Ehlers-Danlos Syndrome
How to diagnose, when to refer, and why it matters
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Douglas Ball, MD, DrPH | Clinical Geneticist
Why this matters today
1
Recognize
when to suspect EDS
2
Decide who needs
testing and/or referral
3
Identify red flags for
vEDS and dangerous conditions
4
Manage EDS and associated conditions in clinic
1
The EDS Spectrum
Overview
• Ehlers-Danlos Syndromes (EDS) are a group of heritable connective tissue disorders (HCTDs).
• The 2017 International Classification recognizes 13 distinct subtypes.
The Diagnostic Divide
The 13 Types of EDS (2017 Classification)
EDS Subtype
Causative Gene(s)
Inh.
Classical EDS (cEDS)
COL5A1 / COL5A2
AD
Classical-like EDS (clEDS)
TNXB
AR
Cardiac-valvular EDS (cvEDS)
COL1A2
AR
Vascular EDS (vEDS) ⚠ URGENT
COL3A1
AD
Hypermobile EDS (hEDS)
Unknown — multifactorial
AD
Arthrochalasia EDS (aEDS)
COL1A1 / COL1A2
AD
Dermatosparaxis EDS (dEDS)
ADAMTS2
AR
Kyphoscoliotic EDS (kEDS)
PLOD1 / FKBP14
AR
Brittle Cornea Syndrome (BCS)
ZNF469 / PRDM5
AR
Spondylodysplastic EDS (spEDS)
B4GALT7 / B3GALT6 / SLC39A13
AR
Musculocontractural EDS (mcEDS)
CHST14 / DSE
AR
Myopathic EDS (mEDS)
COL12A1
AD/AR
Periodontal EDS (pEDS)
C1R / C1S
AD
Inh. = Inheritance | AD = Autosomal Dominant | AR = Autosomal Recessive | Pink = Urgent evaluation | Blue = No causative gene
When should you suspect EDS? Joint Clues
• Generalized joint hypermobility or “double-jointed” history
• Atraumatic subluxations / recurrent sprains / frank instability
• Musculoskeletal pain in ≥2 limbs, daily ≥3 months, or widespread chronic pain
• Symptoms start young, persist, and cluster across multiple joints
When should you suspect EDS? Skin / Tissue Clues
• Soft or velvety skin; mild hyperextensibility
• Unexplained striae, atrophic scars, recurrent hernias
• Bilateral heel piezogenic papules
• Dental crowding with high or narrow palate
When should you suspect EDS? Systemic Clues
• Positive family history: 3-generation pedigree
• Dysautonomia / orthostatic symptoms / POTS
• Functional GI or bladder disorders, fatigue, anxiety
• MVP or aortic root dilation, especially with other connective tissue signs
Diagnostic Criteria for hEDS
https://www.ehlers-danlos.com/heds-diagnostic-checklist/
The Beighton Score — Measuring Joint Hypermobility
Beighton Score Methodology
Score out of 9; each side is evaluated independently.
Age-Adjusted Cut-offs (Malfait 2017)
Strict adherence to cut-offs is required for hEDS diagnosis:
≥6 for pre-pubertal children and adolescents.
≥5 for pubertal men and women up to age 50.
≥4 for individuals >50 years of age.
The Beighton Score — Measuring Joint Hypermobility
https://commons.wikimedia.org/wiki/File:Ehlers-Danlos_skala_Beighton%27a.png
Diagnostic Criteria for hEDS
Standardizing the Skin Exam
Skin Extensibility
Measured on the volar surface of the mid-non-dominant forearm and neck. Positive cut-offs:
Piezogenic Papules
Herniations of subcutaneous fat in the heel visible upon standing.
>1.5 cm for distal forearms/hands.
>3.0 cm for neck, elbows, and knees.
Must be bilateral to count toward criteria.
•
•
https://www.ehlers-danlos.com/skin/
https://share.google/U5aboMzvQbIv0p65n
Diagnostic Criteria for hEDS
��Diagnosing hEDS at the bedside
1
Criterion 1
Generalized joint hypermobility
• ≥6 pre-pubertal children/adolescents
• ≥5 pubertal adults to age