Ehlers-Danlos Syndrome: Diagnostic Criteria and Subtypes
The 2017 International Classification recognizes 13 distinct EDS subtypes, with hypermobile EDS (hEDS) being the most common (80-90% of cases) and the only subtype diagnosed purely on clinical grounds without genetic confirmation. 1, 2
Classification Overview
EDS comprises a clinically and genetically heterogeneous group of heritable connective tissue disorders characterized by the defining triad of joint hypermobility, skin hyperextensibility, and tissue fragility. 1, 3 Twelve of the 13 subtypes have identified causative genes (19 genes total), mostly related to collagen synthesis or extracellular matrix proteins, while hEDS remains without a known genetic cause. 2, 1
The 13 Recognized Subtypes
The current classification includes: classical EDS, classical-like EDS, cardiac-valvular EDS, vascular EDS, hypermobile EDS, arthrochalasia EDS, dermatosparaxis EDS, kyphoscoliotic EDS, brittle cornea syndrome, spondylodysplastic EDS, musculocontractural EDS, myopathic EDS, and periodontal EDS. 1, 4
Hypermobile EDS (hEDS): Diagnostic Criteria
All three major criteria must be met for diagnosis, as hEDS is a clinical diagnosis of exclusion. 5, 6
Major Criterion 1: Generalized Joint Hypermobility
Joint hypermobility must be confirmed using the Beighton scale with age-adjusted thresholds: 5, 2
- ≥6/9 points for prepubertal children
- ≥5/9 points for adults under 50 years
- ≥4/9 points for adults over 50 years
The 9-point Beighton scale includes: 5
- Passive dorsiflexion of each fifth finger >90° (1 point each side)
- Passive apposition of each thumb to the flexor surface of the forearm (1 point each side)
- Hyperextension of each elbow >10° (1 point each side)
- Hyperextension of each knee >10° (1 point each side)
- Ability to place palms flat on floor when bending forward with knees fully extended (1 point)
Major Criterion 2: Skin Characteristics
The skin must be soft or velvety with normal or slightly increased extensibility. 5, 6 Skin is rarely hyperextensible in hEDS, distinguishing it from classical EDS. 5
Major Criterion 3: Absence of Skin/Soft Tissue Fragility
There must be an absence of skin or soft tissue fragility, as this suggests other EDS subtypes (particularly classical or vascular types). 5, 6
Minor (Supportive) Criteria
While not sufficient for diagnosis alone, these features support the diagnosis: 5, 6
- Autosomal dominant family history of similar features without skin abnormalities
- Recurrent joint dislocations or subluxations
- Chronic joint or limb pain
- Easy bruising
- Functional bowel disorders (functional gastritis, irritable bowel syndrome affecting up to 98% of hEDS patients) 5, 2
- Neurally mediated hypotension or postural orthostatic tachycardia syndrome (POTS)
- High, narrow palate
- Dental crowding
Essential Diagnostic Evaluation for All Suspected EDS
Clinical Assessment
Physical examination must document: 5, 6
- Complete Beighton scale scoring
- Skin texture, extensibility, and presence of atrophic scarring
- Evidence of tissue fragility or easy bruising
- Three-generation family pedigree focusing on sudden deaths, arterial ruptures, organ perforations, and autosomal dominant inheritance patterns 7
Mandatory Screening Tests
Echocardiogram is required for all suspected EDS cases to evaluate for aortic root dilation, which occurs in 25-33% of classical and hypermobile EDS patients. 5, 2, 6 While there is no thought to be dissection risk without significant aortic root dilation in hEDS, surveillance is essential. 5
Dilated eye examination should be performed to exclude Marfan syndrome, which shares overlapping features. 5
Cardiovascular Surveillance Protocol
For normal aortic root size: 5
- Repeat echocardiogram every 2-3 years until adult height is reached
- If no dilation develops, repeat only if cardiovascular symptoms develop or when major increase in physical activity is planned
For aortic root dilation: 5
- Echocardiogram every 6 months if diameter >4.5 cm in adults OR rate of increase >0.5 cm/year
- Annual echocardiogram if root diameter <4.5 cm in adults AND rate of increase <0.5 cm/year
Vascular EDS (Type IV): The Life-Threatening Subtype
Vascular EDS requires urgent recognition due to median survival of 48 years and risk of spontaneous arterial and organ ruptures. 2, 6 This subtype poses the greatest mortality risk among all EDS types. 2
Clinical Features Suggesting Vascular EDS
- Thin, translucent skin with visible veins 7
- Characteristic facial features (thin lips, small chin, prominent eyes)
- Easy bruising without significant trauma
- Arterial, intestinal, or uterine rupture, particularly in young adults 2
Definitive Diagnosis
