How do connective tissue disorders contribute to musculoskeletal asymmetry in a 39-year-old female patient with a Beighton score >5 and generalized joint hypermobility, after ruling out vascular and other types of Ehlers-Danlos Syndrome (EDS) through genetic testing?

Mechanisms of Musculoskeletal Asymmetry in Hypermobile EDS

In a patient with Beighton score >5 and confirmed hypermobile EDS (after excluding vascular and other genetic EDS subtypes), musculoskeletal asymmetry develops through a cascade of biomechanical instability: abnormal collagen structure leads to joint laxity, which causes compensatory muscle imbalances, repetitive microtrauma from subluxations, and progressive asymmetric loading patterns that ultimately result in unilateral joint degeneration and chronic pain syndromes. 1

Primary Pathophysiologic Mechanisms

Collagen Structural Abnormalities

• The underlying connective tissue defect in hEDS involves changes in collagen structure or extracellular matrix molecules, though the specific genetic basis remains unidentified 1, 2
• These structural changes reduce the amount of functional collagen available for tissue stability, creating a foundation for asymmetric biomechanical stress 3
• Connective tissue is ubiquitously distributed throughout the body, meaning these defects affect virtually every organ system and musculoskeletal structure 2

Joint Instability and Compensatory Patterns

• Generalized joint hypermobility (confirmed by Beighton score ≥5) creates inherent instability across multiple joints, but patients unconsciously develop asymmetric movement patterns to protect more symptomatic joints 1, 4
• Recurrent joint dislocations and subluxations—particularly affecting shoulders, patellae, and digits—occur more frequently on one side due to dominant limb usage and repetitive stress 4
• The lack of adequate joint stabilization leads to compensatory muscle recruitment patterns that differ between left and right sides 1

Progressive Muscle Imbalances

• Chronic joint instability triggers protective muscle guarding that becomes asymmetric over time, with patients favoring less painful sides and creating progressive strength discrepancies 1
• The general decrease in joint stabilization capacity means that even minor asymmetries in muscle tone or strength become magnified through daily activities 1
• Physical therapy for myofascial release is often necessary before patients can even participate in low-resistance exercise programs, indicating the severity of muscle dysfunction 1

Secondary Biomechanical Consequences

Asymmetric Loading and Degeneration

• Repetitive microtrauma from subluxations creates cumulative damage that preferentially affects the dominant or more frequently used side 1, 4
• Altered loading patterns lead to asymmetric cartilage wear and secondary osteoarthritis, which develops earlier and more severely in hEDS patients 5
• The soft, velvety skin with normal or slightly increased extensibility provides inadequate support for underlying joints, allowing progressive deformity 1, 6

Chronic Pain and Functional Limitations

• Chronic joint and limb pain—a major diagnostic criterion for hEDS—becomes asymmetric as patients preferentially use less painful limbs 1, 4
• Pain management specialists are crucial participants in care, as chronic pain syndromes perpetuate asymmetric movement patterns 1
• Up to 40% of patients report a viral infection as the precipitating event for symptom onset, suggesting that inflammatory triggers may worsen pre-existing asymmetries 4

Associated Systemic Factors Contributing to Asymmetry

Autonomic Dysfunction (POTS)

• Postural Orthostatic Tachycardia Syndrome affects up to 37.5% of hEDS patients and causes orthostatic intolerance with lightheadedness and generalized weakness 1, 4
• Autonomic dysfunction leads to asymmetric blood pooling in dependent limbs, creating unilateral edema and discomfort that reinforces asymmetric posturing 1, 4
• Cognitive dysfunction (brain fog) impairs proprioception and body awareness, preventing patients from recognizing and correcting asymmetric postures 4

Gastrointestinal Manifestations

• Up to 98% of hEDS patients experience GI symptoms including nausea, abdominal pain, constipation, and bloating 1, 4
• Chronic abdominal pain causes protective posturing and asymmetric trunk muscle activation patterns 1
• Functional bowel disorders and delayed gastric emptying contribute to nutritional deficiencies that impair muscle function bilaterally but manifest asymmetrically based on usage patterns 1, 4

Osteoporosis and Bone Density Loss

• Low bone density is common in hEDS, with recommendations for DXA scanning when height loss exceeds one inch 1
• Asymmetric weight-bearing due to joint pain leads to unilateral bone density loss through Wolff's law, creating a vicious cycle of further instability 1
• Calcium and vitamin D supplementation with low-impact weight-bearing exercise is recommended but difficult to implement symmetrically when pain limits movement 1

Clinical Implications and Management Approach

Surveillance Requirements

• Echocardiography is essential as aortic root dilation occurs in 25-33% of hEDS cases, though dissection risk is low without significant dilatation 1, 6, 4
• Repeat echocardiogram every 2-3 years until adult height is reached if aortic root is normal 1, 6

Therapeutic Strategy

• Low-resistance exercise is the cornerstone of management to improve joint stability by increasing muscle tone symmetrically, but physical therapy for myofascial release must precede exercise programs 1
• Orthopedic surgery should be delayed if possible in favor of physical therapy, as patients with hEDS experience decreased stabilization, reduced pain relief, and shorter duration of improvement compared to those without EDS 1
• Pain management specialists are crucial for addressing chronic pain that perpetuates asymmetric movement patterns 1

Critical Pitfalls to Avoid

• Do not assume symmetric pathology—hEDS patients develop highly individualized asymmetric patterns based on their specific injury history and compensatory mechanisms 1, 4
• Avoid aggressive surgical interventions for asymmetry, as outcomes are generally poorer in hEDS patients compared to the general population 1
• Do not overlook cardiovascular surveillance despite the musculoskeletal focus, as 25-33% have aortic root dilation requiring monitoring 1, 6, 4
• Recognize that 26.4% of patients meeting hEDS criteria may have alternative or additional diagnoses on genetic testing with distinct management implications 7