Ehlers Danlos Syndrome

The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders characterised by joint hypermobility, skin hyperextensibility and tissue fragility. The 2017 international classification recognises 13 subtypes, each with defined clinical criteria and genetic basis. Overall prevalence is about 1 in 5,000, with hypermobile EDS the most common and its genetic basis still unknown.

Main subtypes

• Classical EDS (cEDS): COL5A1 and COL5A2 (collagen V), rarely COL1A1 p.Arg312Cys. Autosomal dominant. Skin hyperextensibility, atrophic scarring, joint hypermobility.
• Classical-like EDS (clEDS): TNXB (tenascin-X deficiency), autosomal recessive.
• Cardiac-valvular EDS: COL1A2 biallelic. Severe valvular disease.
• Vascular EDS (vEDS): COL3A1 (collagen III). Autosomal dominant. Arterial, uterine and bowel rupture. Median survival about 48-51 years.
• Hypermobile EDS (hEDS): no confirmed gene. Generalised joint hypermobility, systemic connective tissue manifestations, and chronic pain. Diagnosed clinically.
• Arthrochalasia EDS: COL1A1/COL1A2 exon 6 mutations. Congenital hip dislocation.
• Dermatosparaxis EDS: ADAMTS2.
• Kyphoscoliotic EDS: PLOD1 and FKBP14. Scoliosis, muscle hypotonia, ocular fragility.
• Brittle cornea syndrome: ZNF469, PRDM5.
• Spondylodysplastic EDS: B4GALT7, B3GALT6, SLC39A13.
• Musculocontractural EDS: CHST14, DSE.
• Myopathic EDS: COL12A1.
• Periodontal EDS: C1R, C1S.
• Pathophysiology: abnormalities in collagen structure, processing, or extracellular matrix proteins (tenascin-X) produce weak, fragile tissues. In vEDS, collagen III is vital for hollow organ and arterial walls.
• Hypermobility spectrum disorders (HSD) describe symptomatic hypermobility not meeting hEDS criteria.
• Complications: joint dislocations and subluxations, early osteoarthritis, chronic pain and fatigue, dysautonomia (postural orthostatic tachycardia syndrome), gastrointestinal dysmotility, mast cell activation symptoms, pelvic organ prolapse, bleeding and bruising, poor wound healing, hernias, mitral valve prolapse, aortic root dilatation, and psychological distress. In vEDS: arterial dissection and rupture, bowel perforation (sigmoid colon), uterine rupture in pregnancy, and pneumothorax.

General features

• Joint hypermobility: Beighton score 5 or more of 9 (adults, 6 or more in children and 4 or more in over 50s) by passive dorsiflexion of the fifth fingers beyond 90 degrees, thumb to forearm apposition, elbow and knee hyperextension over 10 degrees, and palms to floor with straight knees. History of dislocation, chronic arthralgia, and early arthritis.
• Skin: soft, velvety, hyperextensible (over 1.5 cm at the volar forearm or over 3 cm in neck), fragile, easy bruising, wide atrophic "cigarette paper" scars (in classical type), molluscoid pseudotumours, subcutaneous spheroids, piezogenic papules, and striae.
• Fatigue, pain (musculoskeletal, neuropathic), headaches (Chiari malformation, cranio-cervical instability), dysautonomia, gastrointestinal problems (reflux, gastroparesis, constipation), pelvic floor disorders, and anxiety.

Vascular EDS (Villefranche or 2017 criteria)

• Family history of vEDS with documented COL3A1 variant, arterial rupture at young age, spontaneous sigmoid colon perforation, uterine rupture in the third trimester, carotid-cavernous sinus fistula, and unexplained organ rupture.
• Thin translucent skin with visible veins (especially on chest and abdomen), extensive bruising, characteristic facial appearance (thin lips and philtrum, small chin, narrow nose, prominent eyes, lobeless ears), acrogeria (aged hands), early-onset varicose veins, tendon and muscle rupture, talipes equinovarus, clubfoot, pneumothorax and haemothorax, gingival recession, and small joint hypermobility.
• Other subtype clues: kyphoscoliosis with muscle hypotonia and scleral fragility (kyphoscoliotic), severe periodontitis (periodontal), early joint contractures (musculocontractural), and congenital hip dislocation (arthrochalasia).
• Differential diagnosis: Marfan syndrome, Loeys-Dietz syndrome, osteogenesis imperfecta, cutis laxa, Stickler syndrome, joint hypermobility spectrum disorder, fibromyalgia, chronic fatigue syndrome, Beals syndrome, Klinefelter syndrome, homocystinuria, pseudoxanthoma elasticum, and normal hypermobility (children).
• Red flags (vEDS): sudden severe abdominal, chest or neck pain (rupture or dissection), neurological deficit, unexplained bleeding, and pregnancy.

Diagnosis follows the 2017 International criteria, using clinical features and molecular confirmation for all subtypes except hEDS.

hEDS diagnostic criteria (all three required)

• Generalised joint hypermobility (Beighton score threshold by age).
• Two or more of: systemic manifestations of connective tissue disorder (at least 5 of 12 features: soft skin, mild skin hyperextensibility, unexplained striae, bilateral piezogenic papules, recurrent hernias, atrophic scarring, pelvic floor or rectal prolapse, dental crowding with high palate, arachnodactyly, arm span to height ratio over 1.05, mitral valve prolapse, aortic root dilatation); positive family history; musculoskeletal complications (daily pain for 3 months, recurrent dislocations, chronic widespread pain).
• Exclusion of other connective tissue disorders and alternative diagnoses.

Genetic testing

Multigene panel (NGS) for COL5A1, COL5A2, COL3A1, COL1A1, COL1A2, TNXB, PLOD1, ADAMTS2, and others. COL3A1 sequencing and deletion/duplication analysis in suspected vEDS. Biochemical assay of collagen on cultured fibroblasts (skin biopsy) if variants of uncertain significance. Cascade testing for relatives. Prenatal and preimplantation testing available.

Baseline investigations

• Echocardiography (aortic root, mitral valve), vascular imaging (non-invasive MR angiography or CT angiography, duplex) in vEDS, bone density (DEXA), ophthalmology (corneal thickness, myopia), orthostatic vital signs and tilt table testing for dysautonomia, coagulation screening (platelet function, von Willebrand disease), gastroenterology evaluation (gastric emptying, manometry), and pelvic floor evaluation.
• Spine and craniocervical imaging (MRI/CT, upright MRI) for headaches and neurological features.
• Avoid invasive angiography in vEDS (arterial fragility), contrast CT and MRI are preferred.

There is no cure. Management is multidisciplinary, focusing on prevention of complications, symptom control and function.

General measures (all subtypes)

