Hypermobile Ehlers-Danlos Syndrome

Hypermobile Ehlers-Danlos syndrome is the commonest Ehlers-Danlos syndrome, defined clinically by generalised joint hypermobility, systemic connective tissue features and positive family history, with no known gene. Pain, autonomic dysfunction and gastrointestinal symptoms usually determine disability.

Pathophysiology. No causative gene has been identified, and a polygenic or multifactorial basis is suspected. Altered extracellular matrix and joint proprioception, autonomic dysregulation and mast cell activity may contribute to symptoms.

It is much commoner in women and most often presents in adolescence or early adulthood. It overlaps with hypermobility spectrum disorder, which has the same symptoms without the full diagnostic criteria.

Diagnosis requires exclusion of other heritable connective tissue disorders.

• Generalised joint hypermobility with recurrent subluxation, dislocation and sprains
• Chronic widespread or joint pain and fatigue
• Soft, velvety skin with mild hyperextensibility, striae and easy bruising
• Postural tachycardia, presyncope and orthostatic intolerance
• Functional gastrointestinal symptoms: reflux, bloating, constipation, gastroparesis
• Pelvic floor dysfunction, hernia and prolapse
• Temporomandibular joint dysfunction and headache
• Anxiety, sleep disturbance and cognitive complaints

• Beighton score of 5 or more of 9 in adults under 50 years (adjusted by age), plus a 5-point questionnaire of past hypermobility.
• Diagnostic features: two or more of systemic connective tissue signs (skin, hernia, pelvic organ prolapse, dental crowding, arachnodactyly, mitral valve prolapse), family history of a first degree relative with confirmed disease, and musculoskeletal complications such as chronic pain or recurrent dislocation.
• Exclusion of other conditions: genetic testing of connective tissue gene panels when atrophic scarring, marked skin hyperextensibility, arterial or aortic features are present.
• Autonomic assessment: 10 minute active stand test with heart rate rise of 30 beats/minute or more without orthostatic hypotension suggests postural tachycardia.
• Basic investigations: full blood count, ferritin, thyroid function, vitamin D and inflammatory markers to exclude other causes of fatigue and pain.

Differential diagnosis.

• Hypermobility spectrum disorder
• Classical Ehlers-Danlos syndrome and other rarer subtypes
• Marfan syndrome and Loeys-Dietz syndrome
• Fibromyalgia and chronic fatigue syndrome
• Inflammatory arthritis and systemic lupus erythematosus
• Postural tachycardia syndrome of other causes

• Education and self-management: explain the condition, the benign outlook for survival, and the role of pacing, sleep and graded activity.
• Physiotherapy: supervised strengthening of stabilising muscles, proprioceptive training, and low impact aerobic exercise. Avoid end range stretching and forced manipulation.
• Pain: paracetamol 1 g orally up to four times daily (maximum 4 g daily), topical NSAID gels, and amitriptyline 10 to 50 mg at night or duloxetine 30 to 60 mg daily. Use long term opioids rarely, since they worsen gut dysmotility and outcomes.
• Postural tachycardia: fluids 2 to 3 litres daily, salt 6 to 10 g daily if no hypertension, waist high compression garments, and graded recumbent exercise. If needed, propranolol 10 to 20 mg orally two to three times daily, ivabradine 2.5 to 7.5 mg twice daily, midodrine 2.5 to 10 mg three times daily in daytime (last dose 4 hours before bed, avoid supine hypertension), or fludrocortisone 0.1 to 0.2 mg daily.
• Gastrointestinal symptoms: proton pump inhibitor for reflux, soluble fibre and osmotic laxatives (macrogol 1 to 3 sachets daily) for constipation, small frequent meals, and a dietetic review.
• Mast cell symptoms when present: cetirizine 10 mg once daily and famotidine 20 mg twice daily (reduce at creatinine clearance under 50 mL/min).
• Psychological support: cognitive behavioural therapy for pain, anxiety and sleep.
• Local anaesthetic: anaesthetic effect may be reduced, and higher doses or repeat dosing may be needed within safe maximum doses.
• Surgery: avoid joint surgery unless clear structural indication, since outcomes are poorer than in the general population.

Special groups.

• Adolescents: school adjustments, avoid contact sports, and plan transition to adult services.
• Pregnancy: pelvic girdle pain and preterm rupture of membranes are commoner; plan delivery with obstetric awareness.

Monitoring. Review function, pain and orthostatic symptoms every 6 to 12 months. Consider echocardiography once to exclude aortic root dilatation.

Referral and escalation. Refer to rheumatology, rehabilitation or a pain service for complex pain, and to cardiology for syncope. Urgent for new vascular symptoms, atrophic scarring, or an unusual family history of rupture, which should prompt re-evaluation for another type.