What is Ehlers-Danlos Syndrome?
Ehlers-Danlos syndrome (EDS) is a group of 13 heritable connective tissue disorders caused by mutations in genes involved in collagen synthesis and structure, characterized by the clinical triad of joint hypermobility with recurrent dislocations, skin hyperextensibility, and tissue fragility. 1
Genetic Basis and Classification
EDS comprises 13 recognized subtypes, with 12 being rare monogenic conditions caused by pathogenic variants in 19 different genes, predominantly related to collagen synthesis and extracellular matrix maintenance. 1, 2 Almost every family has its own specific mutation, and no genotype-phenotype correlations exist—meaning the specific mutation does not predict disease type, course, or severity. 1
The hypermobile type (hEDS) is by far the most common, accounting for 80-90% of all EDS cases. 1 Critically, hEDS has no identified genetic cause and remains a purely clinical diagnosis, making it unlikely to represent a single gene disorder in most affected individuals. 1, 2
Key Clinical Features by Subtype
Hypermobile EDS (Most Common)
- Joint hypermobility confirmed by Beighton scale scores: ≥6/9 points for prepubertal children, ≥5/9 for adults under 50, and ≥4/9 for adults over 50. 1
- Soft or velvety skin with normal or slightly increased extensibility (not fragile like other types). 1, 3
- Chronic joint or limb pain, recurrent dislocations or subluxations, and easy bruising. 1
- Aortic root dilation occurs in 25-33% of cases, requiring cardiovascular surveillance. 1, 3
- Up to 98% experience gastrointestinal manifestations including reflux, abdominal pain, constipation, and bloating. 3
- Postural orthostatic tachycardia syndrome (POTS) is common, affecting up to 37.5% of hEDS patients. 4, 3
Vascular EDS (Type IV - Most Dangerous)
- Poses the greatest mortality risk due to spontaneous arterial and organ ruptures, even without aneurysm formation. 1
- Caused by mutations in the COL3A1 gene encoding type III collagen. 1
- Thin, translucent skin with visible veins distinguishes this from hypermobile type. 4
- Median survival is 48 years due to vascular complications. 4
- Defective collagen in arterial walls leads to spontaneous dissection and rupture. 1
Classical EDS (Types I and II)
- Caused by mutations in COL5A1 or COL5A2 genes. 4
- Features more pronounced skin hyperextensibility and atrophic scarring compared to hypermobile type. 5
- Follows autosomal dominant inheritance with genetic heterogeneity. 1
Pathophysiology
The molecular defects involve abnormal collagen structure and function. 6, 5 In vascular EDS, structurally abnormal type III collagen is produced by fibroblasts. 1 In hEDS, skin biopsies reveal altered collagen fibril structure that triggers fibroblast dysfunction with abnormal adhesion and cytoskeletal response. 1 Some subtypes involve glycosaminoglycan abnormalities affecting proteoglycan synthesis. 7
Associated Complications and Comorbidities
Cardiovascular
- Aortic root dilation in 25-33% of hypermobile and classic types requires echocardiographic surveillance. 1, 3
- Vascular EDS carries risk of arterial dissection, rupture, and aneurysms throughout the vascular tree. 1, 4
Musculoskeletal
- Osteoporosis, scoliosis, and congenital hip dislocation may occur. 3
- Short stature is present in 44% of cases. 3
- Chronic musculoskeletal pain and recurrent joint dislocations are hallmark features. 1, 5
Obstetric
- Pregnancy in women with EDS carries increased risk of bruising, hernias, varicosities, and vascular rupture. 1
- Postpartum hemorrhage may be severe due to defective vascular collagen. 1
- Incisions heal slowly, requiring extended suture retention to avoid wound dehiscence. 1
Critical Diagnostic Pitfall
Do not diagnose hEDS without excluding alternative diagnoses through appropriate genetic testing when clinically indicated, as 26.4% of clinically diagnosed hEDS cases had alternative genetic conditions requiring different management. 3 However, genetic testing for hEDS itself is not indicated since no causative genes have been identified. 4, 2