Vascular Ehlers-Danlos Syndrome

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Inheritance

1

Autosomal dominant inheritance HP:0000006

Vascular EDS is autosomal dominant; about half of affected individuals have an affected parent and about half have a de novo COL3A1 pathogenic variant.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:20301667 SUPPORT Human Clinical

"Vascular EDS is an autosomal dominant disorder."

GeneReviews directly states autosomal dominant inheritance for vEDS.

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Pathophysiology

2

Type III collagen matrix fragility

COL3A1 variants disrupt type III collagen triple-helix formation, secretion, and extracellular-matrix deposition. Glycine substitutions destroy the triple-helical winding, so misfolded procollagen III is retained in the endoplasmic reticulum and secretion of functionally mature collagen III is impaired. The resulting collagen III matrix weakness compromises blood-vessel and hollow-organ tensile strength, leading to arterial dissection or rupture, intestinal perforation, uterine rupture, easy bruising, and thin translucent skin.

fibroblast CL:0000057

collagen fibril organization GO:0030199 ⚠ ABNORMAL extracellular matrix organization GO:0030198 ⚠ ABNORMAL

Downstream

Arterial and hollow-organ rupture Weak type III collagen matrix reduces tensile strength in arteries, bowel, uterus, and other organs, producing spontaneous or trauma-triggered dissection, rupture, and perforation.

Thin skin Defective type III collagen matrix contributes to thin translucent skin.

Easy bruising Perivascular connective-tissue fragility increases bruising susceptibility.

Prematurely aged appearance Dermal connective-tissue fragility produces acrogeric, prematurely aged facial and skin features.

Show evidence (3 references)

PMID:31409039 SUPPORT Other

"vEDS is caused by mutations in COL3A1 encoding collagen III that shows a predominant expression in blood vessels and hollow organs"

This review links COL3A1/type III collagen biology to vEDS target tissues.

PMID:31409039 SUPPORT Other

"Most disease-causing variants in COL3A1 are glycine substitutions that destroy the triple helical winding, thus altering the structural integrity of collagen III due to misfolded procollagen III in the ER, and thereby impairing the secretion and deposition into the ECM of functionally mature molecules"

This supports collagen triple-helix disruption, intracellular retention of misfolded procollagen III, and impaired secretion as core molecular mechanisms.

PMID:31409039 SUPPORT In Vitro

"dominant negative mutations in COL3A1 lead to the reduced secretion of collagen I into the ECM"

In cultured patient fibroblasts, the collagen III defect also reduces secretion of collagen I, consistent with the role of collagen III in assembling heterotypic collagen I-containing fibrils.

Arterial and hollow-organ rupture

Weak type III collagen matrix in arteries, bowel, uterus, and other organs produces spontaneous or minor-trauma vascular rupture, dissection, gastrointestinal perforation, and pregnancy-associated uterine rupture.

fibroblast CL:0000057

extracellular matrix organization GO:0030198 ⚠ ABNORMAL

Downstream

Arterial rupture Arterial wall fragility can culminate in spontaneous arterial rupture.

Arterial dissection Fragile arterial walls can separate along vessel-wall layers before or without rupture.

Intestinal perforation Hollow-organ fragility can produce gastrointestinal perforation.

Uterine rupture Gravid uterine connective-tissue fragility can result in pregnancy-associated uterine rupture.

Show evidence (3 references)

PMID:20301667 SUPPORT Human Clinical

"Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS."

This supports vascular and hollow-organ rupture as the main downstream consequence of type III collagen matrix fragility.

PMID:31409039 SUPPORT Other

"vascular EDS (vEDS, OMIM#130050) is the most severe type and is primarily characterized by life-threatening features of tissue fragility leading to arterial dissection or aneurysm, gastrointestinal ruptures, and pregnancy complications at a young age"

This mechanistic review connects tissue fragility with arterial, GI, and pregnancy complications.

PMID:31409039 SUPPORT Model Organism

"Col3a1 deficient mice show a reduced lifespan mainly due to arterial ruptures and abnormalities of collagen fibril organization in several collagen-rich organs, i.e., aorta, skin, lung, and bowel"

The Col3a1-deficient mouse recapitulates fatal arterial rupture and disordered collagen fibrils, giving cross-species support for the collagen III fragility mechanism.

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Pathograph

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Phenotypes

11

Blood 1

Easy bruising Bruising susceptibility HP:0000978

Show evidence (1 reference)

PMID:20301667 SUPPORT Human Clinical

"characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising"

GeneReviews lists easy bruising among core vEDS features.

Integument 3

Thin skin Thin skin HP:0000963

Show evidence (1 reference)

PMID:20301667 SUPPORT Human Clinical

"characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising"

GeneReviews lists thin translucent skin among core vEDS features.

Dermal translucency Dermal translucency HP:0010648

Show evidence (1 reference)

PMID:20301667 SUPPORT Human Clinical

"thin, translucent skin"

GeneReviews describes thin, translucent skin, the dermal translucency that renders the subcutaneous venous pattern visible in vEDS.

Prematurely aged appearance Prematurely aged appearance HP:0007495

Show evidence (1 reference)

ORPHA:286 SUPPORT Other

"HP:0007495 | Prematurely aged appearance | Very frequent (99-80%)"

Orphanet lists prematurely aged appearance as very frequent in vEDS.

Limbs 1

Clubfoot Talipes equinovarus HP:0001762

Show evidence (1 reference)

PMID:20301667 SUPPORT Human Clinical

"Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands."

GeneReviews identifies clubfoot as a neonatal presenting feature of vEDS.

Musculoskeletal 1

Small-joint hypermobility Joint hypermobility HP:0001382

Show evidence (1 reference)

PMID:20301667 SUPPORT Human Clinical

"distal joint hypermobility, easy bruising, thin skin, and clubfeet"

GeneReviews lists distal joint hypermobility among the minor diagnostic features of vEDS.

Other 5

Arterial rupture Arterial rupture HP:0025019

Show evidence (1 reference)

PMID:20301667 SUPPORT Human Clinical

"Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously."

GeneReviews directly supports arterial rupture/dissection in vEDS.

Arterial dissection Arterial dissection HP:0005294

Show evidence (1 reference)

PMID:20301667 SUPPORT Human Clinical

"Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously."

GeneReviews directly supports arterial dissection as part of the vEDS vascular phenotype.

Intestinal perforation Intestinal perforation HP:0031368

Show evidence (1 reference)

PMID:20301667 SUPPORT Human Clinical

"Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS."

This supports intestinal perforation as a key vEDS complication.

Uterine rupture Uterine rupture HP:0100718

Show evidence (1 reference)

PMID:20301667 SUPPORT Human Clinical

"Treatment may include medical or surgical management for arterial complications, bowel rupture, or uterine rupture during pregnancy."

GeneReviews directly identifies uterine rupture during pregnancy as a vEDS complication requiring emergency management.

Thin vermilion of the lips Thin vermilion border HP:0000233

Show evidence (1 reference)

PMID:20301667 SUPPORT Human Clinical

"characteristic facial appearance (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes)"

GeneReviews describes the characteristic vEDS facial appearance including thin vermilion of the lips.

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Genetic Associations

1

COL3A1 (Causal heterozygous pathogenic variants)

Gene: COL3A1 hgnc:2201

Show evidence (3 references)

PMID:20301667 SUPPORT Human Clinical

"The diagnosis of vEDS is established in a proband by identification of a heterozygous pathogenic variant in COL3A1."

GeneReviews directly links vEDS diagnosis to a heterozygous COL3A1 pathogenic variant.

PMID:25758994 SUPPORT Human Clinical

"Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe autosomal dominant disorder caused by variants at the COL3A1 gene."

This molecularly proven cohort supports the COL3A1 gene-disease relationship and inheritance pattern.

PMID:25758994 SUPPORT Human Clinical

"This study also confirms that patients with variants located in the C- and N-termini or leading to haplo-insufficiency have milder course of the disease and less prevalent diagnostic criteria."

This molecular cohort shows that COL3A1 haploinsufficiency and terminal non-glycine variants confer a milder course, supporting the variant-class severity gradient noted above.

💊

Medical Actions

2

Vascular surveillance and emergency planning

Action: supportive care MAXO:0000950

Management centers on specialized multidisciplinary care, emergency documentation, periodic arterial imaging, blood pressure monitoring, and avoidance of high-risk trauma or invasive procedures when possible.

Show evidence (2 references)

PMID:20301667 SUPPORT Human Clinical

"Surveillance: May include periodic arterial screening by ultrasound examination, magnetic resonance angiogram, or computed tomography angiogram with and without venous contrast."

GeneReviews supports periodic arterial screening as part of vEDS surveillance.

PMID:20301667 SUPPORT Human Clinical

"arteriography should be discouraged and used only to identify life-threatening sources of bleeding prior to surgical intervention because of the risk of vascular injury"

This supports avoidance of high-risk invasive vascular procedures.

Celiprolol-centered medical care

Action: Pharmacotherapy NCIT:C15986

Agent: celiprolol NCIT:C79558

Celiprolol, a beta-1-adrenoceptor antagonist with beta-2-agonist action, has randomized-trial and observational support for lowering arterial event or mortality risk in vEDS, but risk is not eliminated and evidence remains limited by small trials and observational cohorts.

Show evidence (2 references)

PMID:20825986 SUPPORT Human Clinical

"The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls"

This pivotal randomized trial shows celiprolol reduces arterial events (rupture or dissection) in vEDS from 50% in controls to 20%.

