What is hypermobile Ehlers-Danlos Syndrome: What We Know Based on Recent Studies

The Norris Lab
Jan 22
7 min read

What is hypermobile Ehlers-Danlos Syndrome: What We Know Based on Recent Studies

Recent publications from the Norris Lab have provided striking insights and new research directions to better define and understand the pathophysiology of hypermobile Ehlers-Danlos syndrome. These studies support one of our main objectives at the Norris Lab: to investigate the genetic and biological drivers of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders to advance scientific discovery, improve clinical understanding, develop more relevant diagnostics, and spur the development of effective treatments.

An uncomfortable truth about science is that our understandings of our research topics are constantly evolving, shifting, and expanding. Researchers must work tirelessly to adjust hypotheses, troubleshoot failed theories and experiments, and ask the hard questions that may have complex answers.

Hypermobile Ehlers-Danlos syndrome is no exception to that rule. Traditionally, hEDS has been classified as a primary connective tissue disorder, meaning it is an inherited condition affecting the collagen and elastin of connective tissues. A secondary connective tissue disorder results from the immune system attacking connective tissue and can often follow a trigger or be related to other inflammation or immune issues. According to our recent studies, which are outlined below, it no longer remains so apparent as to which category hypermobile Ehlers-Danlos syndrome falls into. This article offers a breakdown of four recent publications by the Norris lab, how they relate to one another, and their implications for the diagnosis and treatment of hEDS.

Defining the Chronic Complexities of hEDS and HSD: a global survey of diagnostic challenges, lifelong comorbidities and unmet needs

This study describes the clinical scope of symptoms and comorbid conditions experienced by people with hEDS and HSD. What stands out about this study is how multisystemic these conditions are, with patients in the hEDS cohort having on average 24 co-occuring conditions and experiencing chronic pain in approximately 6 joint sites. Hypermobile EDS patients reported chronic pain, GI issues, and autonomic dysfunction as their three most bothersome symptoms. These win out over joint laxity, stretchy skin, easy bruising, and other typical symptoms you might see listed in a medical textbook for hEDS. There was a frequent overlap between allergies, migraine, anxiety, depression, POTS, GERD, constipation, tendonitis, TMJ disorder, insomnia, PTSD, bursitis, and asthma. A significant proportion of participants also experienced complications related to local and/or general anesthesia. The hEDS group was over two times more likely to experience shortened effect, insufficient pain control, intubation complications, and anaphylaxis.

Most notably, triggering events were common among this patient population. 70.1% of individuals with hEDS and 65.0% of those with HSD identified a specific triggering event that they believed contributed to the onset or heightening of their disease symptoms. Puberty and pathogens (viral or bacterial) were the most commonly reported triggers, but other triggers included pregnancy, physical accidents, and psychological or emotional events.

The high prevalence of comorbidities and symptoms across many body systems, along with the prevalence of triggering events, suggests possible immune dysregulation contributing to, worsening, or driving hEDS. These findings raised an important question: if immune dysregulation is present, how might it intersect with connective tissue biology at a molecular level?

Proteomic Discoveries in Hypermobile EDS Reveal Insights into Disease Pathophysiology

In this study researchers took an unbiased approach to identify detectable protein differences in the blood. By studying changes in these protein levels, scientists hoped to better understand what was happening in the bodies of patients with all of these symptoms and comorbidities that are so prevalent in hEDS.

Of the 478 proteins identified in the blood samples, 35 showed significantly altered expression between hEDS patients and controls. Some of the proteins were upregulated, meaning there were higher levels of that protein in hEDs patients compared to the control sample, whereas some were downregulated, meaning there were lower levels. Many of the proteins that were significantly different were proteins involved in the complement cascade or associated with kallikrein activity. Altogether, 28 of 35 proteins (80%) were linked to immune response, coagulation, blood pressure regulation, or inflammatory processes. Researchers also found signs of inflammation; many cytokines were significantly lower in abundance in hEDS patients than in controls, which could suggest a couple different things. Complement and cytokine changes point to altered immune regulation.

So what does this mean? Researchers found evidence of immune dysregulation in the blood of individuals with hypermobile Ehlers–Danlos syndrome that was not present in controls. Using this blood-based proteomic approach, they did not detect differences in circulating extracellular matrix proteins that make up connective tissue. Instead, the differences were primarily in immune-related proteins involved in immunity, inflammation, complement activation, blood clotting, and other biological processes that could influence connective tissue and multiple organ systems.

Importantly, the absence of detectable connective tissue protein differences in blood does not mean that connective tissue itself is normal in hEDS. Many key structural and regulatory extracellular matrix changes occur within tissues and may not be reflected in circulating protein levels or captured by this particular scientific approach.

Does this mean hEDS is driven by immune dysregulation? Maybe, maybe not. While blood levels of complement proteins may suggest increased activation or consumption, more research is needed to determine whether immune dysregulation is a primary driver, a contributing factor, or a downstream consequence of connective tissue changes in hypermobile Ehlers–Danlos syndrome.

KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome

Identifying the genetic risk factors for hEDS remains a crucial piece in improving diagnosis and treatment of this condition. Researchers examined the DNA of 200 hEDS patients using a method called Whole Exome Sequencing (WES), which checks all the protein-making instructions in the DNA. They discovered that 1/3 of patients had mutations in a group of genes called KLK genes. Researchers specifically focusing on one mutation in the KLK15 gene (called G226D) because of its presence in two families.

