RheumatologyTier 2Disease (DEADMAN)

Hereditary connective tissue disorders - Ehlers–Danlos syndrome

Description

Heritable disorders of collagen and extracellular matrix -> joint hypermobility + skin hyperextensibility + tissue fragility
13 subtypes (2017 international classification) - a revision is in progress, expected late 2026

The three that matter

Subtype	Gene	Key feature
Hypermobile (hEDS)	*UNKNOWN - the only subtype with no identified genetic marker*	Commonest by far; diagnosis is purely clinical
Classical (cEDS)	COL5A1 / COL5A2 (AD)	Marked skin hyperextensibility, ATROPHIC "cigarette-paper" scars, easy bruising
VASCULAR (vEDS)	*COL3A1* (AD)	*ARTERIAL, BOWEL AND UTERINE RUPTURE* - the lethal one

Other subtypes worth naming

Kyphoscoliotic (PLOD1 - lysyl hydroxylase deficiency) - congenital hypotonia, scoliosis, scleral/globe fragility
Dermatosparaxis (ADAMTS2) - extreme skin fragility, redundant skin
Arthrochalasia (COL1A1/2) - congenital bilateral hip dislocation
Periodontal (C1R/C1S) - early severe periodontitis
Musculocontractural, spondylodysplastic, brittle cornea, cardiac-valvular, myopathic

Hypermobility spectrum disorder (HSD)

Symptomatic hypermobility not meeting hEDS criteria
*Managed identically - the label matters less than the management*

Epidemiology

All EDS combined ~1 in 5,000
*Hypermobile EDS accounts for ~80-90%* of cases
Vascular EDS ~1 in 100,000-200,000 - rare, but disproportionately examined
hEDS: F>M, markedly (referral and reporting bias contribute)
Generalised joint hypermobility itself is common: ~10-20% of the population, much higher in children, women, and people of African and Asian ancestry
*Most hypermobile people do not have EDS* - hypermobility alone is not a disease

Aetiopathogenesis

Collagen and matrix defects -> loss of tensile strength
- Type V collagen (classical) - regulates type I fibril diameter -> irregular "cauliflower" fibrils on EM
- Type III collagen (vascular) - abundant in arteries, bowel and uterus -> explains exactly which organs rupture
- Type I collagen processing enzymes - PLOD1, ADAMTS2
All are AUTOSOMAL DOMINANT except kyphoscoliotic and dermatosparaxis (AR)
hEDS mechanism unknown - no gene, no biomarker, no confirmatory test
- Tenascin-X (TNXB) deficiency causes a rare classical-like phenotype and is the only genetic lead
Associated dysautonomia and mast cell activation are hypothesised to relate to connective tissue support of vessels, but are not proven mechanisms

Diagnosis

Beighton score - generalised joint hypermobility (max 9)

Manoeuvre	Points
5th MCP passive dorsiflexion >90 degrees	1 each side
Thumb to forearm	1 each side
Elbow hyperextension >10 degrees	1 each side
Knee hyperextension >10 degrees	1 each side
Palms flat on floor with knees straight	1

Positive: >=6 pre-pubertal, >=5 adult to age 50, >=4 over 50
Criticised for missing hypermobility outside these five sites - the 5-point questionnaire supplements it historically

2017 hEDS criteria - ALL THREE required

A. Generalised joint hypermobility (Beighton, or Beighton one below cutoff plus the 5-point questionnaire)
B. TWO OR MORE of the following features:
- B1 - >=5 of 12 systemic features (soft/velvety skin, mild hyperextensibility, striae without weight change, piezogenic heel papules, hernias, atrophic scarring, pelvic/rectal prolapse, dental crowding + high palate, arachnodactyly, arm span:height >=1.05, mitral valve prolapse, aortic root dilatation)
- B2 - positive family history (first-degree relative meeting criteria)
- B3 - musculoskeletal complications (daily pain >3 months in >=2 limbs, chronic widespread pain >=12 months, recurrent joint dislocations/instability)
C. ALL of the exclusion criteria met
- No unusual skin fragility (would suggest another subtype)
- Other heritable/acquired connective tissue disease excluded
- Alternative diagnoses excluded (neuromuscular disease, myopathy, hypotonia, other laxity syndrome)
A revised criteria set from the international hEDS/HSD criteria review is due December 2026