PMID:30999998 SUPPORT Human Clinical

"Patients treated with celiprolol had a better survival than others (p = 0.0004)."

Long-term observational evidence supports celiprolol-associated survival benefit in molecularly confirmed vEDS.

{ }

Source YAML

click to show

name: Vascular Ehlers-Danlos Syndrome
category: Mendelian
creation_date: "2026-06-13T00:00:00Z"
description: >
  Vascular Ehlers-Danlos syndrome is a COL3A1-related Ehlers-Danlos subtype
  caused by heterozygous pathogenic variants affecting type III collagen. It is
  distinguished by arterial, intestinal, uterine, and other hollow-organ
  fragility, thin translucent skin, easy bruising, and risk for arterial
  dissection or rupture at young ages. Variant class influences severity, with
  dominant-negative glycine substitutions and splice or in-frame variants
  generally more severe than COL3A1 haploinsufficiency.
disease_term:
  preferred_term: Ehlers-Danlos syndrome, vascular type
  term:
    id: MONDO:0017314
    label: Ehlers-Danlos syndrome, vascular type
synonyms:
- vEDS
- vascular EDS
- Ehlers-Danlos syndrome type IV
- EDS type IV
parents:
- Ehlers-Danlos Syndrome
- Connective Tissue Disorder
references:
- reference: PMID:20301667
  title: "Vascular Ehlers-Danlos Syndrome."
  tags:
  - GeneReviews
  findings:
  - statement: Vascular EDS is caused by heterozygous COL3A1 pathogenic variants.
  - statement: Vascular EDS causes arterial, intestinal, and uterine fragility.
  - statement: >
      Neonates may present with clubfoot, hip dislocation, or limb deficiency,
      and distal joint hypermobility, easy bruising, thin skin, and clubfeet are
      recognized minor diagnostic features in children without a major complication.
  - statement: >
      Characteristic facial features include thin vermilion of the lips, narrow
      nose, and prominent eyes.
- reference: PMID:25758994
  title: "The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome."
  findings:
  - statement: COL3A1 variant type influences vEDS phenotype and severity.
  - statement: >
      Across 215 molecularly proven patients the median age at first complication
      was 29 years, with arterial (48%) and digestive (24%) ruptures the most
      frequent events.
  - statement: >
      Glycine substitutions and splice/in-frame variants are significantly more
      severe than haploinsufficiency and terminal non-glycine missense variants,
      which have a milder course and lack digestive events.
- reference: PMID:31409039
  title: "Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers-Danlos Syndromes."
  findings:
  - statement: COL3A1 mutations impair collagen III folding, secretion, and ECM deposition in vEDS.
  - statement: >
      Glycine substitutions destroy the triple-helical winding, causing misfolded
      procollagen III retention in the endoplasmic reticulum and impaired secretion
      of functionally mature collagen III.
  - statement: >
      Dominant-negative COL3A1 variants also reduce secretion of collagen I into
      the ECM, and Col3a1-deficient mice have a reduced lifespan due to arterial
      rupture.
- reference: PMID:30999998
  title: "Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study."
  findings:
  - statement: Long-term observational evidence supports structured care and celiprolol-associated survival benefit.
  - statement: >
      The mortality reduction associated with celiprolol was dose-dependent, with
      the best protection observed at 400 mg/day.
- reference: PMID:20825986
  title: "Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial."
  findings:
  - statement: >
      In the pivotal randomized trial, celiprolol reduced the arterial-event
      endpoint (rupture or dissection) from 50% in controls to 20%, with a hazard
      ratio of 0.36.
inheritance:
- name: Autosomal dominant inheritance
  description: >
    Vascular EDS is autosomal dominant; about half of affected individuals have
    an affected parent and about half have a de novo COL3A1 pathogenic variant.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vascular EDS is an autosomal dominant disorder."
    explanation: GeneReviews directly states autosomal dominant inheritance for vEDS.
progression:
- phase: Childhood major complications in early-presenting cases
  age_range: Childhood
  notes: >
    Children without a known family history may present with a major vEDS
    complication, with reported average age around 11 years in the GeneReviews
    summary.
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years."
    explanation: >
      GeneReviews supports early major complications in children who are not
      identified through family-history screening.
- phase: Adult vascular or hollow-organ events
  age_range: Young to middle adulthood
  notes: >
    Vascular dissection or rupture, gastrointestinal perforation, and organ
    rupture are typical adult presenting events. Molecular cohort data show a
    median first complication around age 29 years, with severity varying by
    COL3A1 variant class.
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS."
    explanation: >
      GeneReviews supports the characteristic adult event pattern.
  - reference: PMID:25758994
    reference_title: "The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "median age at first complication of 29 years (IQR 22-39)"
    explanation: >
      This molecular cohort quantifies age at first complication and shows
      variant-class effects on severity.
genetic:
- name: COL3A1
  association: Causal heterozygous pathogenic variants
  presence: Positive
  gene_term:
    preferred_term: COL3A1
    term:
      id: hgnc:2201
      label: COL3A1
  notes: >
    COL3A1 encodes type III collagen, a fibrillar collagen enriched in blood
    vessels and hollow organs. Pathogenic variants include dominant-negative
    glycine substitutions, splice or in-frame variants, and haploinsufficiency
    alleles with different average severities.
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of vEDS is established in a proband by identification of a heterozygous pathogenic variant in COL3A1."
    explanation: GeneReviews directly links vEDS diagnosis to a heterozygous COL3A1 pathogenic variant.
  - reference: PMID:25758994
    reference_title: "The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe autosomal dominant disorder caused by variants at the COL3A1 gene."
    explanation: This molecularly proven cohort supports the COL3A1 gene-disease relationship and inheritance pattern.
  - reference: PMID:25758994
    reference_title: "The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study also confirms that patients with variants located in the C- and N-termini or leading to haplo-insufficiency have milder course of the disease and less prevalent diagnostic criteria."
    explanation: >
      This molecular cohort shows that COL3A1 haploinsufficiency and terminal
      non-glycine variants confer a milder course, supporting the variant-class
      severity gradient noted above.
pathophysiology:
- name: Type III collagen matrix fragility
  conforms_to: "aortopathy_tgfbeta_dysregulation#Aortic Wall ECM or Contractile Apparatus Defect"
  description: >
    COL3A1 variants disrupt type III collagen triple-helix formation, secretion,
    and extracellular-matrix deposition. Glycine substitutions destroy the
    triple-helical winding, so misfolded procollagen III is retained in the
    endoplasmic reticulum and secretion of functionally mature collagen III is
    impaired. The resulting collagen III matrix weakness compromises blood-vessel
    and hollow-organ tensile strength, leading to arterial dissection or rupture,
    intestinal perforation, uterine rupture, easy bruising, and thin translucent
    skin.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: collagen fibril organization
    modifier: ABNORMAL
    term:
      id: GO:0030199
      label: collagen fibril organization
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:31409039
    reference_title: "Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers-Danlos Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "vEDS is caused by mutations in COL3A1 encoding collagen III that shows a predominant expression in blood vessels and hollow organs"
    explanation: This review links COL3A1/type III collagen biology to vEDS target tissues.
  - reference: PMID:31409039
    reference_title: "Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers-Danlos Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most disease-causing variants in COL3A1 are glycine substitutions that destroy the triple helical winding, thus altering the structural integrity of collagen III due to misfolded procollagen III in the ER, and thereby impairing the secretion and deposition into the ECM of functionally mature molecules"
    explanation: >
      This supports collagen triple-helix disruption, intracellular retention of
      misfolded procollagen III, and impaired secretion as core molecular
      mechanisms.
  - reference: PMID:31409039
    reference_title: "Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers-Danlos Syndromes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "dominant negative mutations in COL3A1 lead to the reduced secretion of collagen I into the ECM"
    explanation: >
      In cultured patient fibroblasts, the collagen III defect also reduces
      secretion of collagen I, consistent with the role of collagen III in
      assembling heterotypic collagen I-containing fibrils.
  downstream:
  - target: Arterial and hollow-organ rupture
    description: >
      Weak type III collagen matrix reduces tensile strength in arteries,
      bowel, uterus, and other organs, producing spontaneous or trauma-triggered
      dissection, rupture, and perforation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301667
      reference_title: "Vascular Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS."
      explanation: GeneReviews identifies vascular and hollow-organ rupture as typical adult presenting complications.
  - target: Thin skin
    description: Defective type III collagen matrix contributes to thin translucent skin.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301667
      reference_title: "Vascular Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising"
      explanation: GeneReviews links the connective-tissue fragility syndrome to thin translucent skin.
  - target: Easy bruising
    description: Perivascular connective-tissue fragility increases bruising susceptibility.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301667
      reference_title: "Vascular Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising"
      explanation: GeneReviews links vEDS tissue fragility to easy bruising.
  - target: Prematurely aged appearance
    description: Dermal connective-tissue fragility produces acrogeric, prematurely aged facial and skin features.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:286
      reference_title: "Vascular Ehlers-Danlos syndrome (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0007495 | Prematurely aged appearance | Very frequent (99-80%)"
      explanation: Orphanet records prematurely aged appearance as a very frequent vEDS phenotype.
- name: Arterial and hollow-organ rupture
  conforms_to: "aortopathy_tgfbeta_dysregulation#Aortic Dissection and Rupture"
  description: >
    Weak type III collagen matrix in arteries, bowel, uterus, and other organs
    produces spontaneous or minor-trauma vascular rupture, dissection,
    gastrointestinal perforation, and pregnancy-associated uterine rupture.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS."
    explanation: >
      This supports vascular and hollow-organ rupture as the main downstream
      consequence of type III collagen matrix fragility.
  - reference: PMID:31409039
    reference_title: "Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers-Danlos Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "vascular EDS (vEDS, OMIM#130050) is the most severe type and is primarily characterized by life-threatening features of tissue fragility leading to arterial dissection or aneurysm, gastrointestinal ruptures, and pregnancy complications at a young age"
    explanation: >
      This mechanistic review connects tissue fragility with arterial, GI, and
      pregnancy complications.
  - reference: PMID:31409039
    reference_title: "Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers-Danlos Syndromes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Col3a1 deficient mice show a reduced lifespan mainly due to arterial ruptures and abnormalities of collagen fibril organization in several collagen-rich organs, i.e., aorta, skin, lung, and bowel"
    explanation: >
      The Col3a1-deficient mouse recapitulates fatal arterial rupture and
      disordered collagen fibrils, giving cross-species support for the
      collagen III fragility mechanism.
  downstream:
  - target: Arterial rupture
    description: Arterial wall fragility can culminate in spontaneous arterial rupture.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301667
      reference_title: "Vascular Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously."
      explanation: GeneReviews directly supports arterial rupture as a vEDS outcome.
  - target: Arterial dissection
    description: Fragile arterial walls can separate along vessel-wall layers before or without rupture.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301667
      reference_title: "Vascular Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously."
      explanation: GeneReviews identifies arterial dissection as part of the vascular complication pathway.
  - target: Intestinal perforation
    description: Hollow-organ fragility can produce gastrointestinal perforation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301667
      reference_title: "Vascular Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS."
      explanation: GeneReviews directly supports gastrointestinal perforation as a vEDS outcome.
  - target: Uterine rupture
    description: Gravid uterine connective-tissue fragility can result in pregnancy-associated uterine rupture.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301667
      reference_title: "Vascular Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Treatment may include medical or surgical management for arterial complications, bowel rupture, or uterine rupture during pregnancy."
      explanation: GeneReviews supports uterine rupture during pregnancy as a vEDS complication.
phenotypes:
- name: Arterial rupture
  description: Arterial rupture or dissection is a hallmark and life-threatening vEDS manifestation.
  phenotype_term:
    preferred_term: Arterial rupture
    term:
      id: HP:0025019
      label: Arterial rupture
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously."
    explanation: GeneReviews directly supports arterial rupture/dissection in vEDS.
- name: Arterial dissection
  description: Arterial dissection is a major vascular fragility manifestation in vEDS.
  phenotype_term:
    preferred_term: Arterial dissection
    term:
      id: HP:0005294
      label: Arterial dissection
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously."
    explanation: GeneReviews directly supports arterial dissection as part of the vEDS vascular phenotype.
- name: Intestinal perforation
  description: Gastrointestinal perforation is part of the hollow-organ fragility phenotype.
  phenotype_term:
    preferred_term: Intestinal perforation
    term:
      id: HP:0031368
      label: Intestinal perforation
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS."
    explanation: This supports intestinal perforation as a key vEDS complication.
- name: Uterine rupture
  description: >
    Uterine rupture during pregnancy is a life-threatening hollow-organ
    complication in affected women.
  phenotype_term:
    preferred_term: Uterine rupture
    term:
      id: HP:0100718
      label: Uterine rupture
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment may include medical or surgical management for arterial complications, bowel rupture, or uterine rupture during pregnancy."
    explanation: >
      GeneReviews directly identifies uterine rupture during pregnancy as a
      vEDS complication requiring emergency management.
- name: Thin skin
  description: Thin translucent skin is a characteristic connective-tissue feature.
  phenotype_term:
    preferred_term: Thin skin
    term:
      id: HP:0000963
      label: Thin skin
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising"
    explanation: GeneReviews lists thin translucent skin among core vEDS features.
- name: Dermal translucency
  description: >
    Thin translucent skin with a visible subcutaneous venous pattern is a
    characteristic vEDS feature.
  phenotype_term:
    preferred_term: Dermal translucency
    term:
      id: HP:0010648
      label: Dermal translucency
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thin, translucent skin"
    explanation: >
      GeneReviews describes thin, translucent skin, the dermal translucency
      that renders the subcutaneous venous pattern visible in vEDS.
- name: Easy bruising
  description: Easy bruising reflects perivascular connective-tissue fragility.
  phenotype_term:
    preferred_term: Easy bruising
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising"
    explanation: GeneReviews lists easy bruising among core vEDS features.
- name: Prematurely aged appearance
  description: Acrogeric, prematurely aged appearance is a frequent vEDS connective-tissue feature.
  phenotype_term:
    preferred_term: Acrogeric appearance
    term:
      id: HP:0007495
      label: Prematurely aged appearance
  evidence:
  - reference: ORPHA:286
    reference_title: "Vascular Ehlers-Danlos syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007495 | Prematurely aged appearance | Very frequent (99-80%)"
    explanation: Orphanet lists prematurely aged appearance as very frequent in vEDS.
- name: Small-joint hypermobility
  description: >
    Distal, small-joint hypermobility is a recognized minor diagnostic feature,
    particularly in children ascertained without a major complication.
  phenotype_term:
    preferred_term: Small-joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "distal joint hypermobility, easy bruising, thin skin, and clubfeet"
    explanation: GeneReviews lists distal joint hypermobility among the minor diagnostic features of vEDS.
- name: Clubfoot
  description: >
    Congenital talipes equinovarus (clubfoot) is a neonatal presenting feature
    and a recognized minor diagnostic criterion in vEDS.
  phenotype_term:
    preferred_term: Clubfoot
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands."
    explanation: GeneReviews identifies clubfoot as a neonatal presenting feature of vEDS.
- name: Thin vermilion of the lips
  description: >
    A characteristic facial appearance with thin lips (thin vermilion), a narrow
    nose, and prominent eyes is typical of vEDS.
  phenotype_term:
    preferred_term: Thin vermilion border
    term:
      id: HP:0000233
      label: Thin vermilion border
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic facial appearance (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes)"
    explanation: GeneReviews describes the characteristic vEDS facial appearance including thin vermilion of the lips.
treatments:
- name: Vascular surveillance and emergency planning
  description: >
    Management centers on specialized multidisciplinary care, emergency
    documentation, periodic arterial imaging, blood pressure monitoring, and
    avoidance of high-risk trauma or invasive procedures when possible.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surveillance: May include periodic arterial screening by ultrasound examination, magnetic resonance angiogram, or computed tomography angiogram with and without venous contrast."
    explanation: GeneReviews supports periodic arterial screening as part of vEDS surveillance.
  - reference: PMID:20301667
    reference_title: "Vascular Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "arteriography should be discouraged and used only to identify life-threatening sources of bleeding prior to surgical intervention because of the risk of vascular injury"
    explanation: This supports avoidance of high-risk invasive vascular procedures.
- name: Celiprolol-centered medical care
  description: >
    Celiprolol, a beta-1-adrenoceptor antagonist with beta-2-agonist action, has
    randomized-trial and observational support for lowering arterial event or
    mortality risk in vEDS, but risk is not eliminated and evidence remains
    limited by small trials and observational cohorts.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: celiprolol
      term:
        id: NCIT:C79558
        label: Celiprolol
  evidence:
  - reference: PMID:20825986
    reference_title: "Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls"
    explanation: >
      This pivotal randomized trial shows celiprolol reduces arterial events
      (rupture or dissection) in vEDS from 50% in controls to 20%.
  - reference: PMID:30999998
    reference_title: "Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients treated with celiprolol had a better survival than others (p = 0.0004)."
    explanation: Long-term observational evidence supports celiprolol-associated survival benefit in molecularly confirmed vEDS.

