ISCHEMIC STROKE / CLASSIFICATION AND ETIOPATHOGENESIS
Ehlers-Danlos syndrome
Created 09/05/2023, last revision 11/05/2023
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
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 β3GalT6 ZIP13 |
11 | Musculocontractural EDS (myopatic) |
mcEDS | AR | D4ST1 DSE |
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
Management
- symptomatic therapy