What is the initial workup for a patient presenting with possible Ehlers-Danlos (EDS) syndrome?

Workup for Possible Ehlers-Danlos Syndrome

Begin with the Beighton score to assess joint hypermobility: ≥5/9 points for adults under 50, ≥4/9 for those over 50, and ≥6/9 for prepubertal children, then apply the 2017 diagnostic criteria for hypermobile EDS (hEDS) or proceed directly to urgent COL3A1 genetic testing if vascular EDS is suspected based on thin translucent skin, arterial/organ rupture history, or family history of sudden death. 1, 2

Initial Clinical Assessment

Joint Hypermobility Evaluation (Beighton Score)

• Assess passive dorsiflexion of each fifth finger >90 degrees (1 point per side) 3, 1
• Test passive apposition of each thumb to flexor surface of forearm (1 point per side) 3, 1
• Evaluate hyperextension of each elbow >10 degrees (1 point per side) 3, 1
• Check hyperextension of each knee >10 degrees (1 point per side) 3, 1
• Assess ability to place palms flat on floor when bending forward with knees extended (1 point) 3, 1

Skin and Tissue Assessment

• Examine for soft, velvety, or hyperextensible skin 1, 2
• Document easy bruising patterns without significant trauma 1, 2
• Look for atrophic scarring or abnormal wound healing 1, 4
• Assess for thin, translucent skin with visible veins (suggests vascular EDS—requires urgent workup) 1

Family History Documentation

• Obtain three-generation family history focusing on sudden deaths, arterial ruptures, organ perforations, and autosomal dominant inheritance patterns 1

Essential Baseline Laboratory Testing

Cardiovascular Screening

• Order echocardiogram to evaluate aortic root diameter (dilation occurs in 25-33% of hEDS cases) 1, 2
• 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 3, 1, 2

Gastrointestinal Screening

• Perform celiac disease serological testing in all hEDS patients with any GI symptoms (risk is elevated compared to general population) 1, 2

Mast Cell Activation Syndrome (MCAS) Screening

• Obtain baseline serum tryptase level ONLY if patient presents with episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing) 3, 1
• Do NOT perform routine MCAS testing in all hEDS patients with isolated GI symptoms 1

Genetic Testing Strategy

For Suspected Vascular EDS (URGENT)

• Order COL3A1 gene mutation testing immediately if patient has thin translucent skin, family history of arterial/organ rupture, or sudden death (median survival 48 years; this is life-threatening) 1, 2
• Avoid invasive vascular imaging in suspected vascular EDS as fatal complications have been reported 1

For Suspected Classical EDS

• Order COL5A1 or COL5A2 gene mutation testing for molecular confirmation 1

For Hypermobile EDS (hEDS)

• Do NOT order genetic testing for hEDS as no causative genes have been identified 1, 5
• Apply the 2017 diagnostic criteria clinically (available at https://www.ehlers-danlos.com/wp-content/uploads/2017/05/hEDS-Dx-Criteria-checklist-1.pdf) 1, 2

When EDS Subtype is Unclear

• Order multi-gene panel testing covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes 1
• Avoid routine whole-genome or exome sequencing in suspected hEDS 1

Additional Diagnostic Testing Based on Symptoms

For Gastrointestinal Symptoms (present in up to 98% of hEDS patients)

• Consider anorectal manometry, balloon expulsion test, or defecography for lower GI symptoms like incomplete evacuation (high prevalence of pelvic floor dysfunction) 1
• Order gastric emptying studies for chronic upper GI symptoms after excluding anatomical/structural disease 1

For Suspected POTS (if postural vital signs positive)

• Consider tilt table testing for formal autonomic function assessment 1

To Exclude Related Conditions

• Perform dilated eye examination to exclude Marfan syndrome 1, 2
• Consider Wood's lamp examination to exclude other connective tissue disorders 1

Critical Pitfalls to Avoid

• Never delay COL3A1 testing if vascular EDS is suspected—this is a medical emergency with high mortality risk from arterial or organ rupture 1
• Never perform invasive diagnostic procedures in suspected vascular EDS patients as this can lead to fatal complications 1
• Never order genetic testing for hEDS—diagnosis is purely clinical using 2017 criteria 1, 5
• Never perform universal POTS/MCAS testing in all hEDS patients—target testing only to those with specific clinical manifestations 3

When to Refer to Specialists

Medical Genetics

• Refer all suspected EDS cases to medical genetics for definitive diagnosis and classification 1, 2
• Genetic counseling is essential before mutation screening due to financial, insurance, familial, and social implications 1

Cardiology

• Refer if aortic root dilation is found on echocardiogram 2
• Refer if POTS symptoms are refractory to lifestyle modifications 2

Gastroenterology

• Refer patients with refractory GI symptoms despite appropriate management 1

Vascular Surgery

• Refer suspected vascular EDS patients for surveillance imaging protocols 1

Allergy/Mast Cell Disease Center

• Refer if MCAS diagnosis is supported through serum tryptase increases of 20% above baseline plus 2 ng/mL during symptom flares 1