Ehlers-Danlos Syndrome
Summary
Ehlers-Danlos Syndromes (EDS) are a heterogeneous group of hereditary connective tissue disorders caused by defects in collagen structure, processing, or related proteins. The syndromes are characterised by joint hypermobility, skin hyperextensibility, and tissue fragility. There are 13 recognised subtypes, with hypermobile EDS (hEDS) being the most common. Classical EDS (cEDS) features skin hyperextensibility and atrophic scarring, while Vascular EDS (vEDS) is rare but life-threatening due to risk of arterial, uterine, and bowel rupture. Management is primarily supportive, focusing on physiotherapy to stabilise joints, pain management, and surveillance for complications. Vascular EDS requires specialist monitoring and consideration of prophylactic measures.
Key Facts
- Definition: Group of heritable connective tissue disorders affecting collagen and extracellular matrix
- Prevalence: 1 in 5000-20,000 (varies by subtype); hEDS most common
- Subtypes: 13 subtypes; Hypermobile (hEDS), Classical (cEDS), Vascular (vEDS) account for majority
- Inheritance: Mostly autosomal dominant; some subtypes autosomal recessive
- Key features: Joint hypermobility, skin hyperextensibility, tissue fragility
- Beighton Score: Clinical tool to assess hypermobility (≥5/9 positive)
- Critical subtype: Vascular EDS (vEDS) — median survival 50 years; arterial/organ rupture risk
Clinical Pearls
The "5 Ps" of EDS: Pain, Poor wound healing, Prolapse (mitral valve, pelvic organs), Party tricks (hypermobile joints), Prone to bruising.
Think Vascular EDS If: Thin, translucent skin with visible veins + spontaneous arterial or organ rupture + characteristic facies (thin lips, small chin, large eyes). This is a medical emergency when complications occur.
Beighton Score ≠ Diagnosis: A high Beighton score indicates hypermobility but does NOT diagnose EDS. Many hypermobile individuals do not have EDS. Look for the associated symptoms (pain, dislocations, skin changes, positive family history).
Why This Matters Clinically
EDS is often underdiagnosed, with patients experiencing years of unexplained symptoms before diagnosis. Early recognition enables appropriate management, prevents unnecessary investigations, and allows genetic counselling. Identification of vascular EDS is critical due to life-threatening complications. Children with EDS often present to multiple specialties before diagnosis is made.
Incidence & Prevalence
- Overall prevalence: 1 in 5000-20,000 (varies by subtype and diagnostic criteria)
- Hypermobile EDS (hEDS): Most common; exact prevalence unknown (likely underdiagnosed)
- Classical EDS (cEDS): 1 in 20,000-40,000
- Vascular EDS (vEDS): 1 in 50,000-250,000
- Trend: Increasing recognition and diagnosis
Demographics
| Factor | Details |
|---|---|
| Age | Onset in childhood for most; symptoms often worsen with age |
| Sex | Affects both sexes; females may have more symptoms (hormonal effects on collagen) |
| Ethnicity | All ethnic groups |
| Geography | Worldwide distribution |
Risk Factors
Non-Modifiable:
- Family history (autosomal dominant for most subtypes)
- Specific gene mutations (COL5A1, COL3A1, etc.)
