Definition and pathophysiology

  • Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited connective tissue disorders characterized by hyperelastic skin, hypermobile joints, and vascular and other tissue fragility
  • defects in connective tissue cause the signs and symptoms, which range from mild joint hypermobility to life-threatening complications
  • the 2017 classification describes 13 distinct EDS subtypes (Malfait, 2017)
    • inheritance pattern varies by EDS subtype
    • mutations in at least 20 genes have been identified (e.g., COL5A1 or COL5A2 mutations cause the classical type of EDS)
    • stroke is most commonly associated with type 4 (vascular EDS), characterized by an AD inheritance and abnormal production of type I and III procollagen due to mutations in the COL3A1 gene
    • some genes associated with recently described types of Ehlers-Danlos syndrome exhibit functions that seem unrelated to collagen
  • prevalence of all EDS types is ~ 1 in 5000 individuals worldwide
    • hypermobile and classic forms (types 1 and 5) are the most common
    • most types are rare, often with only a few cases or families described in the literature
  • incidence of vascular pathologies tends to increase with age [Pepin, 2000]
  • most deaths in EDS result from arterial rupture

Clinical presentation

Dissection, aneurysm formation

  • increased risk of cerebrovascular events is particularly associated with the vascular subtype (vEDS)
  • dissections primarily affect the carotid arteries and ascending aorta
    • dissection may lead to ischemic stroke or SAH (intracranial dissection)
  • aneurysms may be multiple; their rupture may lead to CCF formation, SAH, or ICH


Dissecting aneurysm of the left ICA and aneurysm of the left vertebral artery in a 48-year-old patient with Ehlers-Danlos syndrome

Carotid-cavernous fistula

  • carotid-cavernous fistula (CCF) typically occurs spontaneously or following head trauma  (Jindal, 2005)
  • most CCFs are direct and result from the rupture of the ICA into the cavernous sinus
    • the bilateral lesion is not uncommon
  • CCF can be visualized by noninvasive vascular imaging, such as magnetic resonance angiography (MRA) and computed tomography angiography (CTA)
  • therapy:  embolization, balloon occlusion

Diagnostic evaluation

  • typical clinical presentation
  • positive family history
  • genetic testing
    • the panel should include at least the COL5A1, COL5A2, COL1A1, and COL1A2 genes
  • if genetic testing is unavailable, electron microscopy (EM) findings can support the clinical diagnosis
    • abnormalities in collagen fibril architecture – irregular fibril diameter, disorganized arrangement, or abnormal interfibrillar spacing
  • vascular imaging – preferably CTA, MRA
clinical subtype abbreviation IP protein
1 Classical EDS cEDS AD type I and V collagen
2 Classical-like EDS clEDS AR tenascin XB
3 Cardiac-valvular cvEDS AR type I collagen
4 Vascular EDS vEDS AD  (COL3A1) type I and III collagen
5 Hypermobile EDS hEDS AD unknown
6 Arthrochalasia EDS aEDS AD type I collagen
7 Dermatosparaxis EDS dEDS AR ADAMTS-2
8 Kyphoscoliotic EDS kEDS AR FKBP22 and LH1
9 Brittle Cornea syndrome BCS AR ZNF469
10 Spondylodysplastic EDS spEDS AR β4GalT7
11 Musculocontractural EDS (myopatic)
12 Myopathic EDS mEDS AD or AR type XII collagen
13 Periodontal EDS pEDS AD C1r or C1s
  • major criteria
    • generalized joint hypermobility (GJH)
    • skin hyperextensibility and atrophic scarring
  • minor criteria
    • easy bruising
    • soft, doughy skin
    • skin fragility (or traumatic splitting)
    • molluscoid pseudotumors
    • subcutaneous spheroids
    • hernia (or history thereof)
    • epicanthal folds
    • complications of joint hypermobility (e.g., sprains, luxation/subluxation, pain, flexible flatfoot)
    • family history of a first-degree relative meeting clinical criteria

Minimal criteria suggestive of cEDS:

skin hyperextensibility and atrophic scarring


generalized joint hypermobility (GJH)  and/or  at least 3 minor criteria


  • acute stroke therapy
    • standard stroke protocols and IVT contraindications apply; extra caution is required due to increased risk of bleeding
    • experience with mechanical thrombectomy is limited; an increased risk of periprocedural arterial injury can be expected
  • stroke prevention
    • blood pressure control to reduce arterial wall stress
    • antiplatelet agents are recommended for secondary prevention
    • serial imaging studies for detection/follow-up of aneurysms or dissections
  • symptomatic therapy
    • pain anagement (analgesics, neuropathic agents like gabapentin)
    • physical therapy should focus on joint stabilization and muscle strengthening
    • orthotic support
    • cardiovascular monitoring
  • genetic counseling
  • surgical interventions are generally reserved for life-threatening situations or severe mechanical dysfunction


What is Ehlers-Danlos Syndrome (EDS)?
  • EDS is a heterogeneous group of inherited connective tissue disorders characterized by hyperelastic skin, hypermobile joints, and vascular and tissue fragility

What causes EDS?
  • EDS is caused by mutations in genes responsible for collagen production, a crucial protein for connective tissue strength and integrity
  • mutations in at least 20 genes have been identified (e.g.,  COL5A1 or COL5A2 mutations cause the classical type)
  • stroke is most commonly associated with type 4 (vascular EDS) with AD inheritance and abnormal type I and III procollagen production (COL3A1gene)

Is EDS hereditary?
  • yes, EDS is often inherited in an autosomal dominant or recessive manner
What are common complications of EDS?
  • complications include joint dislocations, scoliosis, chronic pain, and, in severe cases, life-threatening cardiovascular conditions (arterial dissection, aneurysm rupture, stroke)

Can individuals with EDS lead a normal life?
  • with proper management, many individuals with EDS can lead active and fulfilling lives, though some may face challenges due to chronic pain or mobility issues

Is there a cure for EDS?
  • currently, there’s no cure, but treatment can manage symptoms and prevent complications

What is Ehlers-Danlos syndrome life expectancy?
  • the overall life expectancy of patients with vascular EDS is shortened, largely as a result of vascular rupture, with a median life span of 48 years (range, 6–73 years)

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Ehlers-Danlos syndrome