What is Ehlers-Danlos syndrome and how is it managed?

Ehlers-Danlos Syndrome: Comprehensive Overview

What is Ehlers-Danlos Syndrome?

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of hereditary connective tissue disorders defined by the clinical triad of joint hypermobility with recurrent dislocations, skin hyperextensibility, and tissue fragility. 1

• 13 distinct subtypes are currently recognized, with 12 having identified genetic causes involving 19 different genes, primarily related to collagen synthesis and extracellular matrix organization 1, 2
• The hypermobile type (hEDS) is by far the most common, accounting for 80-90% of all EDS cases, though paradoxically its genetic basis remains unknown 1, 3
• EDS affects connective tissue throughout the body, making it a multisystem disorder with manifestations in virtually every organ system 2

Classification by Subtype and Risk Stratification

Vascular EDS (Type IV) - Highest Mortality Risk

• This is the most dangerous subtype due to spontaneous arterial and organ ruptures 1
• Caused by mutations in the COL3A1 gene encoding type III collagen 1, 4
• Median survival is only 48 years if untreated 4
• Patients typically have short, slim build with prematurely aged hands, triangular faces, large eyes, small chins, thin pinched noses, and small lobeless ears 5
• Thin, translucent skin with visible veins is characteristic 4
• Aortic dissection can occur without preceding dilatation 5

Hypermobile EDS (hEDS) - Most Common

• Accounts for 80-90% of all EDS cases 1, 3
• No genetic markers identified; diagnosis is purely clinical 4
• Up to 98% of patients meet criteria for disorders of gut-brain interaction 3, 4
• Aortic root dilation occurs in 25-33% of cases 1, 4
• 60% experience gastrointestinal symptoms 3
• Asthenic syndrome and kyphotic spinal deformity occur in 75% 3

Classical EDS (Types I and II)

• Caused by mutations in COL5A1 or COL5A2 genes 4
• Follows autosomal dominant inheritance 1
• Aortic root dilation occurs in 25-33% of cases 4

Clinical Features to Recognize

Joint Manifestations

• Joint hypermobility is confirmed using the Beighton scale with age-dependent thresholds: ≥6/9 points for prepubertal children, ≥5/9 for adults under 50, and ≥4/9 for adults over 50 1, 3
• Recurrent dislocations and subluxations are common 1
• Chronic joint and limb pain is a cardinal feature 1

Skin Manifestations

• Soft or velvety skin texture with normal or slightly increased extensibility 1
• Easy bruising without significant trauma 1
• Abnormal scarring and delayed wound healing 6, 7
• In vascular EDS, skin is thin and translucent with visible veins 4

Cardiovascular Manifestations

• Aortic root dilation in 25-33% of hypermobile and classical types 1, 4
• In vascular EDS, arterial rupture and aneurysms can occur spontaneously 1, 4
• Annuloaortic ectasia is diagnosed in 5-10% of patients undergoing aortic valve replacement 5

Gastrointestinal Manifestations

• Up to 98% of hEDS patients experience GI symptoms 3, 4
• Nausea, abdominal pain, constipation, bloating, early satiety, and reflux are common 4
• High prevalence of pelvic floor dysfunction 4

Other Systemic Features

• High palate and earlobe elasticity in 63% of cases 3
• Postural orthostatic tachycardia syndrome (POTS) affects up to 37.5% of hEDS patients 4
• Mast cell activation syndrome (MCAS) may coexist 3, 4

Diagnostic Approach

Who Should Diagnose EDS?

Medical geneticists are the primary specialists who should diagnose and classify EDS, as they have expertise in evaluating inherited connective tissue disorders and can coordinate appropriate genetic testing 4

Initial Clinical Assessment

• Document a three-generation family history focusing on sudden deaths, arterial ruptures, organ perforations, and autosomal dominant inheritance patterns 4
• Perform Beighton scale assessment: ≥5/9 for adults under 50, ≥4/9 for adults over 50, ≥6/9 for prepubertal children 1, 4
• Assess skin texture, hyperextensibility, fragility, and scarring patterns 4
• Evaluate for easy bruising and tissue fragility 1, 4

Essential Screening Tests for All Suspected EDS Cases

Cardiovascular Imaging

• Echocardiogram is required for all suspected EDS cases to evaluate aortic root diameter 4
• Annual echocardiogram if aortic root is normal; every 6 months if diameter >4.5 cm or growth >0.5 cm/year 4
• MR angiography of head, neck, thorax, abdomen, and pelvis for suspected vascular EDS or when arteriopathy is suspected 4

Ophthalmologic Examination

• Dilated eye examination to exclude Marfan syndrome 1, 4

Autonomic Function Testing

• Measure postural vital signs with active stand test: heart rate increase ≥30 beats/min in adults (≥40 beats/min in adolescents 12-19 years) within 10 minutes of standing without orthostatic hypotension to screen for POTS 4
• Tilt table testing if postural vital signs confirm POTS 4

Genetic Testing Strategy

For Suspected Vascular EDS (URGENT)

• COL3A1 gene mutation testing should be performed urgently when vascular EDS is suspected, as this is a life-threatening subtype 4
• Genetic counseling is paramount before mutation screening due to complex financial, insurance, familial, and social implications 4

