    premature-fusion endpoint, mechanistically distinct from the FGFR/BMP
    pro-osteogenic-drive routes.
  gene:
    preferred_term: TWIST1
    description: Basic helix-loop-helix transcription factor; haploinsufficiency causes Saethre-Chotzen syndrome.
    modifier: DECREASED
    term:
      id: hgnc:12428
      label: TWIST1
  cell_types:
  - preferred_term: migratory cranial neural crest cell
    term:
      id: CL:0000008
      label: migratory cranial neural crest cell
  - preferred_term: mesenchymal stem cell
    term:
      id: CL:0000134
      label: mesenchymal stem cell
  locations:
  - preferred_term: coronal suture
    term:
      id: UBERON:0002489
      label: coronal suture
  biological_processes:
  - preferred_term: negative regulation of osteoblast differentiation
    term:
      id: GO:0045668
      label: negative regulation of osteoblast differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:8988166
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutational analysis reveals nonsense, missense, insertion and deletion
      mutations in patients. These mutations occur within the basic DNA binding,
      helix I and loop domains, or result in premature termination of the protein.
    explanation: >-
      Documents the loss-of-function TWIST1 mutation spectrum causing
      haploinsufficiency in Saethre-Chotzen syndrome.
  - reference: PMID:8988167
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Twist gene product is a transcription factor containing a basic
      helix-loop-helix (b-HLH) domain, required in head mesenchyme for cranial
      neural tube morphogenesis in mice.
    explanation: >-
      Establishes TWIST1 as a bHLH transcription factor required in head
      mesenchyme, the anti-osteogenic regulator lost in this disorder.
  - reference: PMID:16540516
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In Twist1(+/-) mice with coronal synostosis, we found that the
      frontal-parietal boundary is defective. Specifically, neural crest cells
      invade the undifferentiated mesoderm of the Twist1(+/-) mutant coronal
      suture.
    explanation: >-
      Demonstrates that TWIST1 haploinsufficiency disrupts the neural-crest/mesoderm
      osteogenic boundary that maintains coronal suture patency.
  - reference: PMID:25799059
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Twist1(+/-) mice with craniosynostosis show reduced Gli1+ MSCs in sutures,
      suggesting that craniosynostosis may result from diminished suture stem
      cells.
    explanation: >-
      Links TWIST1 haploinsufficiency to depletion of the Gli1+ suture stem-cell
      niche, the niche-loss arm of the restraint-loss route.
  downstream:
  - target: De-repressed osteoblast differentiation in coronal suture
    description: >-
      Loss of TWIST1-mediated inhibition of RUNX2 de-represses osteoblast
      differentiation in coronal suture mesenchyme.
    causal_link_type: DIRECT
- name: De-repressed osteoblast differentiation in coronal suture
  conforms_to: "cranial_suture_premature_fusion#Cranial Suture Osteogenic Acceleration"
  description: >-
    With TWIST1 restraint removed, RUNX2-driven osteoblast differentiation is
    de-repressed in coronal suture mesenchyme, the convergent osteogenic-acceleration
    state shared with the FGFR and BMP routes but reached here by loss of
    anti-osteogenic restraint rather than by increased signalling drive.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  locations:
  - preferred_term: coronal suture
    term:
      id: UBERON:0002489
      label: coronal suture
  biological_processes:
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: INCREASED
  evidence:
  - reference: PMID:15030764
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Twist-1 or -2 deficiency leads to premature osteoblast differentiation.
    explanation: >-
      Directly shows that loss of TWIST restraint accelerates osteoblast
      differentiation, the convergent effector of premature suture fusion.
  - reference: PMID:15030764
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, relief of inhibition by Twist proteins is a mandatory event precluding
      osteoblast differentiation.
    explanation: >-
      Establishes TWIST inhibition of RUNX2 as the gate whose loss drives
      osteoblast differentiation in the suture.
  downstream:
  - target: Premature coronal suture fusion
    description: De-repressed osteogenesis prematurely fuses the coronal suture.
    causal_link_type: DIRECT
- name: Premature coronal suture fusion
  conforms_to: "cranial_suture_premature_fusion#Premature Cranial Suture Fusion and Craniosynostosis"
  description: >-
    De-repressed osteogenesis at the coronal suture causes premature bony fusion,
    typically bilateral, producing the coronal craniosynostosis that defines the
    cranial phenotype of Saethre-Chotzen syndrome.
  locations:
  - preferred_term: coronal suture
    term:
      id: UBERON:0002489
      label: coronal suture
  biological_processes:
  - preferred_term: cranial suture morphogenesis
    term:
      id: GO:0060363
      label: cranial suture morphogenesis
    modifier: DYSREGULATED
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: INCREASED
  evidence:
  - reference: PMID:16540516
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Known causes of coronal synostosis include haploinsufficiency of TWIST1 and
      a gain of function mutation in MSX2.
    explanation: >-
      Establishes TWIST1 haploinsufficiency as a cause of coronal synostosis, the
      premature-fusion endpoint of the disorder.
  downstream:
  - target: Coronal Craniosynostosis
    description: Premature coronal suture fusion manifests clinically as coronal craniosynostosis.
    causal_link_type: DIRECT
  - target: Craniofacial dysmorphism
    description: >-
      Premature coronal suture fusion and disturbed head-mesenchyme development
      produce the characteristic facial dysmorphism.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - distorted cranial vault and midface growth after coronal fusion
- name: Craniofacial dysmorphism
  description: >-
    Disturbed head-mesenchyme development and premature coronal fusion produce
    facial asymmetry, ptosis, a low frontal hairline, and prominent ear crura.
