As a physiatrist who spends too much time trying to touch my toes in clinic- run head first at your flaws!- I've developed a fascination with hypermobility syndromes. These complex conditions affect far more than just joint flexibility, impacting multiple body systems through their effects on connective tissue structure and function. For too long, patients with obvious pain and joint instability have been told “eh, nothing’s wrong” or “it’s all in your head,” due to our relative lack of good data and understanding of the topic. This has left millions suffering and simply frustrated.

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The Genetics: From Simple to Head-Scratching-ly Complicated

Bear with me on this brief journey into the physiology rabbit hole, but the genetic landscape of hypermobility syndromes is surprisingly complex.

Classical Ehlers-Danlos Syndrome (cEDS) represents one of the better-understood variants, caused by mutations in COL5A1 and COL5A2 genes, which result in defective type V collagen production. This altered collagen structure affects tissue integrity throughout the body, leading to characteristic symptoms.

Hypermobile EDS (hEDS) remains genetically elusive – we know it runs in families, but pinpointing the exact genetic cause(s) has proven to be quite difficult. Recent research suggests multiple genes might be involved, potentially affecting not just collagen but also tenascin-X, fibrillin, and other structural proteins. The plot thickens when we consider related conditions like Hypermobility Spectrum Disorder (HSD), which shares many clinical features with hEDS but may have distinct underlying mechanisms. For these reasons, I often approach treatment of hypermobile conditions by addressing the anatomical changes that create associated symptoms like joint instability, flat feet, neck/head pain, etc.

The Comorbidity Constellation: Understanding the Connections

The widespread effects of “connective tissue disorders” help explain the numerous other symptoms we see in patients with hypermobility syndromes. While not everyone with hypermobility will have all of the following conditions, here are some of the the major associations I typically see, as well as their underlying mechanisms:

Muscle/joint manifestations:

• Chronic pain results from frequent subluxations (partial dislocations) and microtrauma to joints, tendons, and ligaments lacking proper stabilization. Picture this: if your shoulders sublux every time you throw your arms up to block a spike while playing volleyball, you may shred the labrum around the shoulder “socket,” stretch out the tendons and ligaments, and then have worse instability afterwards.
• Accelerated osteoarthritis develops due to abnormal joint mechanics and repeated injuries.
• Early-onset degenerative disc disease occurs as the compromised connective tissue affects spinal stability.

Cardiovascular complications:

• Blood vessel fragility stems from defective collagen in vessel walls, leading to increased risk of aneurysms and easy bruising.
• Dysautonomia, particularly Postural Orthostatic Tachycardia Syndrome (POTS), may result from blood vessel elasticity problems affecting blood pressure regulation.
• Similar symptoms may also occur after pain or fear of injury leads to inactivity, which then “untrains” the part of the nervous system that is supposed to detect changes in blood pressure/heart rate and respond quickly and precisely. Keep this theme in mind when we get to some treatments later.

Gastrointestinal issues:

• Intestinal hypermotility and delayed stomach emptying occur due to affected smooth muscle tissue
• Increased risk of hernias and prolapse due to weakened supportive tissues

Associated conditions:

• Mast Cell Activation Syndrome (MCAS) is a condition where mast cells inappropriately release inflammatory molecules, causing allergic-type reactions, flushing, and gastrointestinal symptoms. The connection with hypermobility isn't fully understood.
• Small fiber neuropathy, characterized by damage to small nerve fibers causing pain and autonomic nervous system dysfunction, appears more common in hypermobile patients.
• Chronic fatigue often develops as a combination of poor sleep due to pain, chronic pain’s direct effects on energy/mood, cardiovascular deconditioning, and possibly direct effects on energy metabolism.

Treatment: A Comprehensive Approach

Managing hypermobility requires careful attention to both primary symptoms and secondary complications. Our treatment strategies must balance joint protection with maintaining function and preventing deconditioning.

Key therapeutic approaches include:

1. Physical therapy focused on proprioception and motor control, using careful resistance training to improve dynamic stability without overstraining vulnerable joints. This means that strength training will “tighten up” tendons that are often overly stretchy. Resistance training, when done safely, has other benefits for pain and inflammation that may improve the chronic pain that is common to hypermobility.
2. Cardiovascular conditioning programs that accommodate blood pressure fluctuations and joint instability. Aerobic training significantly improves symptoms and objective measures of blood pressure and heart rate in patients with POTS/dysautonomia.
3. Targeted interventions for other specific complications:
   1. Custom orthotics and bracing for problematic joints (when not actively participating in physical therapy)
   2. Medication management for MCAS, dysautonomia, pain, anxiety, and depression
   3. Regular monitoring of heart health, particularly in variants with increased aneurysm riskLifestyle modifications and ergonomic adjustments to chairs and exercise equipment to protect joints while maintaining quality of life

Key Takeaways:

Hypermobility syndromes are complex multisystem disorders affecting connective tissue throughout the body, not simply a condition of being “double-jointed.” The genetic testing landscape continues to improve, revealing new insights of mechanisms and subtypes of hypermobility syndromes/Ehlers Danlos Syndrome. Treatment success depends on understanding and addressing both primary and secondary effects of the condition. Patient education about joint protection and exercise participation- not avoidance!

The field is evolving rapidly, with new research constantly emerging on genetic causes, disease mechanisms, and treatment approaches. Interdisciplinary and informed care is essential for managing the diverse manifestations of these conditions. Regular monitoring for known complications can prevent or minimize the impact of serious secondary problems.

In conclusion, while we've made significant strides in understanding hypermobility syndromes, there's still much to learn. The complexity of these conditions continues to challenge our diagnostic and therapeutic approaches, but emerging research offers hope for more targeted treatments in the future.

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