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 tissue fragility
  • defects in connective tissue cause the signs and symptoms, which range from mild joint hypermobility to life-threatening complications
  • 2017 classification describes 13 subtypes (Malfait, 2017)
    • inheritance pattern varies by EDS type
    • 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)
    • some genes associated with recently described types of Ehlers-Danlos syndrome have functions that appear to be unrelated to collagen
  • prevalence of all EDS types is approx. 1 in 5000 individuals worldwide
    • hypermobile and classic forms are the most common (types 1 and 5)
    • most types are rare, often with only a few cases or families described in the literature
  • incidence of vascular pathologies increases with age   [Pepin, 2000]
  • most deaths are due to arterial rupture

Clinical presentation

Dissection, aneurysm formation

  • the carotid arteries and ascending aorta are most commonly affected
  • aneurysms may be multiple
  • rupture may lead to CCF formation
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) usually occurs spontaneously or after minor trauma  (Jindal, 2005)
  • most CCFs are direct (due to rupture of the ICA into the cavernous sinus)
    • bilateral lesion is not uncommon
  • CCF can be visualized by noninvasive vascular imaging (MRA, CTA)
  • therapy:  embolization, balloon occlusion → CCF

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, transmission electron microscopy (TEM) findings of collagen flowers on skin biopsy can support the clinical diagnosis but cannot confirm it
  • 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 joints hypermobility (GJH)  and/or  at least 3 minor criteria


  • symptomatic therapy
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Ehlers-Danlos syndrome