📚

References & Deep Research

References

5

PMID:20301667

Vascular Ehlers-Danlos Syndrome.

4 findings

Vascular EDS is caused by heterozygous COL3A1 pathogenic variants.

Vascular EDS causes arterial, intestinal, and uterine fragility.

Neonates may present with clubfoot, hip dislocation, or limb deficiency, and distal joint hypermobility, easy bruising, thin skin, and clubfeet are recognized minor diagnostic features in children without a major complication.

Characteristic facial features include thin vermilion of the lips, narrow nose, and prominent eyes.

PMID:25758994

The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome.

3 findings

COL3A1 variant type influences vEDS phenotype and severity.

Across 215 molecularly proven patients the median age at first complication was 29 years, with arterial (48%) and digestive (24%) ruptures the most frequent events.

Glycine substitutions and splice/in-frame variants are significantly more severe than haploinsufficiency and terminal non-glycine missense variants, which have a milder course and lack digestive events.

PMID:31409039

Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers-Danlos Syndromes.

3 findings

COL3A1 mutations impair collagen III folding, secretion, and ECM deposition in vEDS.

Glycine substitutions destroy the triple-helical winding, causing misfolded procollagen III retention in the endoplasmic reticulum and impaired secretion of functionally mature collagen III.

Dominant-negative COL3A1 variants also reduce secretion of collagen I into the ECM, and Col3a1-deficient mice have a reduced lifespan due to arterial rupture.

PMID:30999998

Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study.

2 findings

Long-term observational evidence supports structured care and celiprolol-associated survival benefit.

The mortality reduction associated with celiprolol was dose-dependent, with the best protection observed at 400 mg/day.

PMID:20825986

Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial.

1 finding

In the pivotal randomized trial, celiprolol reduced the arterial-event endpoint (rupture or dissection) from 50% in controls to 20%, with a hazard ratio of 0.36.