COL3A1 gene mutation testing is the definitive diagnostic test and should be performed urgently when vascular EDS is suspected. 2, 7, 6 Mutations in COL3A1 cause structurally abnormal type III collagen production, with mutations widely distributed throughout the gene and no specific clustering patterns. 2
Critical Management Considerations
Avoid all invasive vascular procedures in suspected or confirmed vascular EDS, as fatal complications have been reported. 7, 6 Use exclusively non-invasive imaging (Doppler ultrasound, CT, or MRI) for vascular assessment. 6
Baseline MR angiography from head to pelvis is recommended to evaluate the entire vascular tree for arterial tortuosity and aneurysms. 7, 6 Annual surveillance imaging is required for any dilated or dissected segments. 6
Genetic Testing Strategy
When Genetic Testing is Indicated
For all suspected EDS cases except hEDS, molecular confirmation is required for definitive diagnosis. 1, 8 A critical pitfall: 26.4% of clinically diagnosed EDS cases were found to have alternative genetic conditions requiring different management when comprehensive genetic testing was performed. 6
Recommended Testing Approach
Multi-gene panel testing (covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes) is the most efficient diagnostic approach when EDS is suspected but subtype is unclear. 7
For suspected vascular EDS: Urgent COL3A1 gene testing 2, 7
For suspected classical EDS: COL5A1 or COL5A2 gene mutation testing 7
Avoid routine genetic testing for hEDS, as no causative genes have been identified and diagnosis remains clinical. 7, 6
Genetic Counseling
Genetic counseling is paramount before mutation screening due to complex financial, insurance, familial, and social implications. 7 Almost every family has its own specific mutation, and no genotype-phenotype correlations exist—the specific mutation does not predict disease type, course, or severity. 2
Common Associated Conditions Requiring Screening
Postural Orthostatic Tachycardia Syndrome (POTS)
Measure postural vital signs with active stand test: heart rate increase ≥30 beats/min in adults (≥40 beats/min in adolescents 12-19 years) within 10 minutes of standing without orthostatic hypotension. 7, 6 POTS affects up to 37.5% of hEDS patients. 7
Gastrointestinal Manifestations
Up to 98% of hEDS patients experience GI symptoms including reflux, abdominal pain, constipation, bloating, and early satiety. 2, 7 Consider celiac disease serological testing earlier in hEDS patients with any GI symptoms, as risk is elevated. 7
Mast Cell Activation Syndrome (MCAS)
Obtain baseline serum tryptase level ONLY if patient presents with episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing). 7, 6 Diagnostic threshold: increase of 20% above baseline plus 2 ng/mL during symptom flares. 7
Do not perform routine MCAS testing in all hEDS patients with isolated GI symptoms. 7
Osteoporosis
Encourage calcium and vitamin D supplementation with low-impact weight-bearing exercise. 5 Order DXA scan for height loss greater than one inch. 5, 7
Management Principles for hEDS
Musculoskeletal Management
Low-resistance exercise is recommended to improve joint stability by increasing muscle tone. 5 Physical therapy for myofascial release is often necessary to facilitate participation in low-resistance exercise. 5
Orthopedic surgery should be delayed if possible in favor of physical therapy and bracing, as patients with hEDS experience decreased stabilization, reduced pain reduction, and shorter duration of improvement compared to those without EDS. 5
A pain management specialist is crucial for patients with chronic pain. 5 Avoid opioid dependence, which is particularly problematic in patients with gastrointestinal manifestations. 7, 6
Gastrointestinal Management
- Gastritis and reflux: Proton pump inhibitor, H2-blocker, or sucralfate 5, 6
- Delayed gastric emptying: Promotility agent 5
- Irritable bowel: Antispasmodics, antidiarrheals, and laxatives as needed 5
Do not escalate to invasive nutrition support in hEDS with pain-predominant presentation, as most hEDS patients have visceral hypersensitivity rather than true dysmotility. 6
Critical Pitfalls to Avoid
Failure to recognize vascular EDS, which carries significant mortality risk from arterial or organ rupture 7
Diagnosing hEDS without excluding other genetic conditions through appropriate testing when clinical features are atypical 6, 8
Performing invasive vascular procedures in vascular EDS patients, which can lead to fatal complications 7, 6
Overlooking cardiovascular surveillance in hEDS, despite 25-33% having aortic root dilation 5, 2
Failing to screen for POTS, MCAS, and pelvic floor dysfunction, which significantly impact quality of life 7, 6