How do I diagnose and manage a patient suspected of having Ehlers‑Danlos syndrome, especially the vascular type?

Diagnosis and Management of Ehlers-Danlos Syndrome

For suspected Ehlers-Danlos syndrome, immediately determine whether vascular EDS (Type IV) is possible—if so, order urgent COL3A1 genetic testing and avoid all invasive procedures, as this life-threatening subtype has a median survival of only 48–51 years with arterial rupture as the leading cause of death. 1, 2

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Initial Clinical Assessment

Step 1: Recognize Red Flags for Vascular EDS (Type IV)

• Look for thin, translucent skin with visible subcutaneous veins on the trunk and lower back, characteristic facial features (acrogeria), easy bruising without significant trauma, and a family history of sudden death or arterial rupture. 3, 1
• Vascular EDS represents only 5–10% of all EDS cases but carries catastrophic risk—arterial dissection and rupture can occur at normal or minimally dilated aortic diameters. 2, 3
• Do not perform invasive catheterization or angiography in suspected vascular EDS patients, as these procedures can be fatal. 2, 1

Step 2: Calculate the Beighton Score for Joint Hypermobility

• Award one point for each of the following findings (maximum 9 points): 1, 4
  • Passive dorsiflexion of each fifth finger >90° (1 point per side)
  • Passive thumb apposition to the flexor surface of the forearm (1 point per side)
  • Elbow hyperextension >10° (1 point per side)
  • Knee hyperextension >10° (1 point per side)
  • Ability to place palms flat on the floor when bending forward with knees extended (1 point)
• A score **≥5/9 in adults <50 years** (≥4/9 if >50 years, ≥6/9 in prepubertal children) is required to proceed with further evaluation. 1, 4

Step 3: Document Skin and Tissue Characteristics

• Examine for soft, velvety, or hyperextensible skin by gently pulling the skin on the volar forearm. 1, 4
• Look for atrophic scarring (especially over pressure points like knees and elbows), easy bruising, and delayed wound healing. 5, 6
• Absence of skin fragility distinguishes hypermobile EDS from classical or vascular subtypes. 4

Step 4: Obtain a Three-Generation Family History

• Document any family members with joint hypermobility, sudden death, arterial rupture, organ perforation, or uterine rupture—these suggest autosomal dominant inheritance of vascular EDS. 1, 3

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Genetic Testing Strategy

For Suspected Vascular EDS (Type IV)

• Order urgent COL3A1 gene mutation testing as the definitive diagnostic test; this is a medical emergency. 1, 2
• If COL3A1 testing is negative but clinical suspicion remains high, consider multi-gene panel testing covering COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes. 1

For Suspected Hypermobile EDS (hEDS)

• No genetic test is available for hEDS; diagnosis relies exclusively on the 2017 clinical criteria (Beighton score ≥5, soft skin without fragility, and exclusion of alternative diagnoses). 1, 4
• Genetic testing is still mandatory to exclude alternative diagnoses—26.4% of clinically diagnosed hEDS cases have alternative genetic conditions requiring different management. 4, 7
• Use a multi-gene EDS panel to exclude classical EDS (COL5A1, COL5A2 mutations) and other connective tissue disorders. 1, 5

Critical Pitfall

• Never diagnose hEDS without genetic testing to exclude alternative diagnoses—failure to do so may miss life-threatening conditions like vascular EDS or Loeys-Dietz syndrome. 4, 7

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Cardiovascular Evaluation

Baseline Imaging for All Suspected EDS Patients

• Obtain a transthoracic echocardiogram to assess aortic root diameter—aortic dilation occurs in 25–33% of hypermobile and classical EDS cases. 1, 4, 2
• Perform a dilated eye examination to exclude Marfan syndrome in the differential diagnosis. 1

Imaging for Confirmed or Suspected Vascular EDS

• Order noninvasive MR angiography from head to pelvis to evaluate the entire aorta and all arterial branches (including renal, carotid, and vertebral arteries). 1, 2
• Avoid CT angiography with contrast if possible, as vascular access and contrast injection carry risk in fragile vessels. 3