For Classical EDS

• COL5A1 or COL5A2 gene mutation testing for molecular confirmation 4

For Hypermobile EDS

• No genetic testing is available or recommended for hEDS, as no causative genes have been identified; diagnosis is purely clinical 4

Multi-Gene Panel Approach

• Multi-gene panel testing covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes is the most efficient diagnostic approach when EDS is suspected but subtype is unclear 4

Additional Laboratory Testing

For Suspected Mast Cell Activation Syndrome

• Obtain baseline serum tryptase level ONLY if patient presents with episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing) 4
• Diagnostic threshold: 20% increase above baseline plus 2 ng/mL during symptom flares 4
• Do NOT perform routine MCAS testing in all hEDS patients with isolated GI symptoms 4

For Gastrointestinal Symptoms

• Celiac disease serological testing should be performed earlier in hEDS patients with any GI symptoms 4
• Anorectal manometry, balloon expulsion test, or defecography for lower GI symptoms like incomplete evacuation 4
• Gastric emptying studies for chronic upper GI symptoms after excluding anatomical/structural disease 4

For Suspected Vascular EDS Variants

• Baseline serum tryptase level to help distinguish vascular complications 4
• Vitamin B12 level (characteristically elevated in myeloproliferative variants) 4
• Complete blood count with differential to evaluate for cytopenias or eosinophilia 4
• Comprehensive metabolic panel including liver and renal function 4
• Lactate dehydrogenase as a marker for tissue breakdown 4

Management Approach

Cardiovascular Surveillance and Management

For All EDS Types

• Annual echocardiogram if aortic root is normal 4
• Every 6 months if aortic root diameter >4.5 cm or growth >0.5 cm/year 4

For Vascular EDS

• Surveillance imaging protocols with MR angiography of the entire vascular tree 4
• Avoid invasive vascular imaging in suspected vascular EDS, as fatal complications have been reported 4
• Acute dissection beyond the left subclavian artery not involving the proximal aorta should be managed medically 5
• Progressive dilatation to 5 cm or more, recurrent pain, or signs of fresh dissection are indications for repair 5

Physical Medicine and Rehabilitation

Most Effective Treatments

• Occupational therapy and bracing are the most effective options, with 70% of patients reporting improvement 8
• Physical therapy is widely used and beneficial 8

Medications for Pain Management

• Avoid opioids in patients with chronic pain 4
• Neuropathic modulators are commonly used but least well tolerated, with 47% of patients reporting adverse effects 8
• Nonsteroidal anti-inflammatory drugs are used with variable success 8
• Muscle relaxants may provide benefit 8
• Acetaminophen is a safe option 8

Gastrointestinal Management

• Refer patients with refractory gastrointestinal symptoms despite appropriate management to a gastroenterologist 4
• Address pelvic floor dysfunction with appropriate testing and therapy 4

Autonomic Dysfunction Management

• Refer patients with POTS for evaluation if lifestyle modifications have failed 4
• Consider histamine receptor antagonists and mast cell stabilizers when MCAS is suspected in hEDS patients 3

Pregnancy Considerations

• Women with vascular EDS face significant risks including uterine and arterial rupture, especially during pregnancy 4
• Increased bruising, hernias, varicosities, or rupture of large vessels may occur during pregnancy 5
• Postpartum hemorrhage may be severe 5
• Incisions heal slowly; retention sutures should be used and left in longer than normal (at least 14 days) with extended antibiotic cover 5
• Epidural and spinal anesthesia should be undertaken only after consideration of dural ectasia 5

Surgical Considerations

• Wound healing is delayed; retention sutures should be used and not removed prematurely 5
• Antibiotic cover should be extended until sutures are removed 5

Critical Pitfalls to Avoid

• Failure to recognize vascular EDS, which carries significant mortality risk from arterial or organ rupture 4
• Performing invasive diagnostic procedures in vascular EDS patients, which can lead to fatal complications 4
• Not delaying COL3A1 testing if vascular EDS is suspected, as this is a medical emergency 4
• Routine genetic testing for hEDS (no causative genes identified) 4
• Routine MCAS testing in all hEDS patients with isolated GI symptoms 4
• Using opioids for chronic pain management 4

Prognosis and Long-Term Outlook

• For vascular EDS, median survival is 48 years if untreated, with arterial rupture being the primary cause of mortality 4
• For other EDS types, life expectancy is generally normal, but quality of life is significantly impacted by chronic pain, joint instability, and multisystem complications 6, 2
• No curative treatment exists for any type of EDS; management is entirely supportive and preventive 6, 2
• Early diagnosis is crucial to optimize symptomatic management and prevent avoidable complications 6
• Patients must be treated and monitored by multidisciplinary teams in highly specialized reference centers 6

Genetic Counseling and Family Implications

• Almost every family has its own specific mutation, making genetic testing challenging 1
• No genotype-phenotype correlations have been established; the specific mutation does not predict disease type, course, or severity 1
• Classical and vascular EDS follow autosomal dominant inheritance with genetic heterogeneity 1
• If a mutation has been identified in an affected parent, prenatal diagnosis can be made by chorionic villus biopsy at 13 weeks gestation or amniocentesis 5
• Testing in the newborn period avoids the 1% risk of miscarriage from fetal sampling 5