Deep Research

1

Falcon ▸

Question: You are an expert researcher providing comprehensive, well-cited information.

Edison Scientific Literature 54 citations 2026-06-13T17:24:03.143793

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Prepare a focused, citation-rich deep research report for a dismech Disease entry called 'Vascular Ehlers-Danlos Syndrome'. Research objectives: define disease boundary and synonyms; summarize COL3A1/type III collagen genetics, autosomal dominant inheritance, dominant-negative versus haploinsufficiency genotype-phenotype differences, vascular wall and hollow-organ fragility mechanisms, fibroblast/collagen fibrillogenesis evidence, key phenotypes including arterial rupture/dissection, thin translucent skin, easy bruising, intestinal and uterine rupture, pneumothorax or pulmonary manifestations where relevant; summarize surveillance and treatment evidence including celiprolol, beta-blocker/ARB observational evidence, avoidance of invasive procedures, and emergency care; identify MONDO, HPO, HGNC, GO, and MAXO terms suitable for dismech YAML; include primary literature, GeneReviews, and authoritative reviews with PMID identifiers; flag evidence limitations and model-system caveats. Do not invent citations; provide exact PMID identifiers for key claims and prefer PubMed-indexed sources.

Vascular Ehlers–Danlos Syndrome (vEDS) — Deep Research Report (dismech Disease Entry)

Executive summary

Vascular Ehlers–Danlos syndrome (vEDS; “EDS type IV”) is a monogenic connective-tissue disorder defined by generalized tissue fragility with disproportionate risk of arterial dissection/aneurysm/rupture and hollow-organ rupture (especially sigmoid colon and gravid uterus), plus characteristic external clues such as thin translucent skin and easy bruising. Diagnosis is established by identifying a heterozygous pathogenic/likely pathogenic variant in COL3A1 (type III procollagen). Contemporary management emphasizes (i) avoidance of high-risk invasive procedures, (ii) structured vascular surveillance, and (iii) rapid emergency evaluation for sudden pain suggestive of dissection/rupture. Drug-prevention evidence is dominated by celiprolol (trial-era data plus heterogeneous real-world cohorts), while observational cohorts suggest possible benefit of beta-blocker and/or ARB therapy; overall evidence remains limited by small samples, retrospective designs, and variant heterogeneity. (byers2025vascularehlersdanlossyndrome pages 1-3, bowen2023diagnosisandmanagement pages 8-11, buso2024currentevidenceand pages 1-2)

1) Key concepts, disease boundary, and synonyms (current understanding)

Disease definition / boundary

GeneReviews defines vEDS as a disorder marked by arterial, intestinal, and/or uterine fragility, thin translucent skin, easy bruising, characteristic facial features, and acrogeric/aged-appearing extremities. Diagnosis is molecular: a heterozygous COL3A1 pathogenic variant establishes the diagnosis. (byers2025vascularehlersdanlossyndrome pages 1-3)

Key boundary points that separate vEDS from other EDS types in practice: - vEDS is dominated by vascular and hollow-organ catastrophes rather than generalized large-joint hypermobility (which can be mild or absent). (pepin2014survivalisaffected pages 1-2, bowen2023diagnosisandmanagement pages 1-2) - Confirmatory genetic testing is considered necessary to distinguish vEDS from overlapping presentations in other heritable aortopathies/fragility syndromes. (bowen2023diagnosisandmanagement pages 1-2, byers2025vascularehlersdanlossyndrome pages 1-3)

Synonyms (for dismech normalization)

“Vascular Ehlers–Danlos syndrome” (vEDS) (byers2025vascularehlersdanlossyndrome pages 1-3)
“Ehlers–Danlos syndrome type IV” / “EDS type IV” (schwarze2001haploinsufficiencyforone pages 1-2, pepin2014survivalisaffected pages 1-2)
“Vascular-type EDS” / “vascular EDS” (ishikawa2023clinicalfeaturesand pages 1-2)

Core identifiers available from retrieved sources

OMIM: vEDS / EDS type IV = OMIM 130050 (schwarze2001haploinsufficiencyforone pages 1-2, byers2025vascularehlersdanlossyndrome pages 1-3)
PMID (explicitly present in retrieved text): GeneReviews is cited with PMID: 20301667 (foehr2025vascularehlersdanlossyndrome pages 3-4)

Limitation: MONDO, HGNC, HPO, GO, and MAXO numeric identifiers were not present in the retrieved texts and therefore cannot be reported “exactly” here without external ontology lookup; terms are provided with “needs lookup” flags below. (byers2025vascularehlersdanlossyndrome pages 1-3)

2) COL3A1 / type III collagen genetics (inheritance, dominant-negative vs haploinsufficiency)

COL3A1 biology and why it matters

Type III collagen is a fibrillar collagen enriched in blood-vessel walls and hollow organs, consistent with the tissue distribution of fragility in vEDS. (omar2021fourdecadesin pages 2-4, chiarelli2018transcriptomeanalysisof pages 1-2)

Inheritance and de novo rate

vEDS is autosomal dominant, and approximately half of affected individuals may lack an apparent family history, consistent with de novo pathogenic variants being common. (byers2025vascularehlersdanlossyndrome pages 1-3, schwarze2001haploinsufficiencyforone pages 1-2)

Variant classes and molecular mechanisms

Two broad, clinically useful mechanisms are consistently described:

1) Dominant-negative (DN) mechanisms (typical for glycine substitutions and many splice variants) - Collagen III is a homotrimer; with equal mutant and wild-type chain production, 7/8 of trimers are expected to be abnormal (dominant-negative burden), a classic explanation for severity. (omar2021fourdecadesin pages 4-5) - Dominant-negative variants disrupt triple helix folding, causing misfolding in the endoplasmic reticulum (ER) and retention of misfolded procollagen trimers (described as retention of “seven eighths” of misfolded trimers), consistent with ER stress phenotypes. (chiarelli2018transcriptomeanalysisof pages 1-2) - In a large adult cohort, 80.6% of variants were classified as DN by predicted functional consequence. (adham2022assessmentofarterial pages 1-2)

2) Haploinsufficiency (HI) / loss-of-function mechanisms - Frameshift and some nonsense variants can produce premature termination codons, triggering nonsense-mediated mRNA decay (NMD) and functional haploinsufficiency. (schwarze2001haploinsufficiencyforone pages 1-2) - A terminal-exon nonsense mutation can yield stable mRNA but a truncated chain that does not incorporate into mature procollagen, still producing reduced functional collagen III. (schwarze2001haploinsufficiencyforone pages 1-2) - In the Adham 2022 cohort, 19.4% of variants were classified as HI. (adham2022assessmentofarterial pages 1-2)

Genotype–phenotype: DN vs HI and other correlations

Across cohorts and reviews, DN variants correlate with earlier/more severe disease, while HI (null) variants trend milder with later onset: - Adham 2022: DN variants associated with earlier onset/more severe course and higher prevalence of medium-sized artery lesions, especially supra-aortic trunks and renal arteries. (adham2022assessmentofarterial pages 1-2) - Omar 2021: null variants (~5%) yield ~50% collagen III and are described as milder, with older median age at diagnosis (~46 years in the excerpted review), whereas in-frame exon-skipping splice variants are associated with earlier onset and severe outcomes; glycine substitutions are more severe when glycine is replaced by bulky/charged residues. (omar2021fourdecadesin pages 4-5, omar2021fourdecadesin pages 2-4) - Buso 2024 (Vascular Medicine cohort summary) states HI is linked to a milder phenotype with almost two-decade delayed onset. (buso2024despiteceliprololtherapy pages 1-2)

Natural history varies by mutation type and sex in a very large assembled cohort (1,231 individuals), with median survival 51 years and survival influenced by gender and mutation type. (pepin2014survivalisaffected pages 1-2)

3) Mechanisms of vascular wall and hollow-organ fragility

Vascular and hollow-organ fragility as a type III collagen disorder

At the tissue level, the dominant clinical problem is mechanical failure (dissection/rupture/perforation) in collagen III–rich tissues including arteries and bowel/uterus. (byers2025vascularehlersdanlossyndrome pages 1-3, ishikawa2023clinicalfeaturesand pages 1-2)

Fibroblast / ECM evidence (fibrillogenesis and matrix remodeling)

Patient-derived dermal fibroblasts (dominant-negative COL3A1) show coordinated disturbances that extend beyond type III collagen itself: - Transcriptome profiling highlights changes in pathways involving ER homeostasis, collagen folding, and ECM organization. (chiarelli2018transcriptomeanalysisof pages 1-2) - Protein-level changes include disassembly/reduction of multiple ECM constituents (e.g., fibrillins, EMILINs, elastin) and proteoglycans (perlecan, decorin, versican) important for vascular integrity, consistent with secondary ECM destabilization. (chiarelli2018transcriptomeanalysisof pages 1-2)

Ultrastructural fibrillogenesis evidence (human tissue)

In a 2023 electron microscopy study of skin samples, collagen fibrils in vEDS showed significantly increased irregularity of fibril size versus controls, supporting disturbed fibrillogenesis at the tissue-architecture level; variability between patients was noted, and ER stress was proposed as a contributor to phenotypic variability (e.g., via effects on fibril-associated proteins such as COMP). (ishikawa2023clinicalfeaturesand pages 1-2)

Model systems and caveats (mouse models)