Vascular EDS - recognise it, because the management diverges completely

Thin translucent skin with visible veins, easy bruising, acrogeria (aged hands/feet)
Characteristic facies: thin lips, pinched nose, prominent eyes, lobeless ears
*Hypermobility is often limited to the small joints only - the trap: a vEDS patient may have a LOW Beighton score*
Spontaneous arterial rupture/dissection, bowel (sigmoid) perforation, uterine rupture in pregnancy, pneumothorax, carotid-cavernous fistula
*COL3A1 sequencing - test anyone with the phenotype, a suggestive family history, or unexplained arterial/bowel rupture*

Investigations

Genetic testing (targeted panel or exome) confirms every subtype EXCEPT hEDS
Echocardiogram - aortic root and mitral valve, at diagnosis; repeat per subtype
Skin biopsy/EM - rarely used now
DEXA - fractures are common
Differential: Marfan (FBN1 - lens dislocation, aortic root), Loeys-Dietz (TGFBR - arterial tortuosity, hypertelorism, bifid uvula), osteogenesis imperfecta (blue sclerae, fractures), cutis laxa (skin does not recoil)**

Management

A. Hypermobile EDS and HSD - a rehabilitation problem, not a drug problem

*Graded physiotherapy is the core treatment - low-resistance strengthening and proprioceptive training to stabilise joints; avoid end-range stretching*
Pacing and activity management; hydrotherapy; occupational therapy, splints and orthoses
Pain: paracetamol, topical NSAIDs, *avoid opioids (poor efficacy, high dependence risk in a young chronic-pain population*)
- Neuropathic agents (amitriptyline, duloxetine) for central sensitisation; pain psychology and CBT
Co-manage the associated conditions - they cause more disability than the joints
- POTS/dysautonomia - salt and fluid loading, compression garments, exercise reconditioning, then midodrine, ivabradine or fludrocortisone
- Functional GI disorders and gastroparesis
- Anxiety, depression, fatigue, sleep
- Pelvic floor dysfunction, urinary and rectal prolapse
*Surgery for joint instability has poor and often deteriorating outcomes* - avoid where possible
No disease-modifying therapy exists

B. Classical EDS

Skin protection, careful wound closure with deep sutures left long, avoid contact sports
Ascorbic acid is often given for bruising - evidence is weak

C. Vascular EDS - a completely different management problem

*Avoid arteriography, colonoscopy and elective surgery - vessels and bowel tear on instrumentation; non-invasive imaging (MRA/CTA/ultrasound) only*
Celiprolol - the only agent with RCT evidence (BBEST): reduced arterial events ~3-fold; not marketed in Australia - obtain via the Special Access Scheme; a standard beta blocker is the usual substitute
Strict blood pressure control; avoid heavy lifting, straining and contact sports
MedicAlert bracelet and a written emergency plan - present to a centre that knows the diagnosis; conservative management of rupture is often preferred to operating on friable tissue
Pregnancy is high risk (uterine and arterial rupture; maternal mortality historically ~5-12% per pregnancy) - pre-conception counselling and delivery in a tertiary centre
Cascade genetic testing and counselling for first-degree relatives (50% risk)

Peri-operative and anaesthetic care - all subtypes

Fragile skin and veins, poor wound healing, delayed suture removal
Resistance to local anaesthetic is commonly reported
Cervical spine instability, risk of dislocation with positioning, easy bruising

Associations

POTS and orthostatic intolerance, chronic fatigue
Mast cell activation syndrome (reported association, contested)
Functional GI disorders, gastroparesis, IBS, gastro-oesophageal reflux
Chronic widespread pain, fibromyalgia, central sensitisation
Anxiety disorders, ADHD, autism spectrum - over-represented
Mitral valve prolapse, aortic root dilatation (usually mild and non-progressive in hEDS)
Pelvic organ, rectal and uterine prolapse; hernias; dental crowding and high-arched palate
Osteopenia and fracture; scoliosis; pes planus; temporomandibular dysfunction
Congenital adrenal hyperplasia - CYP21A2/TNXB contiguous gene deletion causes a CAH + EDS phenotype

Natural history & complications

hEDS: normal life expectancy - morbidity is chronic pain, fatigue, deconditioning and disability, not organ rupture
- Joints typically become stiffer and more painful with age as hypermobility declines
- Many patients arrive after years of being disbelieved - the diagnosis itself is therapeutic
Classical EDS: normal life expectancy; recurrent wounds, scarring, joint instability
*Vascular EDS: median survival ~48-51 years*
- 80% have a major event by age 40
- Arterial rupture/dissection is the usual cause of death (mid-sized arteries: renal, splenic, iliac, mesenteric)
- Sigmoid colon perforation in ~25-30%
- Prognosis is better with modern surveillance, celiprolol and avoidance of instrumentation
Pregnancy: hEDS - increased pain, pelvic instability, precipitate labour; vEDS - high maternal mortality

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