  evidence:
  - reference: PMID:8988167
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Saethre-Chotzen syndrome (acrocephalo-syndactyly type III, ACS III) is an
      autosomal dominant craniosynostosis with brachydactyly, soft tissue
      syndactyly and facial dysmorphism including ptosis, facial asymmetry and
      prominent ear crura.
    explanation: >-
      Documents the characteristic facial dysmorphism (ptosis, facial asymmetry,
      prominent ear crura) of Saethre-Chotzen syndrome.
  downstream:
  - target: Ptosis
    description: Drooping of the upper eyelid, a hallmark facial feature.
    causal_link_type: DIRECT
  - target: Facial asymmetry
    description: Asymmetry of the face, often reflecting asymmetric coronal fusion.
    causal_link_type: DIRECT
  - target: Prominent ear crura
    description: Prominent crus of the helix, a characteristic ear anomaly.
    causal_link_type: DIRECT
phenotypes:
- name: Coronal Craniosynostosis
  description: >-
    Premature fusion of the coronal suture, typically bilateral, the defining
    cranial feature of Saethre-Chotzen syndrome.
  phenotype_term:
    preferred_term: Coronal craniosynostosis
    term:
      id: HP:0004440
      label: Coronal craniosynostosis
  evidence:
  - reference: PMID:16540516
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Known causes of coronal synostosis include haploinsufficiency of TWIST1 and
      a gain of function mutation in MSX2.
    explanation: >-
      Identifies TWIST1 haploinsufficiency as a cause of coronal synostosis.
- name: Ptosis
  description: Drooping of the upper eyelid, a hallmark facial feature of Saethre-Chotzen syndrome.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:8988167
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      facial dysmorphism including ptosis, facial asymmetry and prominent ear crura.
    explanation: Lists ptosis as a defining facial feature.
- name: Facial asymmetry
  description: Asymmetry of the face, a characteristic feature.
  phenotype_term:
    preferred_term: Facial asymmetry
    term:
      id: HP:0000324
      label: Facial asymmetry
  evidence:
  - reference: PMID:8988167
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      facial dysmorphism including ptosis, facial asymmetry and prominent ear crura.
    explanation: Lists facial asymmetry as a defining facial feature.
- name: Prominent ear crura
  description: Prominent crus of the helix, a characteristic ear anomaly.
  phenotype_term:
    preferred_term: Prominent crus of helix
    term:
      id: HP:0009899
      label: Prominent crus of helix
  evidence:
  - reference: PMID:8988167
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      facial dysmorphism including ptosis, facial asymmetry and prominent ear crura.
    explanation: Lists prominent ear crura as a defining ear feature.
- name: Low frontal hairline
  description: >-
    A low anterior (frontal) hairline is a classic feature of Saethre-Chotzen
    syndrome.
  phenotype_term:
    preferred_term: Low anterior hairline
    term:
      id: HP:0000294
      label: Low anterior hairline
- name: Brachydactyly
  description: Shortening of the digits, part of the limb anomaly spectrum.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:8988167
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is an autosomal dominant craniosynostosis with brachydactyly, soft tissue
      syndactyly and facial dysmorphism
    explanation: Lists brachydactyly as a limb feature.
- name: Cutaneous syndactyly
  description: Soft-tissue (cutaneous) fusion of the digits, characteristically of the second and third fingers.
  phenotype_term:
    preferred_term: Cutaneous finger syndactyly
    term:
      id: HP:0010554
      label: Cutaneous finger syndactyly
  evidence:
  - reference: PMID:8988167
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is an autosomal dominant craniosynostosis with brachydactyly, soft tissue
      syndactyly and facial dysmorphism
    explanation: Lists soft-tissue (cutaneous) syndactyly as a limb feature.
genetic:
- name: TWIST1 loss-of-function mutations
  association: Causative
  gene_term:
    preferred_term: TWIST1
    term:
      id: hgnc:12428
      label: TWIST1
  notes: >-
    Saethre-Chotzen syndrome results from TWIST1 haploinsufficiency due to
    nonsense, missense (bHLH domain), insertion/deletion, or whole-gene deletion
    variants.
  evidence:
  - reference: PMID:8988167
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report 21-bp insertions and nonsense mutations of the TWIST gene
      (S127X, E130X) in seven ACS III probands and describe impairment of head
      mesenchyme induction by TWIST as a novel pathophysiological mechanism in
      human craniosynostoses.
    explanation: >-
      Identifies loss-of-function TWIST1 mutations in Saethre-Chotzen (ACS III)
      probands as causative.
- name: EFNA4
  association: Modifier
  gene_term:
    preferred_term: EFNA4
    term:
      id: hgnc:3224
      label: EFNA4
  notes: >-
    Ephrin-A4 (EFNA4) acts downstream of TWIST1 in the coronal suture boundary;
    heterozygous EFNA4 mutations were identified in a subset of non-syndromic
    coronal synostosis, implicating the same TWIST1-EphA4 boundary pathway.
  evidence:
  - reference: PMID:16540516
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified heterozygous mutations in the human orthologue, EFNA4, in
      three of 81 patients with non-syndromic coronal synostosis.
    explanation: >-
      Implicates EFNA4, the effector of the TWIST1 osteogenic boundary, in coronal
      synostosis.
treatments:
- name: Cranial vault reconstruction
  description: >-
    Surgical expansion and remodelling of the cranial vault to relieve or prevent
    raised intracranial pressure and correct skull shape.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Ptosis repair
  description: >-
    Oculoplastic surgical correction of eyelid ptosis to protect vision and
    improve the visual axis.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure