• Combined prevalence of all EDS types: approximately 1 in 5,000 (some estimates range from 1/2,500 to 1/5,000)
• Hypermobile EDS (hEDS) is by far the most common subtype, accounting for ~80–90% of cases
• Classical EDS (cEDS) is the second most common (~1 in 20,000–40,000)
• Vascular EDS (vEDS) is rare (~1 in 50,000–250,000) but the most clinically dangerous

• Affects all ethnic groups worldwide with no clear racial predilection
• Most types show no sex predilection (autosomal inheritance), though hEDS is diagnosed more frequently in females, possibly due to hormonal influences on connective tissue laxity and ascertainment bias
• Age of onset: symptoms typically present in childhood or adolescence, but diagnosis is often delayed (median diagnostic delay can be years to decades)

• No large-scale epidemiological data specific to Hong Kong exist
• Awareness and diagnosis rates have been improving with advances in genetic testing available at institutions such as the Clinical Genetic Service at Queen Mary Hospital
• EDS is likely underdiagnosed in the HK population, particularly the hypermobile subtype, which may be dismissed as "benign joint hypermobility"
• In the HK clinical setting, EDS is most relevantly encountered:
  • In paediatrics (a hypermobile child with recurrent joint dislocations)
  • In cardiology/vascular surgery (young patient with aortic dissection or aneurysm — vascular EDS) ^[2]
  • In haematology (bleeding tendency workup where skin hyperelasticity is a physical examination clue) ^[3]

• Collagen (from Greek kolla = glue + gen = producing) is the primary structural protein of the extracellular matrix (ECM)
• There are at least 28 types of collagen identified (types I–XXVIII), but the clinically relevant ones for EDS are:

This is crucial because EDS mutations can affect any step:

• EDS mutations disrupt various steps: gene transcription (reduced quantity), triple helix assembly (structural defect), post-translational modification (abnormal cross-linking), or enzymatic processing
• This contrasts with scurvy (vitamin C deficiency), which impairs hydroxylation of proline/lysine → defective collagen cross-linking → similar clinical features (bleeding, skin fragility) but acquired rather than genetic

• Skin: Type I, III, and V collagen provide tensile strength and elasticity. Defective collagen → hyperextensible, fragile skin
• Joints: Collagen in ligaments and joint capsules provides structural constraint. Defective collagen → hypermobility, dislocations
• Blood vessels: Type III collagen is the major structural component of arterial walls, especially in medium and large arteries. Defective Type III collagen → arterial rupture, dissection, aneurysm (vascular EDS)
• GI tract: Type III collagen in bowel wall → risk of bowel perforation (vascular EDS)
• Heart valves: Collagen in valve leaflets → mitral valve prolapse, aortic root dilatation

The 2017 International Consortium classification (Malfait et al., AJMG Part C) recognises 13 subtypes of EDS. Each has a defined genetic basis. The clinically most important subtypes for exams are:

EDS inheritance patterns relevant to inherited cardiac conditions: ^[1]

• Autosomal dominant inheritance: hypermobile, classical, and vascular EDS
• Autosomal recessive inheritance: kyphoscoliotic EDS

As detailed in the table above — 13 subtypes.

• Autosomal dominant: hEDS, cEDS, vEDS, aEDS, pEDS, mEDS (some)
• Autosomal recessive: kEDS, dEDS, clEDS, spEDS, mcEDS, cvEDS, BCS, mEDS (some)

You may still see the old Roman numeral system in older textbooks/exam papers:

Ehlers-Danlos type IV is specifically the vascular subtype associated with aortic aneurysm and dissection. ^[2][4]

The clinical features of EDS depend on the subtype. However, there are overlapping features across subtypes. I will organise them by symptoms and signs, with the pathophysiological basis explained inline.

Clinical diagnosis (requires all three major criteria OR ≥ 1 major + ≥ 3 minor):

Major criteria:

1. Skin hyperextensibility (standardised measurement: >1.5 cm dorsum of hand, >3 cm volar forearm/neck) + atrophic scarring
2. Generalised joint hypermobility (Beighton ≥ 5 in adults)

Minor criteria:

• Easy bruising
• Soft, doughy skin
• Skin fragility (traumatic skin splitting)
• Molluscoid pseudotumours
• Subcutaneous spheroids
• Hernia (or history thereof)
• Epicanthal folds
• Complications of joint hypermobility (sprains, subluxations, dislocations, flat feet)
• Family history (1st degree relative meeting criteria)

Confirmatory: Molecular testing of COL5A1, COL5A2 (rarely COL1A1)

This is the most important subtype to diagnose early because of its life-threatening vascular complications.

Major criteria:

1. Arterial rupture at a young age
2. Spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology
3. Uterine rupture during the third trimester in the absence of prior C-section or severe peripartum perineum tears
4. Carotid-cavernous sinus fistula in the absence of trauma

Minor criteria:

• Bruising without identified trauma and/or in unusual sites (cheeks, back)
• Thin, translucent skin with visible venous pattern (especially chest, abdomen)
• Characteristic facial features (thin nose, thin lips, small chin, hollow cheeks, prominent eyes, lobeless ears)
• Spontaneous pneumothorax
• Acrogeria (aged appearance of the extremities, especially hands)
• Talipes equinovarus (clubfoot)
• Congenital hip dislocation
• Small joint hypermobility
• Tendon and muscle rupture
• Keratoconus
• Gingival recession and fragility
• Early-onset varicose veins (< 30 years, nulliparous if female)

Confirmatory: Molecular testing of COL3A1 (or rarely COL1A1 with specific arginine-to-cysteine substitutions). Genetic confirmation is essential for vEDS because the implications are so serious.

Major criteria:

1. Congenital muscle hypotonia
2. Congenital or early-onset kyphoscoliosis (progressive)
3. Generalised joint hypermobility with dislocations/subluxations (particularly shoulders, knees, hips)

Minor criteria:

• Skin hyperextensibility
• Easy bruisability
• Rupture/aneurysm of a medium-sized artery
• Marfanoid habitus
• Microcornea
• Radiographically considerable osteopenia
• Scleral fragility (risk of scleral/ocular globe rupture)

Confirmatory: Urinary deoxypyridinoline/pyridinoline ratio (elevated → indicates deficient lysyl hydroxylase activity). Molecular testing of PLOD1 or FKBP14.

This subtype has autosomal recessive inheritance ^[1]

Interpretation considerations: A variant of uncertain significance (VUS) on genetic testing does not confirm or exclude EDS — it means the variant's pathogenicity is unclear. Clinical correlation is essential. A negative genetic test in the context of strong clinical features may indicate an uncharacterised subtype or a deep intronic/structural variant not detected by standard sequencing.

Genetic counselling with a 3-generation family tree and genetic screening should be offered ^[12], analogous to the approach for inherited cardiomyopathies.

These are important when a patient presents with easy bruising / bleeding tendency and EDS is in the differential:

In the approach to bleeding disorders, physical examination for skin hyperelasticity indicates Ehlers-Danlos syndrome ^[3][8]

EDS is a connective tissue disease associated with inherited cardiac conditions. Cardiac manifestations include aortic root dilatation and mitral valve prolapse ^[1]

Surveillance protocol: In vEDS, current consensus recommends baseline vascular imaging (CTA or MRA from head to pelvis) at diagnosis, then periodic surveillance every 2–3 years or more frequently if abnormalities are detected. In hEDS and cEDS, baseline echocardiography is recommended, with follow-up interval determined by initial findings.

Aortic dissection in EDS: the underlying pathology is medial collagen and elastin degeneration ^[2][10]

This is the single most important intervention for hEDS — more important than any medication.

• Targeted muscle strengthening: Strengthen muscles around hypermobile joints to provide dynamic stabilisation where ligaments fail

  • Why does this work? Joints are stabilised by two systems: (1) passive restraints (ligaments, joint capsule — these are collagen-dependent and defective in EDS) and (2) active restraints (muscles and tendons providing dynamic stability). Since you cannot fix the ligaments, you strengthen the muscles to compensate
  • Low-impact, progressive exercises: swimming, Pilates, clinical Pilates, hydrotherapy, cycling
  • Avoid: high-impact activities, contact sports, heavy weightlifting, activities with sudden deceleration (e.g., sprinting, jumping)

• Proprioceptive training: EDS patients have impaired proprioception (defective collagen in joint capsules → impaired mechanoreceptor signalling → poor joint position sense → increased injury risk)

  • Balance boards, wobble cushions, closed-kinetic-chain exercises

• Supportive footwear and orthotics ^[13] — for pes planus and ankle instability

• Joint bracing / taping: Functional braces for unstable joints (particularly knee, ankle, wrist). Kinesiology taping can provide proprioceptive feedback

• Occupational therapy: Adaptive strategies for daily activities, ergonomic modifications, assistive devices

• Wound closure: Use adhesive strips (Steri-Strips) or tissue adhesive instead of or in addition to sutures. If sutures are used:

  • Leave sutures in for twice the normal duration (e.g., 14 days on limbs instead of 7)
  • Use deep dermal sutures to take tension off the wound edges
  • Apply tension-reducing wound closure strips after suture removal
  • Why? Defective collagen → poor tensile strength during healing → wounds dehisce easily. Prolonged support reduces the risk of wound splitting and atrophic scar formation

• Skin protection: Padding over bony prominences (shins, elbows, knees) to minimise minor trauma → reduce bruising and skin tears

• Sun protection: To minimise UV damage to already-fragile skin

• Avoid contact sports, isometric exercise (e.g., weight lifting, sit-ups, push-ups), and diving ^[6]

  • Why contact sports? Risk of joint dislocation and tissue trauma
  • Why isometric exercise? Increases systemic blood pressure acutely → in patients with aortic root dilatation or vascular fragility, this increases wall stress on the aorta → risk of dissection
  • Why diving? Increases risk of pneumothorax (some EDS subtypes have pulmonary bullae)

• Avoid excessive joint stretching ("party tricks" demonstrating hypermobility) — this worsens joint instability over time

• MedicAlert identification: Especially for vEDS — emergency personnel need to know about tissue fragility, contraindication to certain procedures, and risk of spontaneous vascular events

• Chronic pain, disability, diagnostic delay, and the invisible nature of the condition (especially hEDS) contribute to significant psychological burden
• Cognitive behavioural therapy (CBT) — evidence-based for chronic pain management
• Pain psychology programmes — acceptance and commitment therapy (ACT)
• Peer support groups — EDS support organisations

Pain is the predominant symptom in hEDS and is often the primary driver of disability. A stepwise approach:

Indications for aortic surgery (analogous to Marfan): ^[6]

• Aortic root dilatation > 5 cm (lower threshold in vEDS — some centres intervene at 4.5 cm)
• Rapid enlargement > 1 cm/year
• Significant aortic regurgitation
• Family history of early dissection

All surgeons and anaesthetists must be informed of the EDS diagnosis pre-operatively:

• EDS is a connective tissue disease associated with inherited cardiac conditions ^[1]
• The cardiac manifestations include aortic root dilatation (which may lead to aortic regurgitation) and mitral valve prolapse — these are shared with Marfan syndrome ^[1]
• Pathophysiology: Defective collagen (especially Type III in vEDS, but also Type I and V in other subtypes) in the aortic wall → progressive weakening of the tunica media → dilatation of the aortic root (at the sinus of Valsalva) → loss of coaptation of aortic valve leaflets → aortic regurgitation (AR)
• Clinical significance: AR leads to LV volume overload → LV dilatation → eventual LV systolic dysfunction → heart failure if untreated
• Presentation: Early diastolic decrescendo murmur at the left sternal border, wide pulse pressure, bounding pulses (Corrigan's sign) in significant AR

Aortic dissection is a recognised complication in EDS. ^{[2][5][10][14]}

• Pathology: medial collagen and elastin degeneration → tear in the intima → blood enters the media → creates a false lumen → dissection extends proximally and/or distally ^[2]
• Causes of aortic dissection include: coexisting HT (80%), genetic diseases (Marfan syndrome, Familial aortic aneurysm/dissection, Ehlers-Danlos, Loeys-Dietz aneurysm syndrome), bicuspid aortic valve, and trauma ^[2][10]
• Stanford classification: ^[2]
  • Type A: involves any part of the aorta proximal to the origin of the left subclavian artery (ascending aorta involved)
  • Type B: all dissections not involving the ascending aorta (distal to left subclavian)

Complications of aortic dissection [5][14][15]:

Type A dissection complications:

• Aortic regurgitation — dissection extends into the aortic valvular annulus → early diastolic decrescendo murmur with wide pulse pressure ^[5]
• Cardiac tamponade — dissection ruptures into the pericardium → pericardial effusion → obstructive shock ^[5][14]
• Acute myocardial infarction — dissection extends into or compresses the coronary artery ostia (usually right coronary artery) → inferior STEMI pattern ^[5][14]
  • This is critical because if you misdiagnose dissection as MI and give heparin and antiplatelet agents, the dissection will worsen — what stops the dissection is the thrombus within the aorta; without this thrombus, the dissection is free to keep extending ^[2]
• Focal neurological deficits — syncope, stroke (mostly Type A dissections) due to dissection propagating into carotid or brachiocephalic arteries ^[5]
  • Paraplegia (spinal cord ischaemia)
  • Altered level of consciousness (carotid artery involvement)
  • Horner syndrome (superior cervical ganglion compression)
  • Hoarseness (left recurrent laryngeal nerve compression) ^[5]

Type B dissection complications:

• Dissection into abdominal aortic branches → coeliac / renal / lower limb ischaemia ^[14]
• Focal neurological deficits related to spinal ischaemia ^[14]
• Haemothorax (rupture into left pleural space)

Prognosis of dissection without treatment: ^[2]

• Very poor — approximately 1% mortality per hour within the first 48 hours → ~50% dead in 2 days
• Survival exceeds 90% with prompt diagnosis and management
• Death results from progression of dissection → vascular compromise or rupture

• This is the leading cause of death in vascular EDS
• Unlike Marfan (where the aortic root is the primary site), vEDS characteristically affects medium-sized arteries: iliac, renal, splenic, mesenteric, hepatic, and coronary arteries
• Pathophysiology: Defective Type III collagen → weakened arterial wall → progressive aneurysmal dilatation → spontaneous rupture → massive internal haemorrhage → haemorrhagic shock and death
• Presentation: Sudden severe abdominal, flank, or chest pain → haemodynamic collapse → shock. May present without warning in a previously asymptomatic young person
• Median age of first major vascular event in vEDS: ~20–30 years
• Median survival in untreated vEDS: ~50 years (death usually from arterial rupture)

• MVP is a complication/association of EDS and Marfan syndrome ^[1][16]
• Pathophysiology: Myxomatous degeneration of mitral valve leaflets — collagen is a key structural component of valve leaflets. Defective collagen → redundant, floppy leaflets that prolapse into the left atrium during systole
• Auscultation: Mid-systolic click ± late systolic murmur, best heard at the apex ^[16]
• Complications of MVP: ^[16]
  • Progressive severe mitral regurgitation → may require mitral valve repair/replacement
  • Emboli (embolic stroke)
  • Atrial fibrillation
  • Infective endocarditis (rare, but MVP is a predisposing factor for valvular vegetation)

MVP causes include: isolated/primary (common in females) and secondary to connective tissue diseases (Marfan, EDS, OI), SLE, and PCKD ^[15]

• The most characteristic GI complication of vEDS — occurs in approximately 15–25% of vEDS patients during their lifetime
• Pathophysiology: Type III collagen is a major structural component of the bowel wall (serosa, muscularis). Defective Type III collagen → weakened bowel wall → spontaneous perforation without precipitating factors (no diverticular disease, no trauma)
• Most common site: Sigmoid colon (analogous to where diverticular perforation occurs in the general population — the sigmoid has the highest intraluminal pressures due to Laplace's law, and a relatively thinner wall)
• Presentation: Acute abdomen — sudden severe abdominal pain, guarding, rigidity, rebound tenderness → peritonitis → septic shock if not treated urgently
• Recurrence: High recurrence rate — patients who survive one perforation are at risk for subsequent perforations
• Important: Avoid routine colonoscopy in vEDS unless absolutely clinically necessary — the procedure itself risks perforation in the fragile bowel wall

• Chronic constipation, gastroparesis, functional dyspepsia, IBS-like symptoms
• Pathophysiology: Connective tissue laxity in the bowel wall → impaired peristalsis → dysmotility. Also possible autonomic dysfunction (associated POTS → impaired enteric nervous system regulation)
• Not life-threatening but significantly impairs quality of life

• Common in hEDS — hiatal hernia from connective tissue laxity → reflux
• May present with chest pain, dysphagia, odynophagia

• The hallmark musculoskeletal complication, particularly in hEDS and cEDS
• Most commonly affected: shoulder (glenohumeral), patella, TMJ, fingers (MCP, PIP), ankle, hip
• Pathophysiology: Defective collagen in ligaments and joint capsules → loss of passive joint restraint → joints exceed normal range of motion under physiological loads → subluxation (partial displacement) or frank dislocation
• With each dislocation episode, further damage occurs to the already-deficient capsulolabral structures → progressive instability (a vicious cycle)
• In arthrochalasia EDS: congenital bilateral hip dislocation is pathognomonic

• The most disabling complication of hEDS — often exceeds the impact of the hypermobility itself
• Pathophysiology (multifactorial):
  1. Peripheral nociceptive pain: Repetitive microtrauma from joint instability → local inflammation → nociceptor activation
  2. Neuropathic pain: Nerve entrapment from joint instability (e.g., carpal tunnel from wrist hypermobility)
  3. Central sensitisation: Chronic peripheral nociceptive input → spinal cord dorsal horn upregulation → hyperalgesia and allodynia → pain becomes self-perpetuating even without ongoing tissue damage
  4. Psychological amplification: Chronic pain → anxiety, depression, catastrophising → amplification of pain perception
• Chronic pain in hEDS is notoriously difficult to treat and is the primary reason for disability claims

• Pathophysiology: Joint instability → abnormal biomechanical loading → accelerated cartilage wear → early-onset degenerative osteoarthritis
• Patients may develop radiographic OA in their 30s–40s, decades earlier than expected
• Commonly affects weight-bearing joints (knees, hips) and frequently-subluxating joints (shoulders)

• Particularly in kEDS and spEDS
• Pathophysiology: Collagen is the organic scaffold of bone (Type I collagen constitutes ~90% of bone organic matrix). Defective collagen or defective collagen cross-linking (kEDS — lysyl hydroxylase deficiency) → reduced bone matrix integrity → osteoporosis
• In other subtypes, reduced physical activity due to pain/disability may contribute to disuse osteopenia

• Chronic TMJ subluxation, clicking, locking, pain
• May cause difficulty eating, speaking

• Pathophysiology: Defective collagen deposition during the proliferative phase of wound healing → reduced tensile strength of scar tissue → wounds that were closed may dehisce; healed wounds form widened, atrophic, papyraceous ("cigarette-paper") scars
• Most prominent in classical EDS — scars over bony prominences (shins, knees, elbows, forehead) are characteristic
• Surgical implication: Post-operative wound dehiscence is a significant risk. Sutures must remain longer and wounds require reinforcement

• Pathophysiology: Fragile dermal and subcutaneous blood vessels (collagen-deficient vessel walls) → minor trauma causes capillary rupture → extravasation → bruising
• In vEDS, bruising can be extensive and spontaneous, mimicking coagulopathy or non-accidental injury

• Molluscoid pseudotumours: Fleshy, raised scar-associated lesions over pressure points — represent fat herniation through weakened dermal collagen at sites of prior scarring
• Subcutaneous spheroids: Small, hard, mobile calcified nodules palpable beneath the skin (forearms, shins) — represent calcified subcutaneous fat lobules from prior subcutaneous haemorrhage

• Pathophysiology: Defective collagen in pleural tissue and lung parenchyma → development of subpleural bullae/blebs (especially upper lobes) → spontaneous rupture → pneumothorax
• More common in vEDS and Marfan (shared complication)
• This is why diving is contraindicated in EDS ^[6] — increased intrathoracic pressure + Boyle's law (gas expansion on ascent) → increased risk of bullae rupture → pneumothorax at depth → potentially fatal tension pneumothorax

• Severe progressive kyphoscoliosis → reduced thoracic cage compliance → restrictive ventilatory defect → may eventually cause respiratory failure/cor pulmonale if untreated

• The most feared obstetric complication — Type III collagen is a structural component of the uterine wall (especially myometrium)
• Defective Type III collagen → weakened uterus → spontaneous rupture during the third trimester or during labour
• Maternal mortality: Estimated 5–12% per pregnancy in vEDS
• Management: Pre-conception counselling, planned early caesarean section (~34–36 weeks), delivery at a centre with vascular surgical backup

• Defective collagen in the amniotic membranes → membranes rupture prematurely → PPROM → preterm delivery
• Relevant across multiple EDS subtypes, not just vEDS

• Pathophysiology: Defective collagen in pelvic floor support structures (uterosacral ligaments, cardinal ligaments, endopelvic fascia) → uterine prolapse, cystocele, rectocele
• Can occur in young nulliparous women or even children (a diagnostic clue to underlying EDS)

• Pathophysiology: Two mechanisms:
  1. Defective endometrial vessel collagen → impaired vasoconstriction after menstrual shedding → prolonged bleeding
  2. Impaired platelet-collagen interaction (subendothelial collagen is the primary trigger for platelet adhesion via GPIb-vWF) → impaired primary haemostasis

• Hypermobility of the cervical spine (especially atlanto-axial and atlanto-occipital joints) → instability → risk of spinal cord compression → myelopathy
• Symptoms: neck pain, headaches, upper limb paraesthesiae, gait disturbance, long tract signs (hyperreflexia, Babinski positive)
• Important for anaesthesia: Cervical instability must be assessed pre-operatively; intubation requires careful technique

• Increasingly reported association between hEDS and Chiari I malformation (cerebellar tonsillar descent > 5 mm below the foramen magnum)
• Pathophysiology: Speculation that connective tissue laxity at the craniocervical junction allows downward herniation of the cerebellar tonsils
• Symptoms: occipital headaches worse with Valsalva, cervicogenic headache, syringomyelia

• Widening of the dural sac (lumbosacral spine) — shared with Marfan
• Pathophysiology: Defective collagen in dura → progressive expansion under CSF pressure → erosion of vertebral bone
• Usually asymptomatic but can cause low back pain, radicular symptoms, headache
• Anaesthetic implication: Dural ectasia may cause unpredictable distribution of epidural/spinal anaesthetic drugs and increases the risk of dural puncture

• Present in an estimated 30–80% of hEDS patients
• Pathophysiology: Connective tissue laxity in venous walls → excessive venous compliance → peripheral venous pooling on standing → reduced venous return → reduced cardiac output → baroreceptor-mediated reflex tachycardia (heart rate ≥ 30 bpm increase or > 120 bpm within 10 min of standing, without significant drop in BP)
• Symptoms: lightheadedness, presyncope, palpitations, exercise intolerance, brain fog, fatigue

• Gastrointestinal dysmotility (gastroparesis, constipation)
• Temperature dysregulation
• Abnormal sweating patterns
• Bladder dysfunction