Introduction

Ehlers-Danlos Syndrome (EDS) is an inherited condition that impacts the body’s connective tissues. It is an autosomal dominant condition characterised by abnormal collagen synthesis. EDS is characterised by very stretchy skin, and joints move more than normal. It can also cause thin scars and blood vessels that break easily. 

The International EDS Consortium classifies EDS into 13 distinct categories. This classification includes clinical criteria for every subtype and offers genetic insights as well as molecular diagnostic validation for all subtypes except for the hypermobile one. While many subtypes are rare, the six most frequently encountered are classical, vascular, hypermobile, kyphoscoliotic, arthrochalasia and dermatosparaxis. The hypermobile type is the most commonly occurring form of EDS.

Musculoskeletal manifestations are mostly seen in classical EDS (cEDS) and hypermobile EDS (hEDS). Musculoskeletal symptoms of EDS include joint instability, chronic pain, and hypermobility. Musculoskeletal involvement is an essential component of the clinical criteria, emphasising its significance for the patient's experience and diagnosis.¹

The goal of the article is to discuss all the related points of musculoskeletal manifestations of EDS in detail.

Joint hypermobility

What is joint hypermobility?

An increase in one or more joints' range of motion above their typical range is known as joint hypermobility. Joint laxity and double-jointedness are other names for it. Joint hypermobility is caused by laxity in ligaments, connective tissue, and the surrounding structures of the joint.

Joint laxity is more common in younger people than in older people, and it is more common in women than in men. ^2,3

Classification of joint hypermobility

Joint hypermobility can be classified into 3 main types: ²

• Generalised joint hypermobility: affects many joints. This condition means joints are loose all over the body 
• Localised joint hypermobility: a few loose joints are referred to as localised joint hypermobility. These joints are all in the same area
• Peripheral joint hypermobility: describes limited flexibility. This limitation affects the hands and feet

Clinical assessment tools

Generalised joint hypermobility is evaluated in a clinical setting using the Beighton score. The Beighton score is a nine-point rating system for joint hypermobility. Each of the following joints that exhibit hypermobility during the assessment is worth one point, such as the joints in the fifth finger, thumb, elbows, knees, and spine. The rating system of the Beighton score:

• Base of the right 5th (pinky) finger
• Base of the left 5th (pinky) finger
• Base of the right thumb
• Base of the left thumb
• Right elbow
• Left elbow
• Right knee
• Left knee
• Lower spine

For adults, a Beighton score of 5/9 or higher signals a positive result. Children before puberty need at least 6/9 points and those over 50 require a score of 4/9 or more.²

Pathophysiology of joint hypermobility

Joint hypermobility may stem from abnormalities in collagen and the extracellular matrix (ECM), resulting in diminished structural stability in ligaments, tendons, and various other supportive tissues surrounding the joints.

In more extreme situations, even little physical injuries can cause serious harm to the skin, muscles, ligaments, tendons, and bones, as well as poor wound healing.

Specific subtypes of EDS, such as the classical and vascular forms, are identified by genetic changes that impact collagen synthesis or processing, including genes like COL5A1, COL5A2, and COL3A1, among others. These deficiencies lead to increased hypermobility by compromising the integrity of connective tissues.⁴

Clinical features of joint hypermobility

• Excessive range of motion
• Joint and muscle discomfort and stiffness
• Clicking joints
• Joint dislocations
• Exhaustion (severe fatigue)
• Frequent injuries, such as sprains
• Constipation 
• Irritable bowel syndrome (IBS)
• Fainting
• Lightheadedness
• Thin or swollen skin

Musculoskeletal pain

Acute musculoskeletal pain is described as episodic pain that is due to subluxations or dislocations of joints. Chronic musculoskeletal pain is mostly observed in EDS, where continuous soft tissue stress is often the result of repeated tissue trauma.

Pain experienced in one area or throughout the body can occur suddenly or persist for an extended period. It can lead to both physical and emotional difficulties, interfere with daily activities, and affect the quality of sleep.

Nociceptive pain, which is associated with damaged ligaments, tendons, joints, muscles and connective tissue, is present in the early stages of acute and localised pain. This type of pain arises from damage to ligaments and tendons, typically resulting from joint instability and microtrauma on the joint surface. This leads to excessive strain and compensatory changes in other areas. ⁵

Contributing factors

• Joint microtrauma and repetitive injuries: increased ligamentous laxity raises the likelihood of repeated sprains and subluxations as a result of accumulated nociceptive signals
• Muscle fatigue due to compensatory mechanisms: excessive use, myofascial pain, and fatigue result from dynamic stability in relation to loose joints
• Central sensitisation: heightened sensitivity to pain, known as hyperalgesia or allodynia, plays a role in the persistence and expansion of symptoms, even among adolescents with hEDS

Impact on quality of life

• Reduced physical activity: Daily activities and involvement are restricted by persistent pain
• Sleep disturbance: Sleep issues are prevalent in EDS and are associated with lower physical and mental health outcomes
• Psychological comorbidities: Common conditions such as anxiety, sadness, and kinesiophobia, which are associated with increased pain and exhaustion, impact the quality of life

Joint instability

What is joint instability?

