hEDS and its fellow travelers

If you’ve spent any time in the hypermobile Ehlers-Danlos syndrome (hEDS) community, you’ve likely noticed a pattern.

The conversation inevitably begins with joints – the growing pains, roaming kneecaps, seemingly countless orthopedic adventures that many patients know all too well. But it rarely ends there.

One patient mentions dizziness and fainting. Another struggles with migraines. Someone else talks about chronic digestive problems and urinary issues. Yet another describes mysterious allergic-like reactions that come out of nowhere. Crushing fatigue. Tachycardia. Endometriosis. ADHD. The list can feel endless.

For most people living with hEDS, the condition does not travel alone.

While joint instability and overwhelming pain are hallmarks of the connective tissue disorder, increasingly, researchers and clinicians are recognizing that hEDS is typically accompanied by a collection of related conditions and symptoms referred to as comorbidities. While not every person with hEDS experiences all of them, these conditions appear often enough that they have become a major focus of research and clinical care.

Ask Chip Norris, Ph.D., a question about hEDS, and the conversation almost immediately moves beyond connective tissue.

Visit the Norris Lab and it’s clear that researchers aren’t just studying joints. They’re studying immune cells, genetics, autonomic dysfunction and the biological clues that are beginning to reveal why so many patients experience the same constellation of symptoms. Together, these discoveries are helping researchers to understand the interconnected nature of connective tissue fragility, autonomic dysfunction and hypersensitivity reactions.

“The body doesn’t organize itself the way medical specialties do,” Norris said. “The immune system, nervous system and gastrointestinal system are in constant communication, which may help to explain some of the most debilitating symptoms experienced by patients with hEDS.”

Driven by that curiosity, Norris and his lab are reshaping how researchers think about hEDS and the many conditions that often accompany it.

Why is this important?

For many patients, the answer is simple.

Imagine going through life with a weird cluster of health challenges and no one realizing they might be connected.

You’re told growing pains are normal. Everyone gets dizzy. That’s classic anxiety. It’s all part of aging.

Meanwhile, you’re trying to make sense of symptoms that seem to have little in common. It can feel a bit like driving cross-country without a map.

But after decades of explaining, convincing, even begging to be believed, patients finally see science catching up. Recognizing that many of these conditions and symptoms aren’t isolated after all, experts are plotting a map that simply didn’t exist a decade ago. This growing understanding offers something many have long sought: context.

Suddenly, the pieces begin to fit together.

Fellow travelers

She walks into the exam room and gives the patient a quick once-over before saying a word. Before the appointment even begins, she’s already making connections. Vascular pooling. Purple feet. Piezogenic papules. Velvety skin. Subtle scars that others might overlook.

For Anne Maitland, M.D., Ph.D., director of the MUSC EDS Center, these clues are part of a much larger story.

Over time, Maitland noticed that hEDS patients frequently described the same constellation of symptoms and coined the term “triad” to describe the connection between it and the condition’s two most common fellow travelers: postural orthostatic tachycardia syndrome (POTS) and mast cell activation disease (MCAD).

“These three conditions co-occur,” she said, “at rates that well exceed statistical probability. Not only do I see it every day, but studies show that at least 25% of women with hEDS suffer with the triad. That’s significant.”

POTS: When standing becomes a challenge

POTS is a form of dysautonomia that causes a malfunction of the autonomic nervous system – the body’s automatic control center for critical functions such as heart rate, blood pressure, breathing and digestion. When it malfunctions, it can fail to regulate blood flow to the brain or stabilize the heart rate when a person moves to an upright position or even during sleep.

People with POTS, Maitland said, typically experience rapid heart rates, dizziness, fatigue, blood pooling in the lower body, heat and exercise intolerance and, in some cases, fainting when they stand.

To the outside world, the symptoms make no sense. Even family members watch in disbelief when a hot shower forces a person with POTS to bed. When standing upright feels like a gamble. When chopping vegetables leaves people with POTS looking like they’ve sprinted a mile. For patients, these aren’t exaggerations. They are daily, debilitating realities.

Mast cells: The body’s overzealous alarm system

MCAD, the other member of the triad that affects some with hEDS, may show up in its best-known form, mast cell activation syndrome (MCAS).

Mast cells are often misunderstood simply as allergy cells, but in reality, they are highly strategic defenders – the first responders of the immune system. Stationed throughout connective tissues, they stand guard at many of the body’s front lines – the skin, lungs and digestive tract – where they help to orchestrate immune responses.