Modifiable:
| Factor | Association |
|---|---|
| High-impact activities | Worsen joint damage |
| Improper exercise | Hypermobility without strength training worsens symptoms |
| Delayed diagnosis | Leads to inappropriate management |
Mechanism
Step 1: Genetic Mutation
- Mutations in genes encoding collagen (COL1A1, COL3A1, COL5A1, COL5A2) or collagen-modifying enzymes
- Different genes affected in different subtypes
- hEDS: Genetic basis unknown (no identified gene mutation)
Step 2: Abnormal Collagen Production
- Defective collagen synthesis, structure, or cross-linking
- Collagen is the major structural protein in connective tissue
- Affects skin, joints, blood vessels, and internal organs
Step 3: Tissue Fragility
- Weakened connective tissue leads to:
- Joint hypermobility and instability
- Skin that stretches excessively and heals poorly
- Fragile blood vessels (in vascular EDS)
- Organ fragility (bowel, uterus in vascular EDS)
Step 4: Clinical Manifestations
- Joint dislocations and subluxations
- Chronic pain from joint instability
- Abnormal scarring
- In vEDS: life-threatening arterial dissection or rupture
Classification
2017 International Classification (13 Subtypes):
| Subtype | Gene | Inheritance | Key Features |
|---|---|---|---|
| Hypermobile (hEDS) | Unknown | AD | Generalised hypermobility, pain, fatigue |
| Classical (cEDS) | COL5A1, COL5A2 | AD | Skin hyperextensibility, atrophic scars |
| Vascular (vEDS) | COL3A1 | AD | Thin skin, arterial/organ rupture, facies |
| Kyphoscoliotic (kEDS) | PLOD1, FKBP14 | AR | Severe kyphoscoliosis, hypotonia |
| Arthrochalasia (aEDS) | COL1A1, COL1A2 | AD | Severe hypermobility, congenital hip dislocation |
| Dermatosparaxis (dEDS) | ADAMTS2 | AR | Extremely fragile, sagging skin |
| Others | Various | Variable | Rare subtypes with specific features |
Beighton Score (Hypermobility Assessment)
| Manoeuvre | Points (per side) |
|---|---|
| Passive dorsiflexion of 5th MCP greater than 90° | 1 (each hand) |
| Passive apposition of thumb to forearm | 1 (each hand) |
| Hyperextension of elbow greater than 10° | 1 (each arm) |
| Hyperextension of knee greater than 10° | 1 (each leg) |
| Forward flexion with palms flat on floor (knees straight) | 1 |
| Total | 9 |
Interpretation:
- Children: ≥6/9 indicates generalised joint hypermobility
- Adults: ≥5/9 indicates generalised joint hypermobility
- High Beighton score alone does NOT diagnose EDS
Symptoms
Musculoskeletal:
Skin:
Other Systems:
Signs
General:
Musculoskeletal:
Skin:
Red Flags
[!CAUTION] Red Flags — Urgent vascular surgery/emergency review if:
- Sudden severe chest, abdominal, or flank pain (arterial rupture/dissection)
- Signs of stroke (especially in young patient — carotid dissection)
- Acute abdomen (bowel perforation)
- Postpartum haemorrhage or collapse (uterine rupture)
- Known vEDS with any new pain syndrome
Structured Approach
General:
- Assess body habitus and general appearance
- Note skin quality (soft, velvety, thin)
- Look for visible veins (vEDS)
- Facial features (especially in vEDS)
Musculoskeletal:
- Beighton score (all 9 components)
- Assess joint stability
- Look for scoliosis, pes planus
- Examine for old dislocations/subluxations
Skin:
- Test hyperextensibility (forearm, neck)
- Examine scars (atrophic, widened, "cigarette paper")
- Check for bruising
- Look for molluscoid pseudotumours
Cardiovascular:
- Blood pressure (check for postural drop — POTS)
- Heart sounds (mitral valve prolapse click)
- Peripheral pulses
Special Tests
| Test | Technique | Positive Finding | Clinical Significance |
|---|---|---|---|
| Beighton score | Assess 9 manoeuvres | ≥5/9 (adults) or ≥6/9 (children) | Generalised joint hypermobility |
| Skin hyperextensibility | Pinch skin at forearm, pull up | Extends >.5cm | Skin involvement |
| Gorlin sign | Ask to touch nose with tongue | Tongue reaches tip of nose | Hypermobility (not diagnostic) |
| Thumb sign | Thumb across palm, wrap fingers | Thumb extends beyond ulnar border | Hypermobility |
| Active standing test | BP lying then standing | Drop >0mmHg systolic at 10 min | POTS |
First-Line (Bedside)
- Beighton score — Assess hypermobility
- Skin examination — Hyperextensibility, scars
- Blood pressure — Lying and standing (POTS screen)
Laboratory Tests
| Test | Expected Finding | Purpose |
|---|---|---|
| Genetic testing | Mutation in COL3A1, COL5A1, etc. | Confirm diagnosis for specific subtypes |
| FBC, Coagulation | Usually normal | Exclude bleeding disorder (unexplained bruising) |
| Vitamin D | May be low | Associated with chronic pain |
Note: No laboratory test confirms hEDS — diagnosis is clinical.
