A Century of Hidden Complexity: The Evolution of Ehlers-Danlos Syndrome Research

Why I Looked Back: Tracing the Roots of a Modern Paradox

Why does it take fifteen years to diagnose a condition first described in 1901? Why do patients with hypermobile EDS—the most common form—lack a confirmatory test when rarer subtypes have clear genetic markers? Why were chronic pain, autonomic dysfunction, and gastrointestinal symptoms only recently recognized as core features rather than secondary complications?

These questions emerged from a tension I couldn't reconcile:

• Ehlers-Danlos syndrome has been documented for over a century, yet today the average time from first symptoms to diagnosis still exceeds a decade.
• Misdiagnosis remains common, and the vast majority of patients report psychiatric misattribution at some point along the way.

This paradox doesn't just arise from medical neglect or indifference, and for me, it demanded a deeper explanation.

So I decided to trace the historical arc of EDS research, mapping how scientific attention shifted over time. What I found was illuminating: from 1900 to 1950, 90% of EDS research focused on clinical observation, describing what physicians could see and touch. By 2020–2025, that ratio had inverted: 70% of research now emphasizes genetics and molecular mechanisms. This shift accelerated in distinct phases: biochemical characterization technologies advanced through the 1970s–1990s, enabling the identification of collagen defects that would underpin the 1997 Villefranche classification. After 2000, discrete gene identification accelerated dramatically, driven by the genomic revolution and plummeting sequencing costs, ultimately leading to the refined 2017 International Classification that expanded EDS to its current thirteen recognized subtypes.

This profound shift, while scientifically productive, created winners and losers. The subtypes that could be molecularly defined gained legitimacy, confirmatory tests, and research funding. Hypermobile EDS on the other hand remained resistant to genetic explanation, and thus in diagnostic limbo. What surprised me most was recognizing that today's diagnostic challenges are not aberrations but predictable outcomes of specific historical moments: an early overemphasis on skin appearance that created lasting diagnostic blind spots, an asymmetric molecular revolution that left the most common form behind, and a remarkably slow recognition of multisystem involvement despite decades of patient testimony.

Understanding this history reframes present challenges. The diagnostic delays and fragmented care that frustrate patients today reflect structural features of how EDS was first recognized, subsequently classified, and how scientific attention changed over time. Here, I've traced that evolution through five distinct eras: early clinical descriptions, diagnostic missteps that became entrenched, molecular breakthroughs that clarified some forms while leaving others unresolved, and the slow, uneven recognition of the multisystem features that ultimately define the lived experience of the disease.

The Early Clinical Era: 1901–1930s

The history of EDS began with careful clinical observation. In 1901, Danish dermatologist Edvard Ehlers documented a patient with joint hypermobility, fragile skin, and a tendency toward spontaneous bruising. The description was remarkably precise and captures features still considered characteristic today.

Early progress, however, was quickly complicated. In 1908, French dermatologist Henri-Alexandre Danlos presented a patient whose extreme skin extensibility led to lasting misconceptions. Over time, this description fostered an expectation that visible skin hyperextensibility was a defining feature of the syndrome, an assumption that would later exclude many patients whose skin was fragile or soft rather than dramatically stretchable.

The confusion further deepened in 1933 when Achille Miget examined tissue from Danlos's original patient and determined that the findings were inconsistent with what would later be understood as EDS. Miget correctly concluded that the case represented pseudoxanthoma elasticum rather than EDS (Hamonet et al., 2015).

Yet, by the time the condition acquired its hyphenated name in 1936 (coined by Frederick Parkes-Weber), the association with extreme skin stretchiness had already taken hold. This early diagnostic anchor, the idea that EDS must look a certain way, proved surprisingly durable. Even today, patients without overt skin hyperextensibility are often told that EDS is unlikely, despite meeting other criteria.

The Mid-20th Century: Clinical Description and the Villefranche Classification

From the 1950s through the 1970s, clinicians accumulated increasingly detailed case reports. It became clear that EDS was not a single disorder but a group of related conditions with overlapping features. Some patients experienced catastrophic vascular complications; others primarily struggled with joint instability, skin fragility, or musculoskeletal pain.

Yet without molecular tools, classification remained largely descriptive. To make it worse, diagnostic criteria varied across institutions and countries, limiting reproducibility and slowing research progress. The absence of standardized nosology made it difficult to compare studies or build cumulative knowledge.

