Definition and Overview
Ehlers-Danlos syndrome (EDS) is a group of connective tissue disorders caused by genetic defects in collagen and related proteins. According to the 2017 international classification, it is divided into 13 subtypes, each with different genetic bases and clinical manifestations.
The prevalence of hypermobile EDS (hEDS), the most common subtype, is estimated to be approximately 1:5,000 to 1:20,000, but since it takes an average of 10 to 20 years to be diagnosed, the actual prevalence is estimated to be higher.
major subtypes
Hypermobility EDS (hEDS)
It is the most common subtype, accounting for approximately 80-90% of all EDS. Joint hypermobility, chronic pain, fatigue, and autonomic dysfunction are the main characteristics. The causative gene has not yet been identified.
Classic EDS (cEDS)
It is caused by mutations in the COL5A1 or COL5A2 genes. Skin hyperextensibility and fragility are prominent, delayed wound healing, and extensive atrophic scars (cigarette paper scars) are characteristic.
Vascular EDS (vEDS)
It is the most serious subtype caused by COL3A1 gene mutation. There is a high risk of fatal complications such as artery rupture, intestinal perforation, and uterine rupture. With the median life expectancy being approximately 50 years, regular vascular monitoring is essential.
autonomic dysfunction
Association between EDS and autonomic dysfunction
In EDS patients, especially hEDS, autonomic dysfunction occurs at a very high frequency. In a study by De Wandele et al., autonomic dysfunction was identified in approximately 78% of hEDS patients.
Postural orthostatic tachycardia syndrome (POTS)
It is the most common autonomic disorder in patients with EDS. Due to connective tissue abnormalities, venous elasticity is reduced, causing excessive blood retention in the lower extremities when standing, and sympathetic overactivity to compensate for this causes tachycardia.
Symptoms include dizziness, palpitations, general weakness, and presyncope when standing, and the diagnostic standard is an increase in heart rate of more than 30 bpm (or more than 120 bpm) within 10 minutes of standing.
Orthostatic hypotension
Some EDS patients are accompanied by orthostatic hypotension, and the frequency of neurally mediated syncope (vasovagal syncope) is also high.
Gastrointestinal autonomic dysfunction
Gastroparesis, decreased intestinal motility, and functional constipation are common, and may also show signs of irritable bowel syndrome (IBS). This is the result of a combination of abnormalities in the connective tissue of the intestinal wall and dysregulation of the autonomic nervous system.
pain
Mechanisms of Chronic Pain
Chronic pain in EDS involves a combination of repetitive micro-damage caused by joint instability, muscle spasms, central sensitization, and neuropathy. More than 90% of hEDS patients complain of chronic pain, and many are diagnosed with fibromyalgia.
pain management
- Physical therapy: Joint stabilization and strengthening of deep muscles are most important. Exercise without moving beyond the safe joint range.
- Medication: Neuropathy pain medications, including NSAIDs (short-term), duloxetine, and gabapentin.
- Non-drug treatment: aquatic exercise, cognitive behavioral therapy (CBT), TENS
diagnosis
hEDS diagnostic criteria (2017)
According to the 2017 international standards, all three of the following must be met:
1. Generalized joint hypermobility: Beighton score ≥ 5 (adults), ≥ 6 (children/adolescents) 2. Two or more of the following: (A) five or more systemic connective tissue abnormalities, (B) diagnosis of hEDS in a first-degree relative, (C) musculoskeletal complications (chronic pain, recurrent joint dislocations/subluxations) 3. Rule out other connective tissue diseases
Beighton Score
It is a joint hypermobility evaluation tool with a 9-point score.
- 5th metacarpophalangeal joints on both sides dorsiflexed more than 90° (2 points)
- Touch both thumbs to the flexors of the forearm (2 points)
- Bilateral elbow hyperextension of more than 10° (2 points)
- Bilateral knee hyperextension of more than 10° (2 points)
- Touch both palms to the floor (forward bend with knees straight) (1 point)
EDS-POTS-MCAS triple disease
The “trifecta” of EDS, POTS, and mast cell activation syndrome (MCAS) simultaneously is frequently observed clinically. Although the common mechanism of the three diseases has not been fully elucidated, it is assumed that connective tissue abnormalities simultaneously affect vascular elasticity, mast cell stability, and autonomic nervous system regulation.
Treatment and Management
Multidisciplinary approach
EDS is difficult to manage with a single treatment, and requires collaboration with neurology, rehabilitation medicine, rheumatology, gastroenterology, cardiology, genetic medicine, and pain medicine.
joint protection
Joint protection education, use of braces, and avoidance of high-impact exercises are important in preventing subluxation and pain.
Management of autonomic symptoms
For POTS, increased fluid and salt intake, compression stockings, and a progressive aerobic exercise program are the first-line treatments. If necessary, use midodrine, fludrocortisone, or ivabradine.
genetic counseling
For subtypes whose genes have been identified, such as vEDS, genetic counseling is essential, and family screening is recommended.