What is hypermobile Ehlers-Danlos syndrome?
Ehlers-Danlos syndrome (EDS) is a group of heritable connective tissue disorders affecting collagen — the structural protein that gives strength and elasticity to skin, joints, blood vessels, and other tissues. There are thirteen recognised subtypes. Hypermobile EDS (hEDS) is by far the most common, accounting for the majority of EDS diagnoses, and is distinguished from other subtypes by the absence of a known single-gene mutation.[1]
hEDS is characterised by generalised joint hypermobility (joints that move beyond their normal range), musculoskeletal pain, joint instability and recurrent dislocations, and a range of systemic features including autonomic dysfunction, fatigue, gastrointestinal problems, and skin features. It is currently diagnosed on clinical grounds using the 2017 International Classification criteria.
Hypermobile EDS is a systemic connective tissue disorder in which abnormal collagen results in joint laxity, pain, and — through its effects on blood vessel walls — a significant predisposition to autonomic dysfunction including PoTS.
Core features of hEDS
Generalised joint hypermobility · Chronic musculoskeletal pain · Recurrent joint dislocations and subluxations · Soft, stretchy, or mildly fragile skin · Fatigue · Pelvic floor dysfunction
Systemic features
Autonomic dysfunction (PoTS, orthostatic hypotension) · Gastrointestinal dysmotility · Headache and migraine · Anxiety and mood disorder · Mast cell activation syndrome · Sleep disturbance
How often do PoTS and hEDS co-occur?
The co-occurrence of PoTS and hEDS is well documented and substantially exceeds what would be expected by chance. Estimates vary across studies, but the most consistent finding is that approximately 50% of patients with PoTS have features consistent with hEDS or joint hypermobility syndrome.[2] Conversely, autonomic dysfunction — primarily PoTS — is found in a significant proportion of patients with hEDS when formally assessed.
This overlap has important clinical implications: a patient presenting with PoTS should be assessed for features of hEDS, and a patient being managed for hEDS should be asked about orthostatic symptoms — dizziness, palpitations, and fatigue on standing — and formally assessed if present.
Why do PoTS and hEDS co-occur?
The relationship between hEDS and PoTS is not coincidental — there are plausible and well-described biological mechanisms that explain why abnormal connective tissue predisposes to autonomic dysfunction.
Venous laxity and blood pooling
Collagen forms the structural matrix of blood vessel walls. In hEDS, abnormal collagen means that veins — particularly in the lower limbs and splanchnic (abdominal) circulation — are more distensible than normal. When a person with hEDS stands up, these lax veins allow excessive blood pooling, reducing venous return to the heart. The heart compensates by increasing its rate, producing the tachycardia that defines PoTS.[1]
Small fibre neuropathy
Evidence of small fibre neuropathy — damage to the small autonomic nerve fibres that regulate blood vessel tone — is found in a significant proportion of both PoTS and hEDS patients. It is unclear whether this is a primary feature of hEDS or a secondary consequence, but the coexistence of connective tissue abnormality and autonomic neuropathy may compound the orthostatic intolerance seen in these patients.[4]
Mast cell involvement
Mast cells — which are embedded in connective tissue throughout the body — are found in elevated numbers and show increased activation in hEDS. Released mast cell mediators (histamine, prostaglandins) cause vasodilation and can directly worsen orthostatic symptoms. This provides a biological link between the connective tissue disorder, autonomic dysfunction, and MCAS.[3]
Diagnosing hEDS in a PoTS patient
hEDS is diagnosed clinically using the 2017 International Classification criteria, which requires all three of the following criterion groups to be met.[1]
| Criterion | What it involves |
|---|---|
| Criterion 1: Generalised joint hypermobility | Beighton score ≥5 (adults <50); ≥4 (adults ≥50); or ≥6 (pre-pubertal children and adolescents). The Beighton score assesses hypermobility at the little fingers, thumbs, elbows, knees, and spine. |
| Criterion 2: Two or more of three feature groups | Feature A: systemic manifestations of a more generalised connective tissue disorder (5 of 12 features). Feature B: positive family history. Feature C: musculoskeletal complications (recurrent dislocations, chronic pain, or functional impairment). |
| Criterion 3: Exclusions | An alternative diagnosis that accounts for the joint hypermobility is excluded — including Marfan syndrome, other EDS subtypes, osteogenesis imperfecta, and other heritable connective tissue disorders. |
The Beighton score
The Beighton score is a nine-point scale assessing joint hypermobility at five sites (each scored 0–2 for bilateral joints, 0–1 for the spine). It is a useful screening tool but has limitations — many patients with hEDS lose hypermobility with age, and the score should always be interpreted in the clinical context. A patient who was hypermobile in youth but is now less so due to pain-avoidance behaviours or ageing may still meet diagnostic criteria through the other criterion groups.
How hEDS affects PoTS management
The coexistence of hEDS modifies several aspects of PoTS management. The principles remain the same — fluid and salt loading, compression, exercise rehabilitation, medication where needed — but several specific considerations apply.
| Area | Consideration in PoTS + hEDS |
|---|---|
| Compression garments | Particularly important in hEDS due to venous laxity. Waist-high compression (20–30 mmHg) is recommended. Some patients with joint hypermobility find abdominal binders additionally helpful for core stability. Ensure garments do not compress already unstable joints. |
| Exercise rehabilitation | The general PoTS exercise programme applies, but must be adapted to avoid joint injury. Impact activities and those requiring end-range joint loading should be introduced cautiously. Physiotherapy input from someone familiar with hEDS is valuable. Hydrotherapy is well tolerated and beneficial. |
| Pain management | Chronic musculoskeletal pain in hEDS can compound fatigue and limit rehabilitation. Multidisciplinary pain management, physiotherapy, and low-impact conditioning are preferable to opioids, which can worsen autonomic symptoms. |
| MCAS co-management | If MCAS is suspected (flushing, urticaria, GI symptoms alongside PoTS/hEDS), a trial of antihistamines (H1 and H2 blockade) is a reasonable first step. Avoid known mast cell triggers — certain medications, foods, heat, and physical trauma. |
| Medication considerations | No specific pharmacological differences for the PoTS component. However, patients with hEDS often have multiple medication sensitivities; starting at low doses and titrating slowly is advisable. NSAIDs may worsen GI symptoms and should be used cautiously. |
| Referral | Multidisciplinary involvement is often beneficial: Rheumatology or Genetics (hEDS), Cardiology (PoTS), Physiotherapy, and Occupational Therapy. Coordination between teams is important to avoid conflicting advice. |