Ehlers-Danlos syndrome

David Goldemund M.D.
Updated on 09/09/2024, published on 09/05/2023

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 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 located on chromosome 2q32.2
- 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

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

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

typical clinical presentation of arterial dissections or ruptures at a young age
positive family history
genetic testing
- the panel should include at least the COL3A1, 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 (COL5A1 and COL5A2)	type I and V collagen
2	Classical-like EDS (absence of atrophic scarring)	clEDS	AR (TNXB gene)	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 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

EDS is a group of hereditary connective tissue disorders that primarily affect the skin, joints, and blood vessels due to defects in collagen or collagen-modifying proteins
the symptoms vary widely depending on the type

there are 13 recognized types of EDS, including:
- classical EDS (cEDS): affects the skin and joints (mutations in COL5A1 or COL5A2)
- hypermobility EDS (hEDS): primarily affects joint hypermobility (genetic basis is not fully understood)
- vascular EDS (vEDS): affects blood vessels and internal organs (mutations in COL3A1)
- classic-like EDS (clEDS): similar to classical EDS but lacks atrophic scarring (mutations in TNXB)

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)

yes, EDS is often inherited in an autosomal dominant or recessive manner
- autosomal dominant: a single copy of the mutated gene is enough to cause the disorder (e.g., cEDS, vEDS)
- autosomal recessive: both gene copies must be mutated to cause the disorder (e.g., clEDS)

complications include joint dislocations, scoliosis, chronic pain, and, in severe cases, life-threatening cardiovascular conditions (arterial dissection, aneurysm rupture, stroke)

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

currently, there’s no cure, but treatment can manage symptoms and prevent complications

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)