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

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

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