What is Ehlers-Danlos Syndrome (EDS)?

What is Ehlers-Danlos Syndrome (EDS)?

Ehlers-Danlos Syndrome is a heterogeneous group of 13 recognized inherited connective tissue disorders caused by mutations in 19 different genes (mostly affecting collagen synthesis), characterized by the clinical triad of joint hypermobility with recurrent dislocations, skin hyperextensibility, and tissue fragility. 1, 2, 3

Core Pathophysiology

• EDS results from defects in collagen synthesis and structure, with 12 of 13 subtypes having identified genetic causes affecting collagen types I, III, and V, their modifying enzymes, or proteoglycan-modifying enzymes. 3, 4

• The molecular defects cause widespread connective tissue dysfunction affecting skin, ligaments, joints, blood vessels, and internal organs to varying degrees depending on subtype. 5, 3

Classification by Subtype

Hypermobile EDS (hEDS) - Most Common

• Accounts for 80-90% of all EDS cases and is the only subtype without an identified genetic cause, making it a clinical diagnosis of exclusion. 2, 4

• Requires meeting all three major criteria: Beighton score ≥5/9 for joint hypermobility (≥6/9 for prepubertal children, ≥4/9 for adults >50 years), soft/velvety skin without fragility, and exclusion of alternative diagnoses through genetic testing. 1

• Aortic root dilation occurs in 25-33% of hEDS cases, requiring cardiovascular surveillance. 1, 2

• Up to 98% experience gastrointestinal manifestations including reflux, abdominal pain, constipation, and bloating. 1

• Commonly associated with postural orthostatic tachycardia syndrome (POTS), mast cell activation disorder, chronic pain, and pelvic floor dysfunction. 1

Vascular EDS (Type IV) - Most Dangerous

• Caused by COL3A1 gene mutations affecting type III collagen, resulting in spontaneous arterial and organ ruptures even without aneurysm formation. 2

• Median survival is 48 years due to life-threatening vascular complications including arterial dissection, aneurysms, and organ perforation. 6

• Characterized by thin, translucent skin with visible veins, easy bruising, and characteristic facial features. 6

• Invasive vascular procedures carry fatal complication risk and should be avoided; use only non-invasive imaging (Doppler ultrasound, CT, MRI). 1

Classical EDS (Types I and II)

• Caused by mutations in COL5A1 or COL5A2 genes affecting type V collagen. 6

• Features prominent skin hyperextensibility, atrophic scarring, and joint hypermobility with dislocations. 4

• Follows autosomal dominant inheritance pattern. 2

Other Rare Subtypes

• Include kyphoscoliosis EDS (Type VI), arthrochalasia (Type VIIA, B), and dermatospraxis (Type VIIC), each with distinct genetic causes and clinical features. 5, 4

Key Clinical Features Across Subtypes

Joint Manifestations

• Joint hypermobility assessed by Beighton scale (9-point system): passive dorsiflexion of fifth fingers >90°, passive thumb apposition to flexor forearm, elbow hyperextension >10°, knee hyperextension >10°, and palms flat on floor with knees extended. 1, 6

• Recurrent joint dislocations or subluxations with chronic joint and limb pain. 1

Skin Manifestations

• Soft, velvety, or hyperextensible skin with variable degrees of fragility depending on subtype. 1, 2

• Easy bruising, abnormal wound healing, and atrophic scarring in classical types. 3, 4

Cardiovascular Manifestations

• Aortic root dilation requiring echocardiographic surveillance every 2-3 years until adult height reached. 1

• For vascular EDS: renal arterial aneurysms and dissections, arterial tortuosity throughout the vascular tree. 1

Associated Conditions

• POTS affects up to 37.5% of hEDS patients, diagnosed by heart rate increase ≥30 bpm within 10 minutes of standing without orthostatic hypotension. 6

• Functional bowel disorders, gastroesophageal reflux, and gastroparesis are common. 1

• Osteoporosis, scoliosis, and congenital hip dislocation occur frequently, with short stature in 44% of cases. 1

Critical Diagnostic Pitfalls

• Do not diagnose hEDS without genetic testing to exclude alternative diagnoses, as 26.4% of clinically diagnosed cases had alternative genetic conditions requiring different management. 1

• Failure to recognize vascular EDS is life-threatening; urgent COL3A1 testing is required when this subtype is suspected. 6

• Avoid invasive diagnostic procedures in vascular EDS due to fatal complication risk; use only non-invasive imaging modalities. 1, 6

Inheritance and Genetic Counseling

• Most EDS subtypes follow autosomal dominant inheritance, though some classical and vascular cases show recessive patterns. 2

• Almost every family has its own specific mutation, and no genotype-phenotype correlations exist—the specific mutation does not predict disease severity or course. 2

• Genetic counseling is paramount before mutation screening due to complex financial, insurance, familial, and social implications. 6

Management Principles

• Low-resistance exercise and physical therapy are essential for improving joint stability through increased muscle tone. 1, 2

• Cardiovascular surveillance with echocardiogram every 2-3 years; every 6 months if aortic root >4.5 cm or growth >0.5 cm/year. 1

• Celiprolol reduces vascular morbidity in vascular EDS, though it lacks FDA approval in the US. 1

• Avoid opioid dependence for chronic pain management; refer to pain management specialists. 6, 2

• Orthopedic surgery should be delayed in favor of physical therapy and bracing, as EDS patients experience decreased stabilization and shorter duration of improvement. 2

Pregnancy Considerations

• Pregnancy in EDS women carries increased risk of vascular rupture, postpartum hemorrhage, hernias, and varicosities. 2

• Postpartum hemorrhage may be severe due to defective vascular collagen, and incisions heal slowly requiring extended suture retention. 2