Cause of hEDS
The exact cause of hypermobile Ehlers-Danlos syndrome (hEDS) is still being investigated, but researchers are uncovering important clues—especially related to how connective tissue behaves differently in people with this condition.
No Single Gene Mutation Identified (Yet)
Unlike other types of Ehlers-Danlos syndrome that are tied to specific gene mutations (usually involving collagen), hEDS does not have one known genetic cause. Despite extensive research, no single gene has been consistently linked to the condition, which makes diagnosis and understanding more challenging. hEDS might be caused by a combination of gene mutations, but this has not been definitively established. Recent research suggests that hEDS may have a complex genetic architecture, potentially involving multiple genetic variants of small effect rather than a single mutation.
hEDS appears to run in families, and evidence suggests it follows an autosomal dominant inheritance pattern. This means that only one copy of an altered gene—from either parent—is enough to increase the risk of having the condition. Still, some people with hEDS have no known family history, which may be due to spontaneous (new) mutations or undiagnosed relatives with milder symptoms.
Where Gene Mutations Come From
Even though the specific gene for hEDS hasn't been found, gene mutations can occur in three general ways
Hereditary – passed down from a parent who also has the mutation.
Spontaneous – a new mutation arises during early development, not inherited from either parent.
Environmental – rarely, environmental factors like radiation or chemical exposure can cause gene changes, though this is less likely in hEDS.
In hEDS, most cases appear to be inherited, but some may result from spontaneous genetic changes that occurred before or shortly after conception.
Abnormal Collagen and Weak Connective Tissue
Even without a known mutation, scientists have found consistent changes in the structure of collagen and the extracellular matrix (ECM). The extracellular matrix (ECM) is a network of proteins and other molecules that surrounds and supports cells in tissues throughout the body. It provides structural strength, elasticity, and signaling cues that help cells function properly. In people with hEDS
Collagen fibers tend to be disorganized and irregular.
The extracellular matrix is less dense and weaker, which contributes to joint looseness and frequent soft tissue injuries.
Collagen in hEDS may have a lower elastic modulus, meaning it stretches too easily and doesn't return to shape properly.
These abnormalities help explain common symptoms like joint hypermobility, frequent sprains or subluxations, and easy bruising or tissue fragility, even from everyday activities.
Differences at the Cellular Level
Connective tissue cells in hEDS (called fibroblasts) also behave differently:
Many show signs of transforming into myofibroblasts, a more activated cell type that is usually involved in wound healing.
These cells often produce too many enzymes that break down the ECM, weakening tissues further.
There is also increased inflammation and disruptions in how cells stick to their surroundings, which may contribute to widespread pain, fatigue, and multisystem symptoms.
A Complex Puzzle
While the underlying gene hasn't been identified, hEDS appears to result from a complex interaction of
Weak or disorganized collagen
Abnormal behavior of connective tissue cells
Increased inflammation and pain sensitivity
These issues affect the entire body, which explains the wide range of symptoms—not just in the joints and skin, but also in digestion, the nervous system, and beyond.
Summary
Hypermobile Ehlers-Danlos syndrome (hEDS) does not yet have a clearly defined genetic cause, but it likely involves one or more dominant gene mutations that may be inherited, spontaneous, or rarely, environmentally triggered.
What researchers do know is that people with hEDS have
Weakened connective tissue due to abnormal collagen and ECM
Overactive or altered fibroblasts that contribute to tissue breakdown
Increased pain sensitivity and inflammation
Together, these factors cause the hallmark symptoms of hEDS: joint hypermobility, tissue fragility, frequent injuries, and chronic pain.