The KLK15 protein is widely expressed in human tissues, including connective tissue (like ligaments), glandular tissue (thyroid, adrenal glands), and immune cells (mast cells), all of which are relevant to hEDS symptoms. In particular, KLK15 was seen to interact with fibronectin and lysyl oxidase, both ECM and connective tissue components. The researchers found that the mutation on KLK15 causes a misdistribution of the LOX, a disruption that provides a potential explanation for the observed changes in collagen structure and the resulting loss of tissue integrity and mechanical strength present in hypermobile EDS.

To see if this mutation actually caused connective tissue dysfunction, the researchers created a mouse model that carried the same KLK15 mutation. The mice exhibited symptoms that closely mirrored those seen in human hEDS patients. They had:

Connective Tissue Damage: The mice showed structural changes in their connective tissue. For example, their Achilles tendons were mechanically weaker.
Collagen Disruption: The collagen fibrils (the tiny fibers that give tissue strength) were noticeably smaller in diameter.
Heart Problems: The mice developed connective tissue changes in their heart valves, leading to mitral valve prolapse (MVP), a common complication in hEDS.
Beyond the structural defects, the mutant mice also showed systemic changes in their immune signaling, with a consistent downregulation of several cytokines (small proteins that regulate inflammation and immune responses).

So, is KLK15 "the gene" for EDS?

The evidence suggests it is not a single-gene cause, but rather a contributing factor within a broader genetic and biological landscape.

Complex and Regulatory Drivers of Hypermobile Ehlers-Danlos Syndrome: Insights from Genome-Wide Association Study Meta-analysis

This paper is currently a preprint and has not yet been peer-reviewed.

These findings support the theory that hypermobile Ehlers-Danlos Syndrome is polygenic and provide the first solid genetic basis for hEDS involving common genetic variants.

In simpler terms, hypermobile Ehlers-Danlos syndrome is not caused by a single gene; instead, it is likely caused by many common genetic variants that each make small contributions to risk. These genetic differences affect systems involved in pain, the immune system, connective tissue, and the nervous system.

It is scientifically appropriate that the KLK15 variant did not stand out in this type of genetic study (GWAS) because the KLK variants are relatively common. KLK15 mutations, such as G226D (reported in the KLK15 publication), likely have incomplete penetrance, meaning they do not cause symptoms in everyone who carries them. Some individuals may carry other genetic characteristics, or protective alleles, which are genetic variants that buffer or counteract the effects of a harmful mutation, such as KLK15 G226D. For example, large-scale sequencing studies suggest that ~3% of the population carries variants predicted to be damaging. Yet, most do not develop overt disease due to other protective alleles in their genetic background, epigenetic factors, or the absence of environmental exposures.

The fact that KLK15 was not enriched in the GWAS study does not indicate that KLK15 does not play a role in hEDS for some people. The mouse model provides firm evidence of pathogenicity and disrupted collagen organization in mice with this mutation. This supports the idea that KLK variants may act as risk-modifying variants rather than as universally causative mutations. Life events and environmental factors, such as puberty, infections, pregnancy, or physical injury, in combination with genetic background may then act as triggers that determine when symptoms start and how severe they become.

So, what does this mean going forward?

Taken together, these studies support a reconceptualization of hypermobile Ehlers-Danlos syndrome not as a single-gene connective tissue disorder, but as a complex condition arising from interactions among genetic variation, immune regulation, connective tissue biology, and environmental triggers. This integrated view provides a more accurate foundation for future research and represents a critical step forward.

This evolving framework has several important implications.

First, diagnostic criteria must better reflect the multisystem nature of hEDS and HSD and the lived experiences of patients. Current criteria emphasize joint hypermobility and structural features but underrepresent immune, autonomic, gastrointestinal, and pain-related manifestations that dominate patient burden. Efforts to create more comprehensive diagnostic criteria and clinical guidelines are being made in 2026.

Second, continued large-scale genetic and biological research is essential. We are currently collecting whole genome data from individuals with hypermobile Ehlers-Danlos syndrome to conduct expanded genome-wide analyses. These efforts aim to identify additional risk-modifying variants, clarify genetic subtypes, and better understand how common variants interact with environmental exposures to influence disease onset and severity.

Third, immune-connective tissue interactions represent a critical area for future investigation. Ongoing studies are examining how immune signaling pathways intersect with extracellular matrix organization, tissue integrity, and pain signaling. Understanding these interactions may help explain triggering events, fluctuating symptom severity, and the wide clinical variations seen in hEDS and HSD.

Importantly, several pathways implicated in these studies have the potential to open new avenues for therapeutic development. Early work targeting specific pathways based on new genetic and scientific discoveries highlights the possibility of treatments that move beyond symptom management toward mechanism-informed care.

Finally, progress in hEDS research depends on increasing the critical mass of clinicians, scientists, and patient-partners engaged in this work. Patient-science programs, medical education initiatives, biorepositories, and multidisciplinary clinical centers, such as comprehensive EDS programs, are essential to translating research findings into meaningful improvements in care.

Hypermobile Ehlers-Danlos syndrome is not a disorder defined by what we do not yet know. Rather, it is a condition whose complexity is now coming into focus, one that demands integrated, collaborative, and patient-informed approaches to research, diagnosis, and treatment.