Acting as defender cells, mast cells produce more than 1,200 chemical messengers, or mediators, that coordinate inflammation, defend against threats and support tissue repair. When tightly regulated, those responses protect the body. When mast cells become overactive, however, the same mediators can drive persistent inflammation and tissue damage.

In people with mast cell activation disorders, Maitland explained, these cells can overreact and release a flood of inflammatory mediators – such as histamine, tryptase, cytokines and also prostaglandins, which can cause blood vessels to leak – triggering a cascade of often debilitating symptoms throughout the body, including swelling, a choking sensation, hives, gastrointestinal problems, shortness of breath, migraines and heart palpitations.

Because mast cells can be triggered by more than allergens, Maitland said MCAS is far more than just allergies – it’s immune dysregulation.

“While there is still much to be learned about how the immune system and autonomic nervous system interact, there is ample evidence that each condition in the triad shares a close, albeit complex, biological relationship,” she said.

“Hypermobile individuals are frequently the ‘canaries in the coal mine,’ their bodies serving as an early warning system. Mapping these connections helps us to understand the complex ways the body’s systems communicate, adapt and sometimes break down.”

The combination of symptoms can vary widely from person to person; some can be severe and lead to anaphylaxis – a life-threatening systemic reaction. Although these reactions are real, the perceived threat that triggered the cascade was often as harmless as a sudden temperature change, sunlight, strenuous exercise, a strong odor, pollen or mold. Everyday medications can cause mast cells to dump histamine and other inflammatory chemicals into the bloodstream and surrounding tissue. Even food, drinks and leftovers that are perfectly safe for most people can unexpectedly trigger symptoms in these individuals.

Stress. Viruses. Hormones. Scented candles. For many patients, that unpredictability can be among the most challenging aspects of the condition, turning everyday activities into a constant exercise in vigilance.

The migraine, IBS connections

Migraines and gastrointestinal disorders are also among the most common travelers associated with the condition. In fact, a recent study funded by the National Institutes of Health found that approximately 67% of people with hEDS experience migraines. Studies also suggest that people with hEDS experience significantly higher rates of GI disorders, including irritable bowel syndrome, abdominal pain and gastroparesis, than the general population.

Norris and his team are working to understand exactly why migraines, GI disorders and hEDS occur together so frequently. The lab is exploring the neuroimmune-GI axis, an area Norris believes may offer important clues about why so many patients experience a similar constellation of symptoms.

“Connective tissue, the nervous system, immune system and gut microbiome don’t operate independently,” Norris said. “They are part of an interconnected network influenced by genetics and environment. Looking at any one of those systems in isolation risks overlooking important pieces of the hEDS, POTS, MCAS story.”

Other frequent flyers

If only the list ended there.

A recent study conducted by the Norris Lab found that hEDS patients had, on average, 24 co-occurring conditions. Researchers have also identified higher rates of ADHD, endometriosis, anxiety disorders, ME/CFS and, more recently, long COVID among people with hEDS. Studies suggest that joint hypermobility prolongs recovery and greatly increases the likelihood of developing long COVID.

The growing list of fellow travelers does not mean every patient will experience every condition. Or that every person with hEDS will develop POTS, MCAS, migraines or gastrointestinal problems. But it does mean that all concerned are looking closely at how and why these conditions intersect.

“For too long, these conditions were viewed as separate, requiring separate explanations,” Norris said. “We need to continue to ask bigger questions about how multiple systems are contributing to what we’re seeing. To make meaningful progress, research and clinical care must reflect the interconnected nature of these conditions. Through the MUSC EDS Center, we’re doing just that.”

A clearer map

For patients who have long been navigating the healthcare terrain, progress might not always feel fast enough. Still, conversations today are vastly more promising than those of just a decade ago. With each new study published and every dot connected come valuable insights and never-before-imagined questions.

Real progress happens when all are willing to listen and work together. At the end of the day, everyone is on this journey together. And today, the map is being drawn from many perspectives: Maitland’s observations in the clinic, Norris’ discoveries in the lab, patients’ lived experiences and a new generation of medical students entering the field with more knowledge than ever before. There is much to be hopeful for.

Perhaps that’s the most encouraging development of all.

So while the road ahead remains uncharted, the map is finally becoming clearer.