Classical Ehlers-Danlos Syndrome

Classical Ehlers-Danlos syndrome is an autosomal dominant disorder of type V collagen, with hyperextensible skin, atrophic scars and generalised joint hypermobility. Most cases are caused by COL5A1 or COL5A2 variants.

Pathophysiology. Type V collagen regulates fibril assembly of type I collagen. Reduced or abnormal type V collagen produces thin irregular fibrils and weak skin, ligaments and tendons.

A rare subtype with a COL1A1 arginine-to-cysteine variant has risk of arterial rupture. Aortic root dilatation occurs in a minority.

Skin fragility is the dominant problem, and joint instability causes pain, subluxation and early osteoarthritis.

• Hyperextensible, soft, velvety skin that returns slowly after stretch
• Wide, atrophic, papyraceous scars at sites of minor trauma (knees, elbows, forehead, chin)
• Easy bruising and molluscoid pseudotumours
• Generalised joint hypermobility with recurrent subluxation and dislocation
• Hypotonia and delayed motor milestones in children
• Pes planus, hernia, rectal and uterine prolapse
• Premature rupture of membranes in pregnancy
• Chronic pain and fatigue

• Genetic testing: COL5A1 and COL5A2 sequencing with deletion and duplication analysis, with COL1A1 testing when arterial features are present.
• Clinical diagnosis: skin hyperextensibility with atrophic scarring plus generalised joint hypermobility (Beighton score 5 or more in adults) is highly suggestive.
• Echocardiography at baseline to assess aortic root and valves.
• Skin biopsy and electron microscopy (cauliflower collagen fibrils) only when genetic testing is not informative.
• Exclusion of other types: negative COL3A1 testing in cases with significant bruising.

Differential diagnosis.

• Hypermobile Ehlers-Danlos syndrome
• Vascular Ehlers-Danlos syndrome
• Classical like Ehlers-Danlos syndrome (TNXB deficiency)
• Cutis laxa and Marfan syndrome
• Osteogenesis imperfecta
• Joint hypermobility spectrum disorder

• Skin protection: avoid trauma, use protective pads on shins, knees and elbows, and use high sun protection.
• Wound care: close wounds in two layers with deep sutures and leave skin sutures and tape in place for 14 to 21 days, about twice the usual duration. Avoid tension on the skin, and use adhesive strips to reinforce.
• Bruising and bleeding before procedures: desmopressin 0.3 microgram/kg intravenously over 30 minutes before surgery or dental extraction may reduce bleeding in some patients. Avoid anticoagulants and antiplatelet drugs unless essential.
• Joint care: physiotherapy for proprioception and muscle strengthening of stabilising muscles, low impact exercise (swimming, cycling), bracing and taping for unstable joints, and occupational therapy for joint protection.
• Pain: paracetamol 1 g orally four times daily (maximum 4 g daily; 3 g daily in low body weight or liver disease). Neuropathic agents such as amitriptyline 10 to 50 mg at night or gabapentin 300 mg increasing to 900 to 1800 mg daily in divided doses. Avoid long term opioids.
• Surgery: use meticulous soft tissue handling, avoid joint stabilisation without clear indication, and expect delayed healing.
• Cardiac and vascular care: echocardiography every 2 to 5 years when normal; if the aortic root dilates, start losartan 25 to 100 mg orally daily (maximum 100 mg) or a beta blocker and follow growth with imaging. Refer when COL1A1 arginine-to-cysteine is identified.
• Dental and oral care: gentle dental work, since periodontal and gingival fragility is common.

Special groups.

• Pregnancy: risk of premature rupture of membranes, preterm birth, perineal tears and postpartum haemorrhage. Plan delivery in a unit with obstetric expertise, and avoid forceps or vacuum when possible.

Monitoring. Review skin, joints and pain every 6 to 12 months. Echocardiography at baseline and every 2 to 5 years when normal.

Referral and escalation. Refer to clinical genetics, rheumatology or rehabilitation, and cardiology. Urgent for chest pain, new murmurs, or arterial symptoms suggesting a COL1A1 vascular subtype.