Surveillance Imaging Schedule

• For hypermobile or classical EDS with normal aortic root: Repeat echocardiogram every 2–3 years until adult height is reached, then annually if the aortic root remains <4.5 cm and growth rate is <0.5 cm/year. 1, 2
• For aortic root diameter >4.5 cm or growth rate >0.5 cm/year: Repeat echocardiogram every 6 months. 1, 2
• For vascular EDS: Annual surveillance imaging of all vascular segments is required at minimum; any dilated or dissected segments require more frequent monitoring. 2

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Screening for Common Comorbidities

Autonomic Dysfunction (POTS)

• Measure postural vital signs with an active stand test—a sustained heart rate increase of ≥30 beats/min in adults (≥40 beats/min in adolescents aged 12–19) within 10 minutes of standing, without orthostatic hypotension, confirms POTS. 1
• POTS affects up to 37.5% of hEDS patients and may be triggered by viral infections (including COVID-19). 1

Gastrointestinal Manifestations

• Screen for nausea, abdominal pain, constipation, bloating, early satiety, and reflux—up to 98% of hEDS patients experience GI symptoms. 1, 4
• Perform celiac disease serological testing earlier in hEDS patients with any GI symptoms, as the risk is elevated. 1
• Consider anorectal manometry, balloon expulsion test, or defecography for lower GI symptoms like incomplete evacuation, given the high prevalence of pelvic floor dysfunction. 1

Mast Cell Activation Syndrome (MCAS)

• Obtain baseline serum tryptase only if the patient presents with episodic multisystem symptoms involving ≥2 organ systems (flushing, urticaria, wheezing). 1
• Do not routinely test for MCAS in all hEDS patients with isolated GI symptoms. 1
• If MCAS is suspected, repeat tryptase 1–4 hours following a symptomatic flare—a diagnostic threshold of 20% increase above baseline plus 2 ng/mL confirms MCAS. 1

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Management

Medical Therapy for Vascular EDS

• Initiate celiprolol (a beta-blocker with vasodilatory properties) to reduce vascular morbidity three-fold; although it lacks FDA approval in the US, alternative beta-blockers with vasodilatory properties may be substituted. 2
• Maintain aggressive blood pressure control to minimize arterial wall stress. 2
• There is no evidence to support ARB use in vascular EDS, unlike in Marfan syndrome. 2

Musculoskeletal Management

• Prescribe low-resistance exercise and physical therapy to stabilize joints and prevent dislocations. 4
• Avoid high-impact activities and contact sports that increase the risk of joint injury or arterial trauma. 3

Gastrointestinal Management

• Use proton pump inhibitors, H2-blockers, or sucralfate for gastritis and reflux. 4
• Prescribe promotility agents for delayed gastric emptying. 4
• Do not escalate to invasive nutrition support (e.g., feeding tubes) in hEDS with pain-predominant presentation—most hEDS patients have visceral hypersensitivity rather than true dysmotility. 4

Pain Management

• Avoid opioid dependence for chronic pain, as this is particularly problematic in patients with GI manifestations. 4, 1
• Refer to a multidisciplinary pain management team that includes clinical psychology or liaison psychiatry to address anxiety, depression, and maladaptive coping. 1

Surgical Considerations

• Surgery carries extremely high risk in vascular EDS due to tissue fragility, bleeding tendency, and poor wound healing. 2, 3
• If surgery is unavoidable, use pledgeted sutures and meticulous technique to minimize tissue trauma. 2
• The role of prophylactic repair of unruptured aneurysms remains unclear—conservative management is usually recommended unless rupture is imminent. 2, 3

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Critical Pitfalls to Avoid

• Do not delay COL3A1 testing if vascular EDS is suspected—this is a medical emergency with a median survival of 48–51 years. 1, 2
• Do not perform invasive vascular procedures (catheterization, angiography) in vascular EDS patients, as these can be fatal. 2, 1
• Do not diagnose hEDS without genetic testing to exclude alternative diagnoses—26.4% of clinically diagnosed cases have alternative conditions. 4, 7
• Do not overlook pregnancy risks in women with vascular EDS—uterine and arterial rupture risk is significantly elevated. 1, 3
• Do not miss associated conditions—screen for POTS, MCAS, and chronic urinary retention in all hEDS patients. 1, 4

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Multidisciplinary Care Coordination

• Coordinate management between cardiology, vascular surgery, genetics, gastroenterology, rheumatology, and pain medicine with expertise in connective tissue disorders. 2
• Centralize care at centers of excellence whenever feasible, as vascular EDS requires highly specialized management. 2