Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders caused by defects in collagen or in the proteins that interact with collagen. The result is joint hypermobility, skin hyperextensibility and tissue fragility.

Genetics and frequency. Different types have different genes, and most are autosomal dominant. The prevalence is 1 in 5,000, and hypermobile EDS (hEDS) is the most common type.

The collagen defect. Different types affect different collagen genes, and the result is weak ligaments, skin and blood vessels.

Why the joints are unstable. Lax ligaments cannot stabilise the joints, so they subluxate and dislocate recurrently. Microtrauma and joint damage add chronic pain, although laxity alone does not explain the pain (see Multisystem Comorbidities below).

The major types compare as follows.

Hypermobile EDS. The gene is unknown, so the diagnosis is clinical, by the 2017 criteria set out under Investigations. The orthopaedic picture is joint instability and dislocations, with chronic pain and fatigue.

Classical EDS. The skin is hyperextensible, by more than 1.5cm, and heals with atrophic "cigarette-paper" scars. The joints are hypermobile too.

Vascular EDS. Caused by a COL3A1 mutation, it is the most dangerous type. The skin is thin and translucent with visible veins, and the risks are arterial rupture and bowel perforation.

Kyphoscoliotic EDS. A PLOD1 mutation, inherited as an autosomal recessive trait. It brings severe neonatal hypotonia, progressive kyphoscoliosis and joint hypermobility, and scoliosis surgery is undertaken if needed.

History. Ask about dislocations and subluxations, chronic pain and fatigue, easy bruising, problems with wound healing, and the family history.

The Beighton score. Generalised joint hypermobility is scored out of 9:

• Passive dorsiflexion of the fifth metacarpophalangeal joint beyond 90° - one point each side
• Thumb apposition to the flexor surface of the forearm - one point each side
• Elbow hyperextension beyond 10° - one point each side
• Knee hyperextension beyond 10° - one point each side
• Forward trunk flexion with the knees locked and the palms flat on the floor - one point

The cut-off is age-adjusted: 6 or more before puberty, 5 or more from puberty to age 50, and 4 or more over 50.

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Skin and joints. Examine the skin for hyperextensibility, texture and scars, and the joints for instability and signs of previous dislocations.

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Genetic testing. Classical, vascular and other types can be confirmed genetically. hEDS has no genetic test and is diagnosed clinically.

The 2017 hEDS criteria. All three are required:

1. Generalised joint hypermobility on the age-adjusted Beighton score. A 5-point self-report questionnaire can substitute one point if the Beighton is one below the cut-off for age.
2. Two or more of Features A, B and C:
   • Feature A, systemic features of a generalised connective-tissue disorder, five or more of twelve: unusually soft or velvety skin; mild skin hyperextensibility; unexplained striae; bilateral piezogenic heel papules; recurrent or multiple abdominal hernias; atrophic scarring; pelvic-floor, rectal or uterine prolapse; dental crowding with a high narrow palate; arachnodactyly; an arm-span-to-height ratio of 1.05 or more; mitral valve prolapse; aortic root dilatation.
   • Feature B, a positive family history: one or more first-degree relatives meeting the criteria.
   • Feature C, musculoskeletal, one needed: daily musculoskeletal pain in two or more limbs for at least 3 months; chronic widespread pain for at least 3 months; or recurrent joint dislocations or frank instability without trauma.
3. Exclusion of alternatives. Unusual skin fragility is absent (it would suggest another EDS subtype), and other heritable and acquired connective-tissue disorders (including autoimmune disease) and alternative causes of hypermobility or hypotonia (neuromuscular or skeletal dysplasias) are excluded.

Hypermobility spectrum disorder. Symptomatic hypermobility that does not satisfy all three criteria is classified as hypermobility spectrum disorder (HSD), and it is managed identically.

EDS involves the skin and the joints together, with chronic pain. The other conditions in the differential are distinguished below.

