How should Ehlers‑Danlos syndrome be diagnosed and managed?

Diagnosis and Management of Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome (EDS) requires clinical diagnosis using the 2017 international criteria, with hypermobile EDS (hEDS) diagnosed through the Beighton score plus systemic features, while other subtypes require genetic confirmation; management focuses on multidisciplinary symptom control, particularly addressing gastrointestinal manifestations and associated POTS/MCAS. 1, 2

Diagnostic Approach

For Hypermobile EDS (Most Common - 80-90% of Cases)

The diagnosis requires meeting three mandatory criteria 1, 2:

1. Generalized Joint Hypermobility (Beighton Score)

   • ≥6/9 points in prepubertal children
   • ≥5/9 points from puberty to age 50
   • ≥4/9 points for those ≥50 years old
   • The Beighton score assesses: 5th finger hyperextension, thumb-to-forearm apposition, elbow hyperextension >10°, knee hyperextension >10°, and palms flat on floor with knees straight 1

2. Systemic Manifestations of Connective Tissue Disorder

   • At least 2 features including: soft/velvety skin, mild skin hyperextensibility, unexplained striae, piezogenic papules, recurrent hernias, pelvic organ prolapse, dental crowding, high/narrow palate, arachnodactyly, or positive family history 1

3. Exclusion of Alternative Diagnoses

   • This is critical and often underutilized: Genetic testing identified alternative diagnoses in 26.4% of patients who initially met hEDS criteria, requiring different management strategies 3
   • Rule out other EDS subtypes, Marfan syndrome, Loeys-Dietz syndrome, inflammatory diseases, and chromosomal abnormalities 3

For Other EDS Subtypes

Genetic testing is mandatory for definitive diagnosis of all non-hypermobile subtypes 4, 2. Thirteen subtypes are recognized, with 12 having identified genetic causes involving mutations in collagen genes (types I, III, V) or collagen-modifying enzymes 4.

Key Diagnostic Pitfall

Do not skip genetic testing even when hEDS criteria appear met - 26.4% will have an alternative diagnosis requiring different management 3. The molecular basis of hEDS remains unknown, making it a diagnosis of exclusion 4.

Management Strategy

Gastrointestinal Manifestations (Present in 98% of hEDS Patients)

Target the most prominent GI symptoms with diagnostic testing before empiric treatment 1:

• For chronic upper GI symptoms with comorbid POTS: Measure gastric emptying and/or accommodation after excluding structural disease 1
• Treat based on abnormal function test results, not just symptoms 1
• Almost all hEDS patients meet criteria for disorders of gut-brain interaction (DGBI) 1

POTS Management (Present in 37.5% of hEDS Patients)

First-line conservative measures 1:

• Increase fluid intake (2-3 liters daily)
• Increase salt intake (6-10 grams daily)
• Exercise training (recumbent exercises initially)
• Compression garments (waist-high, 30-40 mmHg)

Escalate to pharmacological treatment if conservative measures fail 1:

• Volume expansion agents
• Heart rate control medications
• Vasoconstrictors
• Requires integrated care from cardiology and neurology

Diagnostic confirmation: Heart rate increase ≥30 bpm within 10 minutes of standing (≥40 bpm in adolescents 12-19 years) without orthostatic hypotension 1

MCAS Management (When Suspected)

Initiate histamine receptor antagonists and/or mast cell stabilizers 1, plus:

Strict trigger avoidance 1:

• Foods (patient-specific)
• Alcohol
• Strong smells
• Temperature changes
• Mechanical stimuli (friction)
• Emotional distress
• Specific medications: avoid opioids and NSAIDs
• Environmental allergens (pollen, mold)
• Iodinated contrast

Dietary Interventions

Implement targeted dietary modifications with nutritional counseling 1:

• Gastroparesis diet (small particle diet) for delayed gastric emptying
• Low fermentable carbohydrate diet for bloating/gas
• Gluten-free or dairy-free diets (if indicated)
• Low-histamine diet for MCAS symptoms

Critical caveat: Patients with hEDS have high rates of restrictive eating and ARFID (Avoidant Restrictive Food Intake Disorder), with 24% requiring nutrition support 5. Dietary interventions must include appropriate nutritional counseling to prevent nutritional inadequacy - patients commonly have deficiencies in calories, fiber, vitamins B and D 1, 5.

Screening Approach for Comorbidities

Do not universally test all hEDS patients for POTS/MCAS 1. Instead, test only when clinical manifestations suggest these conditions:

• POTS symptoms: Orthostatic intolerance, lightheadedness, palpitations, fatigue worsening with standing
• MCAS symptoms: Multisystem symptoms (≥2 organ systems) including flushing, urticaria, GI symptoms, respiratory symptoms triggered by specific exposures

General Management Principles

No specific medical or genetic therapies exist for any EDS subtype 4. Management is symptomatic and requires:

• Physical medicine and rehabilitation
• Surveillance for major complications (arterial aneurysm/dissection in vascular subtypes)
• Multidisciplinary care coordination
• Personalized treatment plans 6

Important Clinical Considerations

The evidence shows that hypermobility may represent a shared phenotype across multiple disorders 3, reinforcing why criterion 3 (exclusion of alternatives) is essential. The clinical overlap between EDS subtypes and other hereditary connective tissue disorders makes thorough evaluation mandatory 2.

For oral/maxillofacial practitioners: Be alert for subtype-specific features like nasal bridge depression (arthrochalasia EDS), tooth agenesis (spondylodysplastic/dermatosparactic EDS), and pulpal calcifications (classical EDS) 7.