This began to change with the Villefranche Nosology published in 1998, led by Peter Beighton, the same clinician who had developed the widely-used Beighton score for assessing joint hypermobility in 1973 (Beighton et al., 1973), (Beighton et al., 1998).

Now, for the first time, EDS was organized into six clinical subtypes:

• classical
• hypermobile
• vascular
• kyphoscoliotic
• arthrochalasis
• dermatosparaxis

Crucially, this framework linked specific clinical phenotypes to known molecular defects. Classical and vascular EDS were associated with pathogenic variants in collagen genes, while other subtypes were tied to defects in collagen-modifying enzymes.

This shift fundamentally altered the field. EDS was no longer simply a clinical curiosity but a genetically grounded group of connective tissue disorders. Genetic testing became possible for most subtypes, enabling confirmation, family counseling, and targeted surveillance. At the same time, the limitations of this progress became immediately apparent. Hypermobile EDS (hEDS), the most common form, remained without a known molecular cause and therefore without a confirmatory test (Forghani, 2019). It persisted as a diagnosis based on clinical criteria alone, a distinction that has had long-term consequences for patients and researchers alike.

Molecular Genetics and Collagen Biology: Late 20th Century

Advances in molecular genetics during the 1990s transformed understanding of many EDS subtypes. Researchers identified pathogenic variants in genes encoding fibrillar collagens, particularly COL5A1, COL5A2, and COL1A1, as well as enzymes involved in collagen processing (Ritelli et al., 2013). These discoveries clarified why EDS affects skin integrity, joint stability, wound healing, and vascular strength.

Type V collagen emerged as central to classical EDS, with pathogenic variants in COL5A1 and COL5A2 accounting for the vast majority of cases (Gong et al., 2021). Vascular EDS was linked to pathogenic variants in COL3A1, explaining the arterial fragility and life-threatening complications characteristic of that subtype (Henneton et al., 2019). These findings provided both intellectual coherence and practical clinical benefit. For many patients, a genetic result could finally validate their diagnosis and guide management.

Yet progress stalled when it came to hEDS. Despite extensive investigation, no single gene or consistent molecular mechanism emerged (Scicluna et al., 2021). Proposed associations, including variants affecting tenascin-X or lysyl oxidase pathways, explained only a small fraction of cases. As a result, hypermobile EDS remained solely diagnosed by clinical presentation, and only after other conditions were excluded. This asymmetry, where rarer subtypes had clear molecular explanations while the most common did not, shaped research priorities and clinical attitudes in subtle but lasting ways.

Recognition of Comorbidities: A Fragmented Process

One of the most consequential features of EDS history is how slowly its multisystem nature was recognized (Hamonet et al., 2015). Today, EDS is understood as a condition that affects far more than joints and skin, but that understanding emerged gradually and unevenly.

Chronic Pain

Chronic pain, for example, was long assumed to be a secondary consequence of joint instability (Bénistan & Martinez, 2019). Over time, clinicians began to observe that pain in EDS was often severe, persistent, and disproportionate to structural findings. By the early 2000s, reports described pain with neuropathic features and evidence of central sensitization. Large studies later confirmed that nearly all individuals with hypermobile EDS experience chronic pain, often beginning in childhood. Yet pain remained peripheral in diagnostic frameworks for years, and its underlying mechanisms remain incompletely defined.

You can read my breakdowns of the science and physiology of chronic pain here: Part 1 and Part 2

Autonomic Dysfunction

Autonomic dysfunction followed a similar trajectory (Mathias et al., 2021). Patients frequently reported dizziness, palpitations, syncope, and exercise intolerance decades before these symptoms were formally studied. Only in the late 2000s and 2010s did systematic research demonstrate a markedly increased prevalence of conditions such as postural orthostatic tachycardia syndrome (POTS) in EDS populations (Wu & Ho, 2024). Even now, the biological relationship between connective tissue differences and autonomic regulation is not fully understood, leaving patients caught between specialties and, historically, vulnerable to psychiatric misattribution.

