How do I evaluate a patient for Ehlers‑Danlos syndrome?

How to Evaluate for Ehlers-Danlos Syndrome

Use the 2017 international consensus criteria for hypermobile EDS (hEDS), which requires fulfilling three major criteria: (1) generalized joint hypermobility assessed by Beighton score, (2) presence of at least 2 connective tissue disorder manifestations, and (3) exclusion of alternative diagnoses through targeted genetic testing. 1

Step 1: Assess Joint Hypermobility Using the Beighton Score

The Beighton scoring system is the standardized first criterion for hEDS diagnosis. 1 Test the following five maneuvers bilaterally where applicable:

• Fifth finger (pinkies): With palm flat and fingers straight, can the pinky extend back beyond 90 degrees? (1 point per side) 1
• Thumbs: With arm outstretched and palm down, can the thumb be pushed back to touch the forearm? (1 point per side) 1
• Elbows: With arms outstretched and palms up, does the elbow hyperextend more than 10 degrees? (1 point per side) 1
• Knees: With legs straight, do the knees hyperextend more than 10 degrees? (1 point per side) 1
• Spine/forward flexion: Can the patient place palms flat on the floor with knees straight? (1 point) 1

Positive Beighton score thresholds: 1

• ≥6/9 points in prepubertal children
• ≥5/9 points from puberty to age 50
• ≥4/9 points for those ≥50 years old

Step 2: Identify Connective Tissue Disorder Features

The second criterion requires at least 2 of the following manifestations: 1

• Skin findings: Soft, velvety skin texture; skin hyperextensibility; unexplained striae; atrophic scarring 1
• Musculoskeletal symptoms: Chronic joint pain (≥3 months in multiple joints); recurrent joint dislocations or subluxations 1, 2
• Associated conditions: Pelvic floor dysfunction, rectal or uterine prolapse 1
• Family history: First-degree relative meeting hEDS criteria 1

Common but often overlooked symptoms include: 2

• Chronic pain (most impactful symptom reported by patients) 2
• Fatigue and sleep disorders 2
• Gastrointestinal symptoms (present in >60% of hEDS patients, with 98% meeting criteria for disorders of gut-brain interaction) 1

Step 3: Exclude Alternative Diagnoses Through Genetic Testing

This is the critical and most underutilized step. 3 Genetic testing identified alternative or additional diagnoses in 26.4% of patients who initially met clinical criteria for hEDS, with clinically significant management implications. 3

Order comprehensive genetic testing including: 3, 4

• Next-generation sequencing panel covering collagen genes (COL5A1, COL5A2, COL3A1, COL1A1, COL1A2) 4
• Aortopathy genes (FBN1, TGFBR1, TGFBR2, SMAD3) to identify vascular complications requiring distinct surveillance 4
• Tenascin-X (TNXB) and other candidate genes 5

Why genetic testing matters: Unbiased sequencing detects pathogenic variants outside expected genotype-phenotype relationships and identifies clinically actionable variants requiring different management strategies (e.g., vascular EDS requires specific cardiovascular monitoring). 4 The molecular etiology of hEDS remains unknown, so diagnosis is clinical only after excluding other EDS subtypes. 3, 5

Step 4: Screen for Associated Conditions

Once hEDS is suspected or confirmed, assess for commonly associated conditions that impact management:

Postural Orthostatic Tachycardia Syndrome (POTS): 1

• Measure heart rate increase within 10 minutes of standing (≥30 bpm in adults, ≥40 bpm in adolescents 12-19 years) without orthostatic hypotension 1
• Symptoms must be present ≥6 months: palpitations, lightheadedness, fatigue, blurred vision, cognitive dysfunction 1
• Reported in 37.5% of hEDS patients; those with POTS have higher rates of GI dysmotility 1

Mast Cell Activation Syndrome (MCAS): 1

• Only test patients with clinical manifestations (multisystem symptoms triggered by foods, heat, emotion, mechanical stimuli) 1
• Universal screening for POTS/MCAS in all hEDS patients is not supported by evidence 1

Additional Diagnostic Considerations

Oral and maxillofacial examination may reveal: 6

• Tooth agenesis, pulpal calcifications, root abnormalities 6
• Gingival hyperplasia, absent labial/lingual frenula 6
• Subtype-specific features (e.g., nasal bridge depression, downslanting palpebral fissures) 6

Common pitfalls to avoid:

• Relying solely on clinical criteria without genetic testing leads to misdiagnosis in over 25% of cases 3
• Using outdated nosology terminology from pre-2017 classifications 5, 7
• Missing vascular EDS variants that require urgent cardiovascular surveillance 4
• Failing to recognize that hypermobility may represent a shared phenotype across inflammatory diseases, monogenic syndromes, and chromosomal abnormalities 3