Ehlers-Danlos Syndrome (EDS)
Ehlers-Danlos syndrome is a heterogeneous group of hereditable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility, with 13 recognized subtypes caused by pathogenic variants in 21 confirmed genes (except for hypermobile EDS which has no identified genetic cause). 1, 2
Definition and Classification
Ehlers-Danlos syndromes comprise a group of genetically diverse connective tissue disorders with variable clinical presentations:
- Currently classified into 13 distinct subtypes 2
- 12 subtypes have identified monogenic causes involving 21 different genes 2
- Pathogenesis relates to disturbances in collagen formation and/or stability 2, 3
- Most common subtype is hypermobile EDS (hEDS), which currently has no identified genetic cause 2
Clinical Features
The primary clinical manifestations of EDS include:
- Joint hypermobility: Assessed using the Beighton scale (score ≥5 indicates hypermobility) 1
- Skin abnormalities:
- Hyperextensibility
- Soft or velvety texture
- Fragility and poor wound healing
- Atrophic scarring
- Easy bruising 1
- Tissue fragility: Affecting skin, blood vessels, and internal organs 4
Subtypes of EDS
Major subtypes include:
- Classical EDS (formerly EDS I/II): Characterized by skin hyperextensibility and joint hypermobility 4
- Hypermobile EDS (formerly EDS III): Most common type, diagnosis is clinical without genetic confirmation 2
- Vascular EDS (formerly EDS IV): Most serious form with risk of arterial and hollow organ rupture 4
- Kyphoscoliosis EDS (formerly EDS VI): Features severe scoliosis 4
- Arthrochalasia EDS (formerly EDS VIIA, B): Characterized by congenital hip dislocation 4
- Dermatosparaxis EDS (formerly EDS VIIC): Features extremely fragile skin 4
- Spondylodysplastic EDS: Associated with proteoglycan abnormalities due to pathogenic variants in B4GALT7 or B3GALT6 5
- Musculocontractural EDS: Caused by mutations in CHST14 or DSE affecting dermatan sulfate biosynthesis 5
Cardiovascular Manifestations
EDS can have significant cardiovascular implications:
- Aortic root dilatation occurs in 25-33% of classic and hypermobile EDS 1
- Vascular EDS has high risk of arterial rupture, aneurysm, and dissection 1
- Vascular EDS significantly reduces life expectancy (median age 48 years) primarily due to arterial ruptures 1
- Regular cardiovascular monitoring is essential, particularly for vascular type 1
Diagnosis
Diagnosis of EDS requires:
- Comprehensive clinical evaluation focusing on joint hypermobility and skin examination 1
- Family history assessment 1
- Targeted genetic testing based on suspected EDS subtype 1, 2
- Cardiovascular imaging (echocardiogram) to evaluate for aortic root dilatation and valve abnormalities 1
- For vascular EDS, baseline CT or MRI from head to pelvis to evaluate the entire aorta and branches 1
Management
Management of EDS is multidisciplinary:
- Regular cardiovascular surveillance, particularly for vascular type 1
- Beta blockers (such as celiprolol) may benefit patients with vascular EDS 1
- Surgical interventions are indicated for rapid growth of arterial aneurysms or dissection, but carry increased risk due to tissue fragility 1
- Physical therapy and rehabilitation for joint hypermobility 3
- Special considerations during pregnancy, particularly for vascular type 1
Complications and Prognosis
Potential complications include:
- Vascular rupture (especially in vascular EDS) 1
- Hollow organ rupture 4
- Chronic joint dislocations leading to pain and long-term disability 4
- Surgical complications due to tissue fragility 1
- Reduced life expectancy in vascular type 1
Important Clinical Considerations
- EDS diagnosis remains challenging due to overlapping symptoms between subtypes 4
- Tissue fragility requires gentle handling during examination and procedures 1
- Pregnancy carries significant risks for women with vascular EDS, requiring complete vascular imaging beforehand 1
- No specific medical or genetic therapies are currently available for any type of EDS 3