Animal models support a causal role of collagen III deficiency/mutation in vascular catastrophe, but also illustrate translation limitations: - Homozygous Col3a1 knockout: severe perinatal mortality and catastrophic vessel/intestinal rupture; this extreme phenotype is not typical of most human vEDS (where complete absence of collagen III is rare). (vroman2021animalmodelsof pages 13-14) - Heterozygous haploinsufficient models: may appear grossly normal early but show age-dependent aortic pathology and reduced wall strength; sex effects (male bias) are reported. (vroman2021animalmodelsof pages 13-14) - In-frame deletion or glycine-substitution models: can show sudden aortic dissection/rupture with incomplete penetrance; some models lack prominent skin/GI defects, i.e., partial phenocopy. (vroman2021animalmodelsof pages 13-14, omar2021fourdecadesin pages 5-6) - Overexpression transgenic models may introduce artifacts due to supra-physiological collagen III levels. (omar2021fourdecadesin pages 5-6)

Interpretation caveat: vEDS is strongly variant-class dependent; model selection should match the human mutation mechanism (DN vs HI) and consider penetrance/sex differences. (omar2021fourdecadesin pages 13-14, omar2021fourdecadesin pages 5-6)

4) Phenotypes and recent quantitative data (prioritizing 2023–2024)

Hallmark phenotypes (clinical spectrum)

Core phenotypes across authoritative sources include: - Arterial: aneurysm, arteriovenous fistulae, dissection, spontaneous rupture (byers2025vascularehlersdanlossyndrome pages 1-3) - Skin/soft tissue: thin translucent skin, easy bruising, acrogeria/aged extremities, facial features; small-joint hypermobility may occur (byers2025vascularehlersdanlossyndrome pages 1-3, adham2022assessmentofarterial pages 1-2) - Hollow organ: sigmoid colon rupture/perforation; uterine rupture in pregnancy (byers2025vascularehlersdanlossyndrome pages 1-3) - Pulmonary/pleural: spontaneous/recurrent pneumothorax; hemothorax/hemopneumothorax; hemoptysis is reported (byers2025vascularehlersdanlossyndrome pages 1-3) - Other suggestive vascular presentations: carotid–cavernous sinus fistula (byers2025vascularehlersdanlossyndrome pages 5-7)

Recent quantitative complication rates (2023 systematic review)

A 2023 systematic review of extracutaneous features across EDS subtypes reported for vEDS: - Cerebrovascular events: 25/153 (16.3%) (doolan2023extracutaneousfeaturesand pages 1-2) - Aneurysm: 77/245 (31.4%) (doolan2023extracutaneousfeaturesand pages 1-2) - Arterial dissection/rupture: 89/250 (35.5%) (doolan2023extracutaneousfeaturesand pages 1-2) - “Pneumothorax/hemothorax” and bowel perforation were described as almost entirely exclusive to vEDS; mean age at first pneumothorax/hemothorax 25.6 ± 9.0 years and mean age at first bowel perforation 26.6 ± 10.9 years (doolan2023extracutaneousfeaturesand pages 3-4)

Interpretation caveat: denominators vary by complication, implying heterogeneous reporting rather than a single prospective cohort frequency. (doolan2023extracutaneousfeaturesand pages 1-2)

GeneReviews quantitative features (selected)

GI perforation: ~15% of individuals with COL3A1 pathogenic variants; seldom seen with null variants. (byers2025vascularehlersdanlossyndrome pages 5-7)
Carotid–cavernous sinus fistula: as many as ~10% (female preponderance). (byers2025vascularehlersdanlossyndrome pages 5-7)
Arterial rupture location distribution: thorax/abdomen 66%, head/neck 17%, extremities 17%. (byers2025vascularehlersdanlossyndrome pages 5-7)
Pregnancy risk: ~5% maternal mortality per pregnancy. (byers2025vascularehlersdanlossyndrome pages 1-3)

Natural history statistics from recent cohorts/reviews

A 2024 prevention-focused review summarizes: historical median survival ~50 years; arterial complication rate ~1.3 events per 5 years; overall organ complication rate ~1.6 events per 5 years; up to 85% have major complications by age 43. (buso2024currentevidenceand pages 1-2)
A 2023 EM-based clinical series states most patients have a first major complication in early 20s and >80% have ≥1 complication by age 40, with mean life expectancy ~48 years. (ishikawa2023clinicalfeaturesand pages 1-2)

5) Current applications and real-world implementations (surveillance, avoidance, emergency care)

Surveillance strategies

GeneReviews recommends periodic arterial imaging (ultrasound, MRA, CTA with/without venous contrast) and regular blood pressure monitoring. (byers2025vascularehlersdanlossyndrome pages 1-3)

A UK national service describes a concrete, implementable protocol: - Annual MRA from thoracic/abdominal aorta through cervical vessels (including circle of Willis) down to pelvis/upper legs; CTA used sparingly, targeted to MRA abnormalities. (bowen2023diagnosisandmanagement pages 8-11)

A key evidence gap: the direct mortality benefit of surveillance intervals is uncertain; practice varies by center and genotype (e.g., shorter intervals for DN variants are suggested in a vascular-surgery perspective piece). (schonherr2024diagnosisofvascular pages 2-3)

Avoidance of invasive procedures and procedure planning

GeneReviews and specialty cohorts emphasize avoiding or limiting: - Arteriography except for life-threatening bleeding (byers2025vascularehlersdanlossyndrome pages 1-3) - Routine colonoscopy without symptoms/indication (byers2025vascularehlersdanlossyndrome pages 1-3) - Elective surgery when benefit is limited (byers2025vascularehlersdanlossyndrome pages 1-3)

The UK service operationalizes this with bowel-specific practice: - Colonoscopy is avoided where possible given perforation risk; after perforation, total colectomy with ileostomy may be considered to reduce re-perforation, and colostomies are often not reversed. (bowen2023diagnosisandmanagement pages 8-11)

Emergency care implementation

GeneReviews stresses practical emergency readiness: carry documentation of the genetic diagnosis and seek prompt evaluation for sudden unexplained pain (a potential sentinel symptom of dissection/rupture). (byers2025vascularehlersdanlossyndrome pages 1-3) The UK service uses emergency information cards and electronic record alerts to mitigate delays/mismanagement in emergency departments. (bowen2023diagnosisandmanagement pages 8-11)

6) Treatment and prevention evidence (celiprolol; beta-blockers/ARBs)

Celiprolol

A 2024 narrative review summarizes the BBEST trial signal as a 64% reduction in risk of arterial rupture/dissection with celiprolol versus controls, while noting the overall evidence base remains limited. (buso2024currentevidenceand pages 1-2)
Real-world Italian referral-center experience (2011–2023): 26 genetically confirmed patients, all on celiprolol at last follow-up (80% at 400 mg/day), yet yearly symptomatic vascular event risk was 8.8%, with most events occurring after reaching maximum dose—highlighting substantial residual risk despite therapy. (buso2024despiteceliprololtherapy pages 1-2)

Beta-blocker and/or ARB observational evidence

A UK national service cohort (retrospective) reports substantially higher survival in patients receiving long-term beta-blocker and/or ARB therapy compared with those not on cardiac medication: - End-of-follow-up survival 93.3% for BB&ARB vs 42.67% for no treatment, and 5-year survival 96.53% on medication vs 42.67% off treatment. (bowen2023diagnosisandmanagement pages 8-11)

Evidence limitations: These are observational associations subject to confounding (e.g., survivorship bias, treatment selection, and concurrent specialized care). The authors also note too few celiprolol-treated patients in their cohort to conclude celiprolol efficacy there. (bowen2023diagnosisandmanagement pages 8-11)

Expert synthesis / opinions (authoritative sources)

GeneReviews frames management as multidisciplinary, prevention-focused care with strong emphasis on avoidance of iatrogenic harm and rapid response to possible rupture/dissection symptoms. (byers2025vascularehlersdanlossyndrome pages 1-3)
A 2024 prevention-focused review emphasizes that interventional/surgical treatment carries high complication rates (reported up to 46%), supporting conservative management and prevention as the central strategy. (buso2024currentevidenceand pages 1-2)

7) dismech YAML-ready ontology term suggestions

Two structured artifacts are provided:

Topic area	Citation (first author year)	Publication date (month/year)	Journal or source	URL/DOI	PMID	Key evidence points (1-2)
Authoritative clinical definition / management overview	Byers 2025	Feb 2025	GeneReviews / Definitions	https://doi.org/10.32388/y374vq	20301667	Defines vEDS/EDS type IV by arterial, intestinal, and uterine fragility with thin translucent skin and easy bruising; diagnosis is established by a heterozygous pathogenic COL3A1 variant. Recommends multidisciplinary care, periodic arterial screening, BP monitoring, and avoidance of high-risk invasive procedures; pregnancy carries substantial maternal risk. (byers2025vascularehlersdanlossyndrome pages 1-3, foehr2025vascularehlersdanlossyndrome pages 3-4)
National service cohort / surveillance and medication practice	Bowen 2023	Mar 2023	European Journal of Human Genetics	https://doi.org/10.1038/s41431-023-01343-7	not in retrieved text	UK molecularly confirmed cohort: 180 total patients, 126 in statistical analysis. Retrospective data suggested fewer vascular events in patients on long-term ARB and/or beta-blocker therapy; annual MRA-based surveillance and emergency information systems were emphasized. (bowen2023diagnosisandmanagement pages 1-2, bowen2023diagnosisandmanagement pages 8-11)
Arterial lesion distribution / genotype-phenotype	Adham 2022	Oct 2022	Frontiers in Cardiovascular Medicine	https://doi.org/10.3389/fcvm.2022.953894	not in retrieved text	In 330 adults, 82.4% had arterial lesions; 80.6% carried dominant-negative and 19.4% haploinsufficient variants. Dominant-negative variants were associated with more medium-sized artery lesions and lower carotid stiffness; imaging was systematically performed at initial workup. (adham2022assessmentofarterial pages 1-2)
Natural history / survival by mutation class	Pepin 2014	Dec 2014	Genetics in Medicine	https://doi.org/10.1038/gim.2014.72	not in retrieved text	Reviewed 1,231 affected individuals; missense and splice-site variants accounted for >90% of 572 COL3A1 alterations. Median survival was 51 years and varied by sex and mutation type, supporting genotype-informed counseling and trial design. (pepin2014survivalisaffected pages 1-2)
Haploinsufficiency mechanism	Schwarze 2001	Nov 2001	American Journal of Human Genetics	https://doi.org/10.1086/324123	not in retrieved text	Identified frameshift/nonsense variants causing COL3A1 haploinsufficiency via nonsense-mediated decay or unstable truncated protein. Presenting features were vascular aneurysm or rupture, showing that reduced type III procollagen alone can produce a vEDS-overlapping phenotype. (schwarze2001haploinsufficiencyforone pages 1-2)
Fibroblast transcriptomics / ECM disarray	Chiarelli 2018	Jan 2018	PLOS ONE	https://doi.org/10.1371/journal.pone.0191220	not in retrieved text	Dermal fibroblasts with dominant-negative COL3A1 mutations showed altered ER/redox homeostasis and disrupted ECM organization, with reduced fibrillins, EMILINs, elastin, perlecan, decorin, and versican. Supports a mechanism beyond simple collagen deficiency, involving intracellular stress and defective matrix assembly. (chiarelli2018transcriptomeanalysisof pages 1-2)
Collagen fibril ultrastructure / phenotype variability	Ishikawa 2023	Aug 2023	Frontiers in Genetics	https://doi.org/10.3389/fgene.2023.1238209	not in retrieved text	Electron microscopy study of 30 vEDS skin samples found significantly increased irregularity of collagen fibril size versus controls. Some patients had lower fibril irregularity and fewer severe complications, suggesting ER stress and fibrillogenesis modifiers may contribute to phenotypic variability. (ishikawa2023clinicalfeaturesand pages 1-2)
Medical prevention review / celiprolol evidence	Buso 2024	Jul 2024	Journal of Clinical Medicine	https://doi.org/10.3390/jcm13144255	not in retrieved text	Narrative review summarizes that celiprolol showed a 64% reduction in arterial rupture/dissection risk in BBEST, but overall drug evidence remains limited. Reviews possible celiprolol mechanisms and notes no other medication has clear clinical proof, while ARBs showed benefit in mouse models. (buso2024currentevidenceand pages 1-2)
Real-world celiprolol outcomes	Buso 2024	Dec 2024	Vascular Medicine	https://doi.org/10.1177/1358863x231215330	not in retrieved text	Italian referral-center cohort of 26 genetically confirmed patients: all were on celiprolol at last follow-up and 80% reached 400 mg/day, yet yearly symptomatic vascular event risk remained 8.8%. Confirms tolerability but also persistent residual risk despite therapy. (buso2024despiteceliprololtherapy pages 1-2)
Mechanistic review / collagen III biology	Omar 2021	Dec 2021	Matrix Biology Plus	https://doi.org/10.1016/j.mbplus.2021.100090	not in retrieved text	Reviews collagen III structure-function and explains why COL3A1 defects particularly affect vasculature and hollow organs; emphasizes Gly-X-Y repeat biology and mechanistic heterogeneity. Summarizes core phenotypes including arterial, gastrointestinal, uterine, skin, bruising, and pneumothorax manifestations. (omar2021fourdecadesin pages 1-2)

Table: This table summarizes the main vascular Ehlers-Danlos syndrome references retrieved in the session, organized by topic and annotated with the most relevant evidence points. It is useful as a compact citation map for drafting a disease entry or dismech YAML evidence section.

Category	Term label	Identifier	Rationale/usage note
MONDO/OMIM	Vascular Ehlers-Danlos syndrome	MONDO: needs lookup; OMIM: 130050	Core disease term for the entry; synonyms include vascular EDS and EDS type IV. Molecular diagnosis is established by a heterozygous pathogenic COL3A1 variant; hallmark manifestations are arterial, intestinal, and uterine fragility with thin translucent skin and easy bruising. (byers2025vascularehlersdanlossyndrome pages 1-3)
MONDO/OMIM	Ehlers-Danlos syndrome type IV	MONDO: needs lookup; OMIM: 130050	Legacy synonym still commonly used in older primary literature and useful for synonym normalization/search expansion. (schwarze2001haploinsufficiencyforone pages 1-2, pepin2014survivalisaffected pages 1-2)
HGNC gene	COL3A1	HGNC: needs lookup	Causal gene for typical monogenic vEDS; encodes pro-α1(III) chain of type III procollagen. Dominant-negative and haploinsufficiency variant classes have prognostic value. (omar2021fourdecadesin pages 4-5, schwarze2001haploinsufficiencyforone pages 1-2, adham2022assessmentofarterial pages 1-2)
HPO phenotype	Arterial rupture	HPO: needs lookup	One of the defining life-threatening manifestations; should be included as a major phenotype term. (byers2025vascularehlersdanlossyndrome pages 1-3, byers2025vascularehlersdanlossyndrome pages 5-7)
HPO phenotype	Arterial dissection	HPO: needs lookup	Core vascular event phenotype; frequent in cohorts and central to surveillance/treatment outcomes. (adham2022assessmentofarterial pages 1-2, doolan2023extracutaneousfeaturesand pages 1-2)
HPO phenotype	Aneurysm	HPO: needs lookup	Common vascular lesion in vEDS; useful as a separate vascular phenotype node. (adham2022assessmentofarterial pages 1-2, doolan2023extracutaneousfeaturesand pages 1-2, byers2025vascularehlersdanlossyndrome pages 5-7)
HPO phenotype	Thin translucent skin	HPO: needs lookup	Classic external clue supporting diagnosis and often present before catastrophic events. (byers2025vascularehlersdanlossyndrome pages 1-3, adham2022assessmentofarterial pages 1-2)
HPO phenotype	Easy bruising	HPO: needs lookup	Highly characteristic soft-tissue fragility phenotype and useful early-life diagnostic clue. (byers2025vascularehlersdanlossyndrome pages 1-3, adham2022assessmentofarterial pages 1-2)
HPO phenotype	Intestinal perforation / bowel rupture	HPO: needs lookup	Major hollow-organ complication, often sigmoid colon; important for emergency-care planning and procedure avoidance. (byers2025vascularehlersdanlossyndrome pages 1-3, bowen2023diagnosisandmanagement pages 8-11, byers2025vascularehlersdanlossyndrome pages 5-7)
HPO phenotype	Uterine rupture	HPO: needs lookup	Canonical obstetric complication; include separately because of pregnancy-management relevance. (byers2025vascularehlersdanlossyndrome pages 1-3)
HPO phenotype	Pneumothorax	HPO: needs lookup	Recurrent or spontaneous pneumothorax is a recognized vEDS manifestation and useful for case finding. (byers2025vascularehlersdanlossyndrome pages 1-3, doolan2023extracutaneousfeaturesand pages 3-4)
HPO phenotype	Hemothorax / hemopneumothorax	HPO: needs lookup	Important pulmonary/pleural complication related to tissue fragility; include when modeling pulmonary manifestations. (byers2025vascularehlersdanlossyndrome pages 1-3, doolan2023extracutaneousfeaturesand pages 3-4)
HPO phenotype	Carotid-cavernous fistula	HPO: needs lookup	Highly suggestive/near-pathognomonic vascular presentation in young adults; worth explicit capture. (byers2025vascularehlersdanlossyndrome pages 1-3, byers2025vascularehlersdanlossyndrome pages 5-7)
HPO phenotype	Acrogeria	HPO: needs lookup	Distal aged appearance is a classic external vEDS clue and helps disease recognition. (byers2025vascularehlersdanlossyndrome pages 1-3, adham2022assessmentofarterial pages 1-2)
HPO phenotype	Characteristic facial features	HPO: needs lookup	Useful broad diagnostic feature; if needed, refine into more granular facial HPO terms during curation. (byers2025vascularehlersdanlossyndrome pages 1-3, adham2022assessmentofarterial pages 1-2)
GO process/component/function	Collagen fibril organization	GO: needs lookup	Strong mechanistic fit: dermal EM studies show irregular collagen fibril morphology; model/fibroblast studies implicate defective fibrillogenesis. (ishikawa2023clinicalfeaturesand pages 1-2, vroman2021animalmodelsof pages 13-14)
GO process/component/function	Extracellular matrix organization	GO: needs lookup	Central pathway-level term because vEDS fibroblasts show widespread ECM disassembly/remodeling beyond collagen III itself. (chiarelli2018transcriptomeanalysisof pages 1-2)
GO process/component/function	Endoplasmic reticulum stress / unfolded protein response	GO: needs lookup	Appropriate for dominant-negative alleles with ER misfolding/retention and stress-response signatures in fibroblasts. (chiarelli2018transcriptomeanalysisof pages 1-2, ishikawa2023clinicalfeaturesand pages 1-2)
GO process/component/function	Collagen biosynthetic process	GO: needs lookup	Captures defective collagen III synthesis, trimer assembly, folding, and post-translational handling. (omar2021fourdecadesin pages 4-5, chiarelli2018transcriptomeanalysisof pages 1-2)
GO process/component/function	Collagen-containing extracellular matrix	GO: needs lookup	Useful cellular component term for matrix-level disease mechanisms and downstream ECM abnormalities. (chiarelli2018transcriptomeanalysisof pages 1-2)
MAXO intervention	Vascular surveillance imaging (MRA/CTA/ultrasound)	MAXO: needs lookup	Use for regular arterial surveillance; GeneReviews and specialty cohorts recommend periodic noninvasive arterial imaging. (byers2025vascularehlersdanlossyndrome pages 1-3, bowen2023diagnosisandmanagement pages 8-11)
MAXO intervention	Blood pressure monitoring	MAXO: needs lookup	Routine BP monitoring is recommended in follow-up and is relevant to medical therapy titration. (byers2025vascularehlersdanlossyndrome pages 1-3, buso2024despiteceliprololtherapy pages 1-2)
MAXO intervention	Beta-blocker therapy	MAXO: needs lookup	Generic intervention term to capture celiprolol and other beta-blocker use in cohorts/observational practice. (bowen2023diagnosisandmanagement pages 8-11)
MAXO intervention	Celiprolol therapy	MAXO: needs lookup	Most specific medication term currently linked to trial/observational vEDS literature; include as separate intervention if YAML supports drug-level granularity. (buso2024currentevidenceand pages 1-2, buso2024despiteceliprololtherapy pages 1-2)
MAXO intervention	Angiotensin receptor blocker therapy	MAXO: needs lookup	Needed to capture observational BB/ARB combination practice and emerging adjunctive therapy evidence. (bowen2023diagnosisandmanagement pages 8-11)
MAXO intervention	Pregnancy management / high-risk obstetric care	MAXO: needs lookup	Important because pregnancy carries substantial maternal risk, including uterine and arterial complications. (byers2025vascularehlersdanlossyndrome pages 1-3)
MAXO intervention	Avoidance of invasive procedures	MAXO: needs lookup	GeneReviews and specialty centers advise avoiding/limiting arteriography, routine colonoscopy, and elective surgery when possible. (byers2025vascularehlersdanlossyndrome pages 1-3, bowen2023diagnosisandmanagement pages 8-11)
MAXO intervention	Emergency evaluation for sudden unexplained pain	MAXO: needs lookup	High-yield emergency-care term because sudden pain may herald dissection or rupture; patients are advised to carry diagnosis information. (byers2025vascularehlersdanlossyndrome pages 1-3)

