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Neurological Conditions

Ehlers-Danlos Syndrome

Ehlers-Danlos Syndrome · Q79.6

Ehlers-Danlos syndrome (EDS) is a group of hereditary connective tissue disorders characterized by skin hyperextensibility, joint hypermobility, and tissue fragility due to genetic defects in collagen synthesis or structure.

2026-03-29

At a Glance

EDS is classified into 13 subtypes, with hypermobile EDS (hEDS) being the most common. The prevalence is estimated at approximately 1:5,000 to 1:20,000, but this is likely underestimated due to frequent diagnostic delays [1]. Of neurological importance, approximately 50-80% of EDS patients have concurrent autonomic dysfunction including postural orthostatic tachycardia syndrome (POTS) [2]. Chronic pain, fatigue, and gastrointestinal symptoms are also very common.

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 presentations [1].

The prevalence of the most common subtype, hypermobile EDS (hEDS), is estimated at approximately 1:5,000 to 1:20,000, but the actual prevalence is likely higher as diagnosis takes an average of 10-20 years [5].

Major Subtypes

Hypermobile EDS (hEDS)

The most common subtype, accounting for approximately 80-90% of all EDS cases. Key features include joint hypermobility, chronic pain, fatigue, and autonomic dysfunction. The causative gene has not yet been identified [1].

Classical EDS (cEDS)

Caused by mutations in the COL5A1 or COL5A2 genes. Skin hyperextensibility and fragility are prominent, with delayed wound healing and wide atrophic scars (cigarette paper scars) being characteristic.

Vascular EDS (vEDS)

The most severe subtype, caused by COL3A1 gene mutations. There is a high risk of life-threatening complications including arterial rupture, intestinal perforation, and uterine rupture. The median lifespan is approximately 50 years, making regular vascular surveillance essential.

Autonomic Dysfunction

Association Between EDS and Autonomic Dysfunction

Autonomic dysfunction is found at a very high frequency in EDS patients, particularly in hEDS. A study by De Wandele et al. confirmed autonomic dysfunction in approximately 78% of hEDS patients [2].

Postural Orthostatic Tachycardia Syndrome (POTS)

This is the most common autonomic disorder in EDS patients. Connective tissue abnormalities cause decreased venous compliance, leading to excessive venous pooling in the lower extremities upon standing, with compensatory sympathetic overactivation causing tachycardia [3].

Symptoms include dizziness upon standing, palpitations, generalized weakness, and presyncope. The diagnostic criterion is a heart rate increase of 30 bpm or more (or above 120 bpm) within 10 minutes of standing.

Orthostatic Hypotension

Some EDS patients also experience orthostatic hypotension, and the frequency of neurally mediated syncope (vasovagal syncope) is also elevated.

Gastrointestinal Autonomic Dysfunction

Gastroparesis, reduced intestinal motility, and functional constipation are common, sometimes presenting as irritable bowel syndrome (IBS). This results from the combined effects of connective tissue abnormalities in the intestinal wall and autonomic dysregulation.

Pain

Mechanisms of Chronic Pain

Chronic pain in EDS involves a complex interplay of repetitive microtrauma from joint instability, muscle spasms, central sensitization, and neuropathic components. More than 90% of hEDS patients report chronic pain, and many receive a concurrent diagnosis of fibromyalgia [4].

Pain Management

  • Physical therapy: Joint stabilization and deep muscle strengthening are most important. Exercise should be performed within a range that does not exceed hyperextension limits.
  • Pharmacological treatment: NSAIDs (short-term), duloxetine, gabapentin, and other neuropathic pain medications
  • Non-pharmacological treatment: Aquatic therapy, cognitive behavioral therapy (CBT), TENS

Diagnosis

hEDS Diagnostic Criteria (2017)

According to the 2017 international criteria, all three of the following must be met [1].

1. Generalized joint hypermobility: Beighton score of 5 or higher (adults), 6 or higher (children/adolescents)
2. Two or more of the following: (A) 5 or more systemic connective tissue findings, (B) hEDS diagnosis in a first-degree relative, (C) musculoskeletal complications (chronic pain, recurrent joint dislocations/subluxations)
3. Exclusion of other connective tissue disorders

Beighton Score

A 9-point scale for assessing joint hypermobility.