If the bones in a joint are not securely held together, it can lead to instability. This instability can result in joint subluxations, dislocations, sprains, and various other conditions. Joint instability can lead to both sudden and ongoing pain, which can disrupt everyday activities. The shoulder joint is mostly affected by joint instability, which is seen in hypermobile EDS.^2,6

Pathophysiological mechanisms of joint instability

Joint instability in EDS arises from both structural and functional issues. Impaired collagen leads to looseness, allowing excessive movement in the joints, which results in frequent subluxations and early onset of degenerative changes due to weakened ligaments and joint capsules. ⁶

Consequences

Early-onset osteoarthritis

Joint instability leads to the onset of early osteoarthritis in EDS. Persistent joint pain and stiffness result from rapid deterioration and degeneration of cartilage due to repeated subluxations and atypical mechanical stress.

Functional disability and activity limitation

Significant functional impairment is a result of kinesiophobia, discomfort, and frequent dislocations. To prevent injury, many patients limit their physical activity, which deconditions their muscles and makes it harder for them to participate in everyday, academic, and professional activities.

Risk of long-term joint degeneration

Patients are at risk for increasing joint degeneration due to chronic instability and recurrent microtrauma. This eventually leads to increased disability, persistent physical discomfort, and loss of joint motion.

Interrelationship of hypermobility, pain, and instability

Joint hypermobility, instability, and pain are all interconnected. In EDS, musculoskeletal impairment often follows a cyclical progression. Hypermobility causes instability in the joint due to laxity in ligaments, tendons, and the surrounding structure of the joint. This leads to joint dislocation and joint pain. 

To compensate for this condition, the surrounding muscles work harder to provide stability. These muscles experience pain, inflammation, fatigue, and irritation. This vicious cycle of hypermobility, instability, microtrauma, and pain drives long-term disability and progressive functional decline, contributing significantly to reduced quality of life in affected individuals.⁷

Clinical implications

Due to their frequent overlap with other conditions like fibromyalgia, chronic fatigue syndrome or nonspecific joint hypermobility, musculoskeletal symptoms in EDS pose significant diagnostic challenges and frequently result in misdiagnosis or delayed recognition. 

An integrated approach involving rheumatologists, orthopaedic specialists, physiotherapists, and pain management professionals is essential for effective treatment due to the complex relationships among joint instability, chronic pain, and psychological challenges. 

This type of collaborative assessment not only enhances diagnostic accuracy but also promotes comprehensive care that addresses both the structural and functional aspects of the condition.

Management approaches

Symptom-focused strategies

Physiotherapy and muscle strengthening

Improving physical performance by boosting muscular strength, enhancing proprioceptive awareness, conducting postural exercises such as lumbar spinal stability training, and increasing trunk muscle endurance has been a significant focus of exercise and rehabilitation for those with EDS. ⁸

Pain management (pharmacological and non-pharmacological)

For minor or medium pain, doctors suggest NSAIDS or Tylenol. They are particularly helpful when inflammatory pain is present.

An alternate option would be to use Tramadol, which has both opioid and serotonergic properties. Tramadol has been used to help reduce pain and enhance physical functioning in children with EDS.

It has been discovered that steroids can aid with sudden flare-ups of joint discomfort. To avoid steroid-related negative effects, however, long-term use must be avoided.

Although muscle relaxants like baclofen can help with painful muscular spasms, they shouldn't be used frequently because they may increase joint instability and exacerbate discomfort.⁵

Bracing and joint protection strategies

In unstable joints, the thoughtful use of braces, taping, and orthotic devices can reduce pain and help avoid repeated injuries, emphasising short-term use alongside strengthening exercises to prevent loss of conditioning and teach proper posture for the protection of the joints.⁹

Lifestyle modifications

Strategies such as energy conservation, pacing, ergonomics, sleep hygiene and low-impact aerobic exercises (including swimming or cycling) promote functionality and reduce instances of symptom flare-ups. ¹⁰

Psychological support

In multidisciplinary programs, cognitive behavioural therapy (CBT) and other psychological therapies are advised since they enhance mental health outcomes and pain intensity in EDS patients. ¹¹

Summary

Ehlers-Danlos Syndrome (EDS) is a genetic condition affecting connective tissues, causing symptoms like stretchy skin, hypermobile joints, thin scars, and fragile blood vessels. The International EDS Consortium identifies 13 types of EDS, with classical, vascular, hypermobile, kyphoscoliotic, arthrochalasia, and dermatosparaxis being the most common, and hypermobile EDS being the most prevalent. Musculoskeletal issues are significant in classical and hypermobile EDS, leading to instability, chronic pain, and hypermobility. Joint hypermobility is defined as an increased range of motion at one or more joints and can be classified into generalised, localised, and peripheral types. The Beighton score, a nine-point system, assesses hypermobility, with different threshold scores for adults, children, and older individuals.

The pathophysiology of joint hypermobility involves collagen abnormalities that weaken supportive tissues, increasing injury risk. Clinical features include excessive mobility, joint and muscle pain, clicking joints, fatigue, and digestive issues. Joint instability, particularly in the shoulder, results from loose bones and can lead to subluxations and degenerative changes like early osteoarthritis. These issues impact quality of life by limiting physical activity, causing sleep disturbances, and contributing to psychological conditions. Joint hypermobility, instability, and pain are linked, especially in EDS, leading to a cycle of joint dislocation and muscle strain. This complicates diagnosis due to similarities with other conditions. Treatment requires a team of specialists and involves physiotherapy, pain management, bracing, lifestyle changes, and psychological support.