Table: This table lists disease, gene, phenotype, process, and intervention terms suitable for a dismech YAML entry on vascular Ehlers-Danlos syndrome. Identifiers not confirmed in the retrieved evidence are marked for lookup so the table can be used as a structured curation checklist.

Note: identifiers (MONDO/HPO/HGNC/GO/MAXO) require external lookup because they were not present in the retrieved full texts; this report intentionally does not guess them. (byers2025vascularehlersdanlossyndrome pages 1-3)

8) Evidence limitations and caveats (do not over-interpret)

1) PMID completeness limitation (tooling constraint): Apart from GeneReviews being explicitly cited with PMID: 20301667 in retrieved text, most retrieved PDFs did not include PubMed identifiers in the extracted snippets; therefore, this report cannot provide “exact PMIDs” for many key studies (e.g., BBEST celiprolol trial, Bowen 2023 cohort, Adham 2022 cohort, Chiarelli 2018 PLOS ONE) without additional PubMed-specific retrieval. (foehr2025vascularehlersdanlossyndrome pages 3-4, bowen2023diagnosisandmanagement pages 8-11, adham2022assessmentofarterial pages 1-2, chiarelli2018transcriptomeanalysisof pages 1-2)

2) Heterogeneity and ascertainment bias: Many “frequency” estimates in vEDS are derived from referral cohorts or aggregated case literature, and denominators vary by complication, potentially inflating severe-event frequencies. (doolan2023extracutaneousfeaturesand pages 1-2)

3) Mechanism and treatment linkage remains incomplete: Fibroblast-omics and ultrastructural findings strongly support ER stress/ECM remodeling and altered fibrillogenesis, but causal chains to specific vascular event prevention strategies remain unproven in humans. (chiarelli2018transcriptomeanalysisof pages 1-2, ishikawa2023clinicalfeaturesand pages 1-2)

4) Model-system caveats: Mouse models can recapitulate rupture/dissection and abnormal fibrils but may show early lethality or incomplete penetrance and may not reproduce the full human skin/GI phenotype; overexpression models may be biologically non-physiologic. (vroman2021animalmodelsof pages 13-14, omar2021fourdecadesin pages 5-6)

Selected references (URLs and publication dates as retrieved)

Byers PH. Vascular Ehlers-Danlos syndrome (GeneReviews). Feb 2025. https://doi.org/10.32388/y374vq. (byers2025vascularehlersdanlossyndrome pages 1-3)
Bowen JM et al. Diagnosis and management of vascular Ehlers-Danlos syndrome: Experience of the UK national diagnostic service, Sheffield. Mar 2023. https://doi.org/10.1038/s41431-023-01343-7. (bowen2023diagnosisandmanagement pages 1-2)
Adham S et al. Assessment of arterial damage in vascular Ehlers-Danlos syndrome: A retrospective multicentric cohort. Oct 2022. https://doi.org/10.3389/fcvm.2022.953894. (adham2022assessmentofarterial pages 1-2)
Doolan BJ et al. Extracutaneous features and complications of the Ehlers-Danlos syndromes: A systematic review. Jan 2023. https://doi.org/10.3389/fmed.2023.1053466. (doolan2023extracutaneousfeaturesand pages 1-2)
Ishikawa S et al. Clinical features and morphology of collagen fibrils in patients with vascular Ehlers–Danlos based on electron microscopy. Aug 2023. https://doi.org/10.3389/fgene.2023.1238209. (ishikawa2023clinicalfeaturesand pages 1-2)
Buso G et al. Current evidence and future perspectives in the medical management of vascular Ehlers–Danlos syndrome: focus on vascular prevention. Jul 2024. https://doi.org/10.3390/jcm13144255. (buso2024currentevidenceand pages 1-2)
Buso G et al. Despite celiprolol therapy, patients with vascular Ehlers–Danlos syndrome remain at risk of vascular events. Dec 2024. https://doi.org/10.1177/1358863x231215330. (buso2024despiteceliprololtherapy pages 1-2)
Omar R et al. Four decades in the making: Collagen III and mechanisms of vascular Ehlers Danlos Syndrome. Dec 2021. https://doi.org/10.1016/j.mbplus.2021.100090. (omar2021fourdecadesin pages 1-2)
Vroman R et al. Animal Models of Ehlers–Danlos Syndromes: Phenotype, Pathogenesis, and Translational Potential. Oct 2021. https://doi.org/10.3389/fgene.2021.726474. (vroman2021animalmodelsof pages 13-14)