• Education and lifestyle: low-impact exercise (swimming, cycling, Pilates) to build muscle strength around joints, avoid contact sports, heavy lifting, and joint hyperextension. Joint protection, bracing and splints, proprioceptive training, and occupational therapy. Pacing and graded activity for fatigue.
• Wound care: avoid tension, use deep layered sutures with prolonged retention (14 to 21 days), steri-strips, sun protection, and gentle skin care. Surgical procedures carry risk of delayed healing, dehiscence and hernia recurrence.
• Pain management: paracetamol 1 g, topical NSAIDs, short courses of oral NSAIDs with caution (bleeding), neuropathic agents (gabapentin 300 mg at night titrated, pregabalin 75-150 mg twice daily, amitriptyline 10-50 mg, duloxetine 30-60 mg), low-dose naltrexone, avoid long-term opioids, cognitive behavioural therapy, mindfulness, and pain clinic.
• Dysautonomia/POTS: fluids 2-3 L and salt 6-10 g daily, compression garments (waist-high 20-30 mmHg), exercise reconditioning, fludrocortisone 0.1-0.2 mg daily, midodrine 2.5-10 mg three times daily, propranolol 10-20 mg, ivabradine 2.5-7.5 mg twice daily.
• Gastrointestinal: proton pump inhibitor, prokinetics (metoclopramide 5-10 mg before meals, domperidone, prucalopride 2 mg), laxatives, dietary modification.
• Mast cell symptoms: H1 and H2 blockers (cetirizine 10 mg, famotidine 20 mg twice daily), cromolyn sodium.
• Bleeding and bruising: avoid NSAIDs and aspirin, tranexamic acid 1 g three times daily for 3-5 days for bleeding (heavy menstrual bleeding), desmopressin 0.3 micrograms/kg IV (or 150-300 micrograms intranasal) before procedures when platelet dysfunction, vitamin C 500 mg-1 g daily (unproven).
• Orthopaedic: physiotherapy first. Surgery (stabilisation, arthroscopic repair) for recurrent dislocations with poor outcomes and healing, so carry out only after exhaustive conservative treatment by an experienced surgeon. Spinal bracing and fusion for progressive scoliosis.
• Psychological care: screen for anxiety, depression, and neurodevelopmental conditions (ADHD, autism); counselling, support groups.
• Dental: regular review and gentle care, careful anaesthesia (local anaesthetic resistance).
• Cardiac: yearly echocardiography for aortic root dilatation and valvular disease, beta blocker or ARB if aortic root enlarged, endocarditis prophylaxis only per standard indications.

Vascular EDS (requires a specialist centre)

• Celiprolol 100 mg daily increasing to 400 mg daily (maximum, divided in two doses), a beta-1 selective blocker with beta-2 partial agonist and vasodilating properties, reduced arterial events (rupture, dissection) in a randomised trial (hazard ratio 0.36). Alternative: other beta blockers (metoprolol, bisoprolol) and ARBs (losartan) used when celiprolol is unavailable, aiming for low blood pressure (systolic 100-120 mmHg, below 130/80).
• Avoid fluoroquinolones, fluoroquinolone-associated aortic rupture, strenuous exertion, heavy straining, contact sports, isometric exercise, and unnecessary invasive procedures (arterial catheterisation, endoscopy with insufflation, colonoscopy risk). Use ultrasound, MRI and CT for surveillance. Avoid elective surgery, and operate only for emergencies with experienced vascular surgeons, using minimal tension techniques and teflon pledgets, avoiding arterial clamping where possible.
• Surveillance: baseline and periodic non-invasive vascular imaging (MRA or CTA) of the arterial tree every 1-2 years to monitor aneurysms and dissection, with echocardiography.
• Emergencies: arterial rupture or dissection managed conservatively where possible (endovascular approaches are risky), bowel perforation by segmental resection with end ileostomy (rather than primary anastomosis, which has high leak rate), and subtotal colectomy with ileorectal anastomosis in recurrent diverticular perforation.
• Pregnancy: high risk (uterine rupture, arterial rupture, peripartum haemorrhage, mortality 5-12%), requires preconception counselling and delivery by planned caesarean at 34-38 weeks in a specialist centre, and continuation of celiprolol or labetalol. Advise termination discussion or avoidance of pregnancy.
• Medical alert bracelet and emergency care plan letter, genetic counselling, and cascade testing.
• Classical EDS: skin protection and prolonged suture retention, echocardiography for aortic root and mitral valve at baseline.
• Hypermobile EDS and HSD: physiotherapy, pain control, comorbidity management.

Pregnancy (non-vascular)

• Increased risk of preterm labour, perineal tears, and postpartum haemorrhage, pelvic girdle pain, and joint instability. Plan delivery in a specialist obstetric unit, with an anaesthetic assessment (epidural may be less effective).
• Anaesthesia and surgery: careful positioning, avoid neck hyperextension (craniocervical instability), local anaesthetic may be less effective, tissue handling, and caution with intubation.

Follow-up

Annual review in a multidisciplinary clinic (genetics, rheumatology, cardiology, physiotherapy, pain, gastroenterology, psychology). More frequent follow-up in vEDS (every 6-12 months), genetic counselling for family planning, and education about avoidance of complications.