How should Ehlers‑Danlos syndrome be diagnosed and managed, including subtype‑specific recommendations?

Management of Ehlers-Danlos Syndrome

Management of EDS requires subtype-specific strategies, with hypermobile EDS (hEDS) managed primarily through physical therapy, cardiovascular surveillance, and symptom-directed care, while vascular EDS demands urgent genetic confirmation, celiprolol therapy, and strict avoidance of invasive procedures due to life-threatening arterial rupture risk. 1

Initial Diagnostic Confirmation

Before initiating management, confirm the EDS subtype through appropriate testing:

• Perform genetic testing to exclude alternative diagnoses even when clinical criteria for hEDS appear met, as 26.4% of clinically diagnosed hEDS cases have alternative genetic conditions requiring different management strategies 1, 2
• Order urgent COL3A1 gene mutation testing if vascular EDS is suspected based on thin translucent skin, visible veins, or family history of arterial rupture 3, 1
• Use multi-gene panel testing (covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1) when EDS is suspected but subtype is unclear 3
• Apply the 2017 diagnostic criteria for hEDS available at https://www.ehlers-danlos.com/wp-content/uploads/2017/05/hEDS-Dx-Criteria-checklist-1.pdf, requiring Beighton score ≥5/9, soft/velvety skin without fragility, and exclusion of alternative diagnoses 3, 1

Cardiovascular Surveillance (All EDS Subtypes)

Cardiac complications occur in 25-33% of hEDS and classic EDS patients, requiring systematic monitoring:

• Obtain baseline echocardiogram to evaluate aortic root diameter in all newly diagnosed EDS patients 3, 1, 4
• Repeat echocardiogram every 2-3 years until adult height is reached if aortic root is normal 1, 4
• Increase surveillance to every 6 months if aortic root diameter exceeds 4.5 cm in adults or growth rate exceeds 0.5 cm/year 3, 1
• Perform baseline MR angiography from head to pelvis for vascular EDS or Loeys-Dietz syndrome to assess entire vascular tree for arterial tortuosity and aneurysms 3, 1
• Conduct annual surveillance imaging for any dilated or dissected vascular segments in vascular EDS 1

Vascular EDS-Specific Management

This subtype carries median survival of 48 years with spontaneous arterial rupture risk, requiring aggressive preventive measures:

• Initiate celiprolol therapy to reduce vascular morbidity, despite lack of FDA approval in the US 1
• Avoid all invasive vascular procedures including diagnostic angiography, as fatal complications have been reported 3, 1
• Use exclusively non-invasive imaging (Doppler ultrasound, CT, or MRI) for vascular assessment 1
• Refer to vascular surgery for surveillance imaging protocols and emergency planning 3

Musculoskeletal Management

Joint hypermobility and chronic pain are universal features requiring conservative approaches:

• Prescribe low-resistance exercise and physical therapy as the cornerstone of musculoskeletal management 1
• Avoid opioid dependence for chronic pain management, particularly problematic in patients with gastrointestinal manifestations 1
• Screen for osteoporosis with DXA scan if height loss exceeds 1 inch 3
• Evaluate for scoliosis and congenital hip dislocation, present in significant proportions of hEDS patients 1

Gastrointestinal Management

Up to 98% of hEDS patients experience GI manifestations requiring targeted interventions:

• Perform celiac disease serological testing earlier in hEDS patients with any GI symptoms, as risk is elevated compared to general population 3, 4
• Prescribe proton pump inhibitors, H2-blockers, or sucralfate for gastritis and reflux 1
• Use promotility agents for delayed gastric emptying confirmed by gastric emptying studies 3, 1
• Order anorectal manometry, balloon expulsion test, or defecography for lower GI symptoms like incomplete evacuation, given high prevalence of pelvic floor dysfunction 3
• Avoid escalation to invasive nutrition support in pain-predominant presentations, as most hEDS patients have visceral hypersensitivity rather than true dysmotility 1

Autonomic Dysfunction Screening and Management

POTS affects up to 37.5% of hEDS patients and requires systematic evaluation:

• Measure postural vital signs with active stand test, documenting heart rate increase ≥30 beats/min in adults (≥40 beats/min in adolescents 12-19 years) within 10 minutes of standing without orthostatic hypotension 3, 1, 4
• Refer for tilt table testing if postural vital signs confirm POTS and lifestyle modifications have failed 3, 4
• Initiate lifestyle modifications first, including increased fluid and salt intake, compression garments, and gradual exercise reconditioning 3

Mast Cell Activation Syndrome Evaluation

MCAS may coexist with hEDS but requires specific diagnostic criteria:

• Obtain baseline serum tryptase level ONLY if patient presents with episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing) 3, 4
• Avoid routine MCAS testing in all hEDS patients with isolated GI symptoms 3
• Confirm MCAS diagnosis with tryptase increase of 20% above baseline plus 2 ng/mL during symptom flares 3
• Refer to allergy/mast cell disease research center if MCAS diagnosis is supported through clinical and/or laboratory features 3

Pregnancy Considerations

Women with EDS face specific pregnancy risks requiring preconception counseling:

• Counsel about uterine and arterial rupture risk, especially in vascular type 3
• Coordinate care with maternal-fetal medicine for high-risk pregnancy management 3

Ophthalmologic Surveillance

• Perform dilated eye examination to exclude Marfan syndrome and evaluate for ocular complications 3, 4

Critical Pitfalls to Avoid

• Never diagnose hEDS without genetic testing to exclude alternative diagnoses, as over one-quarter of clinical diagnoses are incorrect 1, 2
• Never perform invasive diagnostic procedures in vascular EDS, using non-invasive imaging exclusively 3, 1
• Never delay COL3A1 testing if vascular EDS is suspected, as this represents a medical emergency 3
• Never overlook associated conditions including POTS, mast cell activation disorder, and chronic urinary retention 1
• Never prescribe long-term opioids for chronic pain management in EDS patients 3, 1