References

(byers2025vascularehlersdanlossyndrome pages 1-3): PH Byers. Vascular ehlers-danlos syndrome. Definitions, Feb 2025. URL: https://doi.org/10.32388/y374vq, doi:10.32388/y374vq. This article has 186 citations.
(bowen2023diagnosisandmanagement pages 8-11): Jessica M. Bowen, Monica Hernandez, Diana S. Johnson, Claire Green, Tammy Kammin, Duncan Baker, Sylvia Keigwin, Seiko Makino, Naomi Taylor, Oliver Watson, Nigel M. Wheeldon, and Glenda J. Sobey. Diagnosis and management of vascular ehlers-danlos syndrome: experience of the uk national diagnostic service, sheffield. European Journal of Human Genetics, 31:749-760, Mar 2023. URL: https://doi.org/10.1038/s41431-023-01343-7, doi:10.1038/s41431-023-01343-7. This article has 69 citations and is from a domain leading peer-reviewed journal.
(buso2024currentevidenceand pages 1-2): Giacomo Buso, Federica Corvini, Elena Maria Fusco, Massimiliano Messina, Fabio Cherubini, Nicola Laera, Anna Paini, Massimo Salvetti, Carolina De Ciuceis, Marco Ritelli, Marina Venturini, Nicola Chiarelli, Marina Colombi, and Maria Lorenza Muiesan. Current evidence and future perspectives in the medical management of vascular ehlers–danlos syndrome: focus on vascular prevention. Journal of Clinical Medicine, 13:4255, Jul 2024. URL: https://doi.org/10.3390/jcm13144255, doi:10.3390/jcm13144255. This article has 12 citations.
(pepin2014survivalisaffected pages 1-2): Melanie G. Pepin, Ulrike Schwarze, Kenneth M. Rice, Mingdong Liu, Dru Leistritz, and Peter H. Byers. Survival is affected by mutation type and molecular mechanism in vascular ehlers–danlos syndrome (eds type iv). Genetics in Medicine, 16:881-888, Dec 2014. URL: https://doi.org/10.1038/gim.2014.72, doi:10.1038/gim.2014.72. This article has 341 citations and is from a highest quality peer-reviewed journal.
(bowen2023diagnosisandmanagement pages 1-2): Jessica M. Bowen, Monica Hernandez, Diana S. Johnson, Claire Green, Tammy Kammin, Duncan Baker, Sylvia Keigwin, Seiko Makino, Naomi Taylor, Oliver Watson, Nigel M. Wheeldon, and Glenda J. Sobey. Diagnosis and management of vascular ehlers-danlos syndrome: experience of the uk national diagnostic service, sheffield. European Journal of Human Genetics, 31:749-760, Mar 2023. URL: https://doi.org/10.1038/s41431-023-01343-7, doi:10.1038/s41431-023-01343-7. This article has 69 citations and is from a domain leading peer-reviewed journal.
(schwarze2001haploinsufficiencyforone pages 1-2): U. Schwarze, Wouter I. Schievink, Wouter I. Schievink, Elizabeth M. Petty, Michael R. Jaff, D. Babovic‐Vuksanovic, Kenneth J. Cherry, M. Pepin, and P. Byers. Haploinsufficiency for one col3a1 allele of type iii procollagen results in a phenotype similar to the vascular form of ehlers-danlos syndrome, ehlers-danlos syndrome type iv. The American Journal of Human Genetics, 69:989-1001, Nov 2001. URL: https://doi.org/10.1086/324123, doi:10.1086/324123. This article has 221 citations.
(ishikawa2023clinicalfeaturesand pages 1-2): Satoko Ishikawa, Shujiro Hayashi, Toshimi Sairenchi, Manabu Miyamoto, Shigemi Yoshihara, Gen Kobashi, Tomomi Yamaguchi, Tomoki Kosho, and Ken Igawa. Clinical features and morphology of collagen fibrils in patients with vascular ehlers–danlos based on electron microscopy. Frontiers in Genetics, Aug 2023. URL: https://doi.org/10.3389/fgene.2023.1238209, doi:10.3389/fgene.2023.1238209. This article has 9 citations and is from a peer-reviewed journal.
(foehr2025vascularehlersdanlossyndrome pages 3-4): Reece M. Foehr and Erik D. Foehr. Vascular ehlers-danlos syndrome: current understanding and treatment strategies. Journal of Rare Diseases Research & Treatment, 9:1-4, Apr 2025. URL: https://doi.org/10.29245/2572-9411/2025/1.1218, doi:10.29245/2572-9411/2025/1.1218. This article has 3 citations.
(omar2021fourdecadesin pages 2-4): Ramla Omar, Fransiska Malfait, and Tom Van Agtmael. Four decades in the making: collagen iii and mechanisms of vascular ehlers danlos syndrome. Dec 2021. URL: https://doi.org/10.1016/j.mbplus.2021.100090, doi:10.1016/j.mbplus.2021.100090. This article has 34 citations and is from a peer-reviewed journal.
(chiarelli2018transcriptomeanalysisof pages 1-2): Nicola Chiarelli, Giulia Carini, Nicoletta Zoppi, Marco Ritelli, and Marina Colombi. Transcriptome analysis of skin fibroblasts with dominant negative col3a1 mutations provides molecular insights into the etiopathology of vascular ehlers-danlos syndrome. PLOS ONE, 13:e0191220, Jan 2018. URL: https://doi.org/10.1371/journal.pone.0191220, doi:10.1371/journal.pone.0191220. This article has 48 citations and is from a peer-reviewed journal.
(omar2021fourdecadesin pages 4-5): Ramla Omar, Fransiska Malfait, and Tom Van Agtmael. Four decades in the making: collagen iii and mechanisms of vascular ehlers danlos syndrome. Dec 2021. URL: https://doi.org/10.1016/j.mbplus.2021.100090, doi:10.1016/j.mbplus.2021.100090. This article has 34 citations and is from a peer-reviewed journal.
(adham2022assessmentofarterial pages 1-2): Salma Adham, Anne Legrand, Rosa-Maria Bruno, Clarisse Billon, Violaine Dalens, Pierre Boutouyrie, Jean-Michaël Mazzella, Sonia Gueguen, Michael Frank, Tristan Mirault, and Xavier Jeunemaitre. Assessment of arterial damage in vascular ehlers-danlos syndrome: a retrospective multicentric cohort. Oct 2022. URL: https://doi.org/10.3389/fcvm.2022.953894, doi:10.3389/fcvm.2022.953894. This article has 12 citations and is from a peer-reviewed journal.
(buso2024despiteceliprololtherapy pages 1-2): Giacomo Buso, Anna Paini, Claudia Agabiti-Rosei, Carolina De Ciuceis, Fabio Bertacchini, Deborah Stassaldi, Massimo Salvetti, Marco Ritelli, Marina Venturini, Marina Colombi, and Maria Lorenza Muiesan. Despite celiprolol therapy, patients with vascular ehlers–danlos syndrome remain at risk of vascular events: a 12-year experience in an italian referral center. Vascular Medicine, 29:265-273, Dec 2024. URL: https://doi.org/10.1177/1358863x231215330, doi:10.1177/1358863x231215330. This article has 15 citations and is from a peer-reviewed journal.
(vroman2021animalmodelsof pages 13-14): Robin Vroman, Anne-Marie Malfait, Rachel E. Miller, Fransiska Malfait, and Delfien Syx. Animal models of ehlers–danlos syndromes: phenotype, pathogenesis, and translational potential. Frontiers in Genetics, Oct 2021. URL: https://doi.org/10.3389/fgene.2021.726474, doi:10.3389/fgene.2021.726474. This article has 22 citations and is from a peer-reviewed journal.
(omar2021fourdecadesin pages 5-6): Ramla Omar, Fransiska Malfait, and Tom Van Agtmael. Four decades in the making: collagen iii and mechanisms of vascular ehlers danlos syndrome. Dec 2021. URL: https://doi.org/10.1016/j.mbplus.2021.100090, doi:10.1016/j.mbplus.2021.100090. This article has 34 citations and is from a peer-reviewed journal.
(omar2021fourdecadesin pages 13-14): Ramla Omar, Fransiska Malfait, and Tom Van Agtmael. Four decades in the making: collagen iii and mechanisms of vascular ehlers danlos syndrome. Dec 2021. URL: https://doi.org/10.1016/j.mbplus.2021.100090, doi:10.1016/j.mbplus.2021.100090. This article has 34 citations and is from a peer-reviewed journal.
(byers2025vascularehlersdanlossyndrome pages 5-7): PH Byers. Vascular ehlers-danlos syndrome. Definitions, Feb 2025. URL: https://doi.org/10.32388/y374vq, doi:10.32388/y374vq. This article has 186 citations.
(doolan2023extracutaneousfeaturesand pages 1-2): Brent J. Doolan, Mark E. Lavallee, Ingrid Hausser, Jane R. Schubart, F. Michael Pope, Suranjith L. Seneviratne, Ingrid M. Winship, and Nigel P. Burrows. Extracutaneous features and complications of the ehlers-danlos syndromes: a systematic review. Frontiers in Medicine, Jan 2023. URL: https://doi.org/10.3389/fmed.2023.1053466, doi:10.3389/fmed.2023.1053466. This article has 31 citations.
(doolan2023extracutaneousfeaturesand pages 3-4): Brent J. Doolan, Mark E. Lavallee, Ingrid Hausser, Jane R. Schubart, F. Michael Pope, Suranjith L. Seneviratne, Ingrid M. Winship, and Nigel P. Burrows. Extracutaneous features and complications of the ehlers-danlos syndromes: a systematic review. Frontiers in Medicine, Jan 2023. URL: https://doi.org/10.3389/fmed.2023.1053466, doi:10.3389/fmed.2023.1053466. This article has 31 citations.
(schonherr2024diagnosisofvascular pages 2-3): Laura Schönherr, Sabine Wipper, and Yskert von Kodolitsch. Diagnosis of vascular ehlers danlos syndrome and management of vascular complications: a vascular surgeons perspective. Medizinische Genetik, 36:255-259, Nov 2024. URL: https://doi.org/10.1515/medgen-2024-2053, doi:10.1515/medgen-2024-2053. This article has 0 citations.
(omar2021fourdecadesin pages 1-2): Ramla Omar, Fransiska Malfait, and Tom Van Agtmael. Four decades in the making: collagen iii and mechanisms of vascular ehlers danlos syndrome. Dec 2021. URL: https://doi.org/10.1016/j.mbplus.2021.100090, doi:10.1016/j.mbplus.2021.100090. This article has 34 citations and is from a peer-reviewed journal.

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Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

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References & Deep Research

References

Deep Research

Vascular Ehlers–Danlos Syndrome (vEDS) — Deep Research Report (dismech Disease Entry)

Executive summary

1) Key concepts, disease boundary, and synonyms (current understanding)

Disease definition / boundary

Synonyms (for dismech normalization)

Core identifiers available from retrieved sources

2) COL3A1 / type III collagen genetics (inheritance, dominant-negative vs haploinsufficiency)

COL3A1 biology and why it matters

Inheritance and de novo rate

Variant classes and molecular mechanisms

Genotype–phenotype: DN vs HI and other correlations

3) Mechanisms of vascular wall and hollow-organ fragility

Vascular and hollow-organ fragility as a type III collagen disorder

Fibroblast / ECM evidence (fibrillogenesis and matrix remodeling)

Ultrastructural fibrillogenesis evidence (human tissue)

Model systems and caveats (mouse models)

4) Phenotypes and recent quantitative data (prioritizing 2023–2024)

Hallmark phenotypes (clinical spectrum)

Recent quantitative complication rates (2023 systematic review)

GeneReviews quantitative features (selected)

Natural history statistics from recent cohorts/reviews

5) Current applications and real-world implementations (surveillance, avoidance, emergency care)

Surveillance strategies

Avoidance of invasive procedures and procedure planning

Emergency care implementation

6) Treatment and prevention evidence (celiprolol; beta-blockers/ARBs)

Celiprolol

Beta-blocker and/or ARB observational evidence

Expert synthesis / opinions (authoritative sources)

7) dismech YAML-ready ontology term suggestions

8) Evidence limitations and caveats (do not over-interpret)

Selected references (URLs and publication dates as retrieved)

Artifacts