What Causes hEDS and HSD If There Is No Genetic Test?

People often wonder how a condition like hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorder (HSD) can be diagnosed and treated if there is no genetic test to prove it exists. The short answer is that hEDS and HSD are real, measurable clinical conditions, but their underlying cause has not yet been linked to a single mutated gene that a standard test can spot ^[1][2].

While other rarer types of EDS (like Classical or Vascular EDS) have identifiable single-gene mutations affecting specific types of collagen ^[3], hEDS and HSD likely result from a complex interaction of inherited susceptibility, connective tissue differences, and nervous system responses ^[1][4]. A lack of a single biomarker means that science is still working to map out the exact molecular steps, but scientific uncertainty about the exact cause is not a dismissal of your symptoms ^[5].

hEDS vs. HSD: Clinical Diagnoses

Because there is no blood test, diagnosis relies on a clinician’s evaluation:

• hEDS is diagnosed using strict, internationally defined clinical criteria that look for generalized joint hypermobility alongside specific systemic features and family history, while ruling out other conditions ^[6].
• HSD is diagnosed when a person has symptomatic joint hypermobility but does not meet the strict criteria for hEDS or another specific connective tissue disorder ^[4].

HSD is not simply “mild hEDS”—symptoms can be severe and disabling in either condition ^[7].

What is Established vs. What is Still Being Studied

Connective Tissue and Extracellular Matrix Studies

Even without a genetic test, researchers are finding physical differences in the tissues of people with hEDS and HSD in research settings. Studies looking at fibroblasts—the cells responsible for building the body’s connective tissues—show that they behave differently in some patients ^[9].

In a healthy body, the extracellular matrix (ECM) acts as a highly organized biological scaffolding that holds cells and tissues together. In laboratory studies of hEDS and HSD samples, this scaffolding sometimes shows signs of disorganization, with altered patterns of collagen, elastin, and fibronectin ^[9][11]. The fibroblasts themselves may show increased matrix-degrading activity, meaning the body remodels this scaffolding abnormally ^[12].

It is important to note that these are preliminary findings from selected research samples, not universal diagnostic biomarkers ^[9]. Additionally, while people with hEDS may experience mild skin changes or bruising, severe skin fragility, characteristic scarring, or unusual vascular or organ ruptures are not standard for hEDS and warrant evaluation for other rarer connective tissue disorders ^[2].

A Complex Genetic Hypothesis

Because hEDS frequently runs in families, researchers know there is an inherited component ^[4]. However, the exact causal architecture remains unresolved ^[8]. One leading hypothesis is that hEDS and HSD might be “polygenic,” meaning multiple gene variants interact with developmental and environmental factors to produce the symptoms ^[1][13].

Scientists are actively researching several promising genetic clues. For example, recent studies (published between 2021 and 2024) have identified associations with a gene family called KLK15 in some families, and other large-scale studies have found genetic signals near a gene called ACKR3 ^[14][15]. These are preliminary candidate findings, not established causes or accepted diagnostic markers ^[8].

Currently, when doctors order genetic testing for someone with hypermobility, it is usually to identify or rule out other rare connective tissue disorders ^[2][16]. A negative genetic panel does not rule out hEDS or HSD, and panels can sometimes return “variants of uncertain significance,” which do not definitively establish or exclude a diagnosis ^[16].

Pain Processing and the Nervous System

The chronic pain associated with hEDS and HSD involves more than just mechanical joint wear-and-tear. Symptoms can be severe even when an X-ray shows little structural change, because imaging does not measure pain or soft-tissue instability ^[10].

• Central Sensitization: Some patients develop central sensitization, a condition where the central nervous system becomes hyper-reactive, amplifying pain signals ^[17]. This is a possible contributor to widespread pain, rather than a universal rule ^[17].
• Small-Fiber Neuropathy: Some studies in specialty clinics have found reduced small nerve-fiber density or abnormal nerve testing in a portion of patients with hEDS ^[18][10]. This can contribute to burning or electrical-type pain, though such pain has other possible causes, and small-fiber testing is individualized rather than a routine confirmation test for hEDS/HSD ^[18].

Autonomic and Movement Contributors

Issues often extend to the autonomic nervous system (which controls background functions like heart rate and blood pressure) ^[19]. Conditions like postural orthostatic tachycardia syndrome (POTS) and orthostatic intolerance are reported more frequently in some hypermobility cohorts ^[19][20]. Researchers hypothesize this could be linked to altered nerve function, connective tissue laxity, or abnormal blood flow regulation ^[21]. However, POTS is not part of the hEDS diagnostic criteria, and symptoms like dizziness or rapid heart rate always require formal clinical assessment to rule out other causes (like anemia, medication effects, or endocrine issues) ^[6][19].

Finally, impaired proprioception—the brain’s ability to sense where the body’s joints are in space—is a proposed mechanism for fatigue ^[22][10]. When joints are unstable, studies suggest that altered muscle activation or tendon stiffness may occur as the body tries to compensate ^[23]. This overcompensation is a possible contributor to movement-related pain and fatigue ^[23].

Glossary of Key Terms

• Dysautonomia: Dysfunction of the autonomic nervous system, which controls automatic body functions like heart rate and blood pressure.
• Extracellular Matrix (ECM): The biological “scaffolding” of proteins (like collagen and elastin) that provides structure to tissues.
• Fibroblasts: Cells that synthesize the extracellular matrix and collagen.
• Polygenic: A condition caused by the combined effect of multiple genes, rather than a single gene.
• Proprioception: The body’s ability to sense its position and movement in space without relying on vision.