Conservative care comes first. Physiotherapy strengthens the muscles around the joints so that they provide the stability the ligaments cannot. Around it sit multimodal pain management, activity modification that avoids hyperextension and high-impact activities, and bracing for unstable joints.

When to operate. Surgery is for recurrent dislocations that have not responded to conservative treatment. Tissue heals poorly and recurrence is high, so expect a higher failure rate than in the normal population.

Joint stabilisation. Recurrent shoulder and patellar dislocations are stabilised with the standard procedures, Bankart repair and MPFL reconstruction among them, but with stronger fixation. The precautions around them follow CARE.

Lifespan. hEDS carries a normal lifespan but chronic symptoms. Vascular EDS reduces life expectancy through arterial rupture: median survival was 48 years in the Pepin 2000 NEJM cohort.

The comorbidity cluster. hEDS commonly co-occurs with a recognised triad of systemic problems:

• Dysautonomia or orthostatic intolerance, most characteristically postural orthostatic tachycardia syndrome (POTS), with light-headedness, palpitations, presyncope and fatigue on standing
• Functional gastrointestinal disorders and dysmotility: reflux, bloating, early satiety and IBS-type symptoms
• Mast cell activation symptoms: flushing, urticaria, and food or drug sensitivities

Chronic fatigue, anxiety and depression, pelvic-floor dysfunction with urogenital or rectal prolapse, and easy bruising are also frequent.

Why the pain persists. Chronic pain in hEDS is not explained by joint laxity alone. It is increasingly understood as nociplastic pain with central sensitisation, compounded by dysautonomia, deconditioning and impaired proprioception. That is why pain frequently continues even when the joints are mechanically "stable", and why isolated stabilisation surgery rarely resolves it.

The orthopaedic take-home. Treat the orthopaedic complaint as one facet of a systemic disorder. Prioritise graded, proprioceptive physiotherapy and pacing, multimodal and neuromodulatory analgesia, and management of the autonomic and GI comorbidities within a multidisciplinary team, and always screen for the vascular-EDS red flags before any intervention.

Global epidemiology

• All EDS types combined: roughly 1 in 5,000. Hypermobile EDS / hypermobility spectrum disorders dominate (the large majority of cases).
• Vascular EDS is rare: 1 in 50,000 to 1 in 200,000 (Byers et al, 2017).
• hEDS shows a marked female predominance in clinic populations; rare recessive types (kyphoscoliotic, dermatosparaxis) cluster in consanguineous populations.

Side-by-side guidance

There is no orthopaedic implant registry signal specific to EDS, but registry-style cohort data (e.g. the Pepin NEJM cohort) underpin natural-history estimates, and the international EDS registry is building genotype-phenotype data.

High- vs limited-resource practice

• Well-resourced: gene-panel/exome testing, MDT (genetics, rheumatology, cardiology, physiotherapy, pain), celiprolol for vascular EDS, annual cross-sectional vascular imaging.
• Limited-resource: diagnosis remains largely clinical (Beighton score, skin and family history); prioritise physiotherapy, activity advice and recognition of vascular EDS red flags for urgent referral when genetic testing and celiprolol are unavailable.

The hEDS / HSD boundary. The distinction between hEDS and HSD is debated. Many "hEDS" patients meet HSD rather than strict 2017 criteria.

Paediatric diagnosis. A higher Beighton cut-off (the 2023 international paediatric framework proposes 6/9 or more) better identifies true hypermobility in children, and the label hEDS is reserved for biologically mature adolescents.

Surgical decision-making. There is no high-level evidence on whether stabilisation procedures (for example shoulder or patellofemoral) durably outperform sustained rehabilitation in EDS. Higher recurrence is consistently reported, but optimal patient selection is unclear.

Celiprolol generalisability. Benefit was shown mainly in COL3A1-confirmed and clinically diagnosed vascular EDS in a small trial; its value in mutation-negative phenotypes and in non-vascular subtypes is unproven.