Check out my breakdown of the science and physiology of dysautonomia here: Dysautonomia

And the new 2025 POTS diagnostic and care consensus here: 2025 POTS Review

Gastrointestinal Involvement

Gastrointestinal involvement was also slow to gain recognition (Brooks et al., 2021). While early reports occasionally noted digestive complaints, large cohort studies in the 2010s revealed that gastrointestinal symptoms are extremely common in hypermobile EDS (Alomari et al., 2020). Whether these arise from primary connective tissue changes, secondary motility dysfunction, autonomic involvement, or a combination of factors remains an area of active investigation.

Mast Cell Activation

Mast cell activation symptoms represent the most recent area of emerging recognition. While allergy-like features were sporadically noted in earlier literature, systematic attention is recent and remains controversial (Wang et al., 2021). Some studies suggest a substantial overlap between EDS and mast cell–related disorders, while others caution against overgeneralization. The relationship is still being defined, reflecting a broader pattern in EDS research: patient experience often precedes formal mechanistic explanation.

New research has recently been published on the EDS/MCAS link, so stay tuned for my in depth breakdown of that work!

Diagnostic Criteria: Evolution and Unintended Consequences

Both the Villefranche criteria and the revised 2017 International Classification represented important attempts to bring clarity to EDS diagnosis (Ralovich et al., 2019). Each, however, introduced trade-offs. Earlier criteria prioritized specificity but missed milder or atypical presentations. The 2017 revisions sought to address this by refining diagnostic thresholds and introducing Hypermobility Spectrum Disorder as a category for individuals with significant symptoms who did not meet full hypermobile EDS criteria (Castori et al., 2017).

This distinction was pragmatic but controversial (Ritelli et al., 2023). Growing evidence suggests that hypermobile EDS and HSD may represent points along a continuum rather than discrete entities. Yet in practice, the diagnostic label carries real consequences, affecting access to care, insurance coverage, and social recognition. For many patients, the persistence of symptoms alongside an ambiguous diagnosis reinforces the sense that their condition exists in a gray zone of medicine.

Notably, diagnostic frameworks have historically emphasized structural connective tissue features, while pain, autonomic dysfunction, and gastrointestinal symptoms remained secondary (McGillis et al., 2019). This legacy continues to shape diagnostic journeys, contributing to delays and fragmentation of care.

Research Volume and Public Awareness: A Stalled Curve

Despite molecular advances, overall research output on EDS remains modest relative to its prevalence. Funding is limited, and clinical expertise is unevenly distributed (Rzenik et al., 2025). Care is often fragmented across specialties, each addressing isolated symptoms without a unifying framework.

Public awareness has followed a different trajectory. For much of the twentieth century, EDS was viewed as rare and unusual. The rise of online patient communities in the 2000s and 2010s dramatically altered this landscape. Patients began recognizing shared patterns long before these were reflected in textbooks or training curricula. This shift empowered many individuals but also exposed a gap between lived experience and clinical recognition, a gap that remains a source of tension.

The Diagnostic Delay Paradox

Today, median diagnostic delays for EDS often exceed fifteen years (Daylor et al., 2025). This persists despite improved criteria and increased awareness. The reasons, however, are historically rooted:

• early diagnostic stereotypes still influence clinical judgment
• hypermobile EDS lacks a confirmatory test
• multisystem symptoms are distributed across specialties
• formal medical education has been slow to incorporate evolving knowledge

These delays are not the result of individual failure. They reflect structural features of how EDS has been conceptualized, studied, and taught over the past century.(Feldman et al., 2023)

Synthesis: How History Shapes Present Challenges

EDS research has advanced through cycles: brief periods of breakthrough alternating with long stretches when prevailing concepts remained fixed. Early diagnostic misconceptions shaped expectations for generations. Molecular breakthroughs clarified some subtypes while leaving the most common one unresolved. Recognition of multisystem involvement emerged gradually, often driven by patient observation rather than formal research.

Understanding this history reframes present challenges. Diagnostic delays and fragmented care are not anomalies but predictable outcomes of how the condition evolved within medicine. Moving forward will require not only additional research and training, but a broader conceptual shift: seeing EDS not as a narrowly defined collagen disorder with secondary complications, but as a complex, multisystem condition whose full biology is still being uncovered (Petrucci-Nelson et al., 2025).

In that sense, the early descriptions by Ehlers remain strikingly relevant. What has changed is our growing awareness of how much more there is to understand, and the recognition that the path to that understanding has been shaped by the accidents of early diagnosis, the limitations of molecular tools, and the voices of patients whose lived experience has consistently exceeded what medicine was prepared to recognize.

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