  • Bilateral passive dorsiflexion of the 5th metacarpophalangeal joint beyond 90 degrees (2 points)
  • Bilateral passive apposition of the thumb to the forearm flexor surface (2 points)
  • Bilateral hyperextension of the elbows beyond 10 degrees (2 points)
  • Bilateral hyperextension of the knees beyond 10 degrees (2 points)
  • Placing both palms flat on the floor with knees straight during forward flexion (1 point)

EDS-POTS-MCAS Trifecta

The concurrent presence of EDS, POTS, and mast cell activation syndrome (MCAS)--the so-called "trifecta"--is frequently observed clinically. The shared mechanism among these three conditions has not been fully elucidated, but it is hypothesized that connective tissue abnormalities simultaneously affect vascular compliance, mast cell stability, and autonomic regulation.

Treatment and Management

Multidisciplinary Approach

EDS is difficult to manage with a single treatment approach and requires collaboration among neurology, rehabilitation medicine, rheumatology, gastroenterology, cardiology, medical genetics, and pain medicine.

Joint Protection

Joint protection education, brace use, and avoidance of high-impact exercise are important for preventing subluxations and pain.

Autonomic Symptom Management

First-line treatment for POTS includes increased fluid and salt intake, compression stockings, and a gradual aerobic exercise program. Midodrine, fludrocortisone, or ivabradine may be used when necessary.

Genetic Counseling

Genetic counseling is essential for subtypes with identified causative genes such as vEDS, and family screening is recommended.

Frequently Asked Questions

Joints are abnormally flexible and frequently subluxate (partially dislocate), the skin is very soft and stretchy, and bruising occurs easily. Chronic joint pain and muscle pain are very common, and chronic fatigue, gastrointestinal problems (abdominal pain, constipation, postprandial bloating), and autonomic symptoms (dizziness upon standing, tachycardia) frequently co-occur [5].

Due to connective tissue abnormalities, the vessel walls are excessively compliant, causing excessive blood pooling in the lower extremities upon standing. Compensatory sympathetic overactivation then causes tachycardia [3]. It is reported that approximately 50-80% of EDS patients meet the diagnostic criteria for POTS [2].

Diagnosis is made clinically according to the 2017 international diagnostic criteria [1]. Hypermobile EDS (hEDS) is determined by combining the Beighton score (5 or more out of 9), systemic connective tissue findings, family history, and musculoskeletal complications. Some subtypes such as vascular EDS are confirmed by genetic testing.

There is no fundamental cure, and the cornerstone of treatment is symptom management and complication prevention. Joint stabilization and muscle strengthening through physical therapy are most important, with pain management, autonomic symptom treatment, and gastrointestinal symptom management approached in a multidisciplinary manner. Joint protection education is essential for preventing subluxations.

Most EDS subtypes follow autosomal dominant inheritance, meaning if one parent is affected, there is a 50% chance of passing it to their children. However, the causative gene for hEDS has not yet been identified, and some cases occur without a family history [1].

References

  1. [1] Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP (2017). "The 2017 international classification of the Ehlers-Danlos syndromes." American Journal of Medical Genetics Part C, 175: 8-26. DOI PubMed
  2. [2] De Wandele I, Rombaut L, Ber-Bram S, De Paepe A, Malfait F, Calders P (2014). "Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome." Seminars in Arthritis and Rheumatism, 44: 93-100. DOI PubMed
  3. [3] Hakim A, O'Callaghan C, De Wandele I, Stiles L, Pocinki A, Rowe P (2017). "Cardiovascular autonomic dysfunction in Ehlers-Danlos syndrome—hypermobile type." American Journal of Medical Genetics Part C, 175: 168-174. DOI PubMed
  4. [4] Castori M, Morlino S, Celletti C, Ghibellini G, Bruschini M, Grammatico P, Blundo C, Camerota F (2013). "Re-writing the natural history of pain and related symptoms in the joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type." American Journal of Medical Genetics Part A, 161: 2989-3004. DOI PubMed
  5. [5] Tinkle B, Castori M, Berglund B, Cohen H, Grahame R, Kazkaz H, Levy H (2017). "Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome Type III and Ehlers-Danlos syndrome hypermobility type): clinical description and natural history." American Journal of Medical Genetics Part C, 175: 48-69. DOI PubMed

Related Articles

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Ehlers-Danlos SyndromeEDSJoint HypermobilityConnective Tissue DisorderPOTS ComorbidityAutonomic DysfunctionJoint Hypermobility

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