Imaging
| Modality | Findings | Indication |
|---|---|---|
| Echocardiogram | Mitral valve prolapse, aortic root dilation | Baseline cardiac screening |
| CT/MR angiography | Aneurysms, dissection | vEDS surveillance |
| MRI spine | Scoliosis, kyphosis | If spinal abnormality suspected |
| DEXA | Reduced bone density | If osteoporosis suspected |
Diagnostic Criteria
2017 Criteria for Hypermobile EDS (hEDS):
Criterion 1: Generalised joint hypermobility (Beighton ≥5/9 adults; ≥6/9 children)
Criterion 2: Two or more of the following features (A, B, and C):
- Feature A (5+ must be present): Soft/velvety skin, mild hyperextensibility, unexplained striae, papyraceous scars, piezogenic papules, hernia, rectal/uterine prolapse, dental crowding, high palate, arachnodactyly, arm span:height ≥1.05, MVP, aortic root dilation
- Feature B: Positive family history (first-degree relative meets criteria)
- Feature C: Musculoskeletal complications (chronic pain >3 months, recurrent dislocations)
Criterion 3: All of the following:
- Absence of unusual skin fragility
- Exclusion of other heritable connective tissue disorders (Marfan, Loeys-Dietz)
- Exclusion of alternative diagnoses (autoimmune rheumatic disease)
Management Algorithm
Conservative Management
Physiotherapy (Core of Management):
- Joint stabilisation exercises (strengthening muscles around joints)
- Proprioceptive training
- Low-impact aerobic exercise (swimming, cycling)
- Avoid high-impact sports and overstretching
- Pacing strategies for fatigue
Lifestyle:
- Activity modification (avoid prolonged standing, repetitive movements)
- Ergonomic assessment for school/work
- Use of supportive devices (splints, braces, orthotics)
- Adequate sleep and energy management
Medical Management
| Drug Class | Drug | Dose | Indication |
|---|---|---|---|
| Simple analgesia | Paracetamol | Standard doses | First-line pain relief |
| NSAIDs | Ibuprofen | Standard doses (caution if GI issues) | Inflammatory pain |
| Neuropathic agents | Amitriptyline | 10-50mg nocte | Chronic pain, sleep disturbance |
| Beta-blocker | Celiprolol | 100-400mg BD | vEDS — reduces arterial events |
| For POTS | Fludrocortisone | 0.1mg daily | Orthostatic intolerance |
| For POTS | Ivabradine | 2.5-7.5mg BD | Heart rate control |
Vascular EDS Specific:
- Celiprolol (evidence from Ong et al. trial — reduces arterial events)
- Strict blood pressure control
- Avoid antiplatelet/anticoagulant unless essential
- Avoid invasive procedures where possible
Surgical Considerations
- Surgery for joint instability generally NOT recommended (recurrence high, tissue fragile)
- If surgery required: specialised surgical techniques, careful tissue handling
- In vEDS: Surgery is high-risk — only for emergencies or after specialist MDT discussion
Disposition
- Primary care management: Supportive care, pain management, physio referral
- Genetics referral: All suspected EDS for confirmation and counselling
- Rheumatology/Paediatric Rheumatology: For ongoing care
- Vascular surgery/Specialist centre: All vascular EDS patients
- Follow-up: Regular (6-12 monthly) for symptom management; more frequent for vEDS
Immediate (Hours-Days)
| Complication | Incidence | Presentation | Management |
|---|---|---|---|
| Arterial rupture (vEDS) | 25% by age 20 in vEDS | Sudden severe pain, collapse | Emergency surgery, blood transfusion |
| Joint dislocation | Common in all EDS | Acute joint pain, deformity | Reduction, splinting |
Early (Weeks-Months)
- Subluxations: Partial dislocations; often self-reduce but cause pain
- Wound dehiscence: Post-surgical wound breakdown (tissue fragility)
- Chronic pain syndrome: Develops early and often undertreated
- POTS symptoms: Palpitations, presyncope, fatigue
Late (Years)
| Complication | Notes |
|---|---|
| Chronic pain | Major cause of morbidity; often requires MDT pain management |
| Osteoarthritis | Premature wear from joint instability |
| Pelvic organ prolapse | Especially in multiparous women with hEDS |
| Aortic root dilation | Requires echo surveillance |
| Reduced life expectancy (vEDS) | Median survival ~50 years |
| Psychiatric comorbidity | Depression, anxiety — often secondary to chronic illness |
Natural History
| Subtype | Prognosis |
|---|---|
| Hypermobile EDS | Normal life expectancy; quality of life impaired by pain |
| Classical EDS | Normal life expectancy; wound healing issues |
| Vascular EDS | Median survival 50-51 years; 80% major complication by age 40 |
| Kyphoscoliotic EDS | Reduced if severe kyphoscoliosis (respiratory compromise) |
Outcomes with Treatment
| Variable | Outcome |
|---|---|
| Physiotherapy | Reduces dislocations, improves function |
| Celiprolol (vEDS) | 68% reduction in arterial events |
| Pain management | Improved quality of life |
| Genetic counselling | Informed reproductive decisions |
Prognostic Factors
Good Prognosis:
- hEDS or cEDS subtype (normal life expectancy)
- Early diagnosis and appropriate management
- Engagement with physiotherapy
- Good social support
Poor Prognosis:
- Vascular EDS (vEDS)
- Delayed diagnosis
- Severe chronic pain
- Psychiatric comorbidity
- Multiple arterial events (vEDS)
Key Guidelines
- 2017 International Classification of EDS — Malfait et al. Definitive classification and diagnostic criteria. PMID: 28306229
- Ehlers-Danlos Society Guidelines — Comprehensive management recommendations. ehlers-danlos.com
- NICE Guidance on Chronic Pain — Applicable to EDS-related chronic pain. NICE
Landmark Trials
Ong et al. (2010) — Celiprolol in Vascular EDS
- 53 patients randomised to celiprolol vs observation
- Key finding: 68% reduction in arterial events (dissection, rupture)
- Clinical Impact: Celiprolol now recommended for all vEDS patients
Tinkle et al. (2017) — hEDS Diagnostic Criteria
- Expert consensus on diagnostic criteria for hypermobile EDS
- Key finding: Established more rigorous clinical criteria to improve diagnostic specificity
- Clinical Impact: Now universally adopted for hEDS diagnosis
Evidence Strength
| Intervention | Level | Key Evidence |
|---|---|---|
| Physiotherapy | 2a | Observational studies |
| Celiprolol (vEDS) | 1b | Ong et al. RCT |
| Avoiding surgery in vEDS | 4 | Expert consensus, case series |
| 2017 Diagnostic Criteria | 4 | Expert consensus |
What is Ehlers-Danlos Syndrome?
Ehlers-Danlos Syndrome (EDS) is a group of inherited conditions that affect your connective tissue — the "glue" that holds your body together. This means your joints may be extra flexible (hypermobile), your skin may be stretchy and soft, and you may bruise easily or have unusual scars.
There are different types of EDS. The most common type (hypermobile EDS) causes joint problems and chronic pain but is not life-threatening. A rarer type (vascular EDS) can be more serious because it affects blood vessels.
Is it serious?
For most people with EDS, the condition is not dangerous, but it can significantly affect quality of life due to joint pain, fatigue, and frequent injuries. The vascular type is more serious and requires careful monitoring because of the risk of blood vessel problems.
How is it treated?
- Physiotherapy: The most important treatment. Strengthening the muscles around your joints helps protect them from dislocations and reduces pain.
- Pain management: Medications and other strategies to manage chronic pain.
- Lifestyle changes: Avoiding high-impact activities, using supportive devices like splints, and pacing yourself to manage fatigue.
- Regular monitoring: Heart checks (echocardiograms) and, for vascular EDS, monitoring of blood vessels.
What to expect
- EDS is a lifelong condition; there is no cure
- Symptoms can be managed effectively with the right support
- Many people with EDS lead full, active lives
- It can be passed on to children (genetic counselling is available)
When to seek help
Seek medical attention urgently if:
- You experience sudden severe chest, abdominal, or back pain
- You have signs of a stroke (facial drooping, arm weakness, speech difficulty)
- You become very unwell after an injury
- You have vascular EDS and develop any new significant pain
Primary Guidelines
- Malfait F, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8-26. PMID: 28306229
- Tinkle B, et al. Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome Type III and Ehlers-Danlos syndrome hypermobility type): Clinical description and natural history. Am J Med Genet C Semin Med Genet. 2017;175(1):48-69. PMID: 28145611
Key Trials
- Ong KT, et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet. 2010;376(9751):1476-1484. PMID: 20825965
- Castori M, et al. Management of pain and fatigue in the joint hypermobility syndrome (a.k.a. Ehlers-Danlos syndrome, hypermobility type): principles and proposal for a multidisciplinary approach. Am J Med Genet A. 2012;158A(8):2055-2070. PMID: 22786715
Further Resources
- The Ehlers-Danlos Society: ehlers-danlos.com
- Hypermobility Syndromes Association: hypermobility.org
- EDS UK: ehlers-danlos.org
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. EDS is a complex condition requiring specialist input. Always consult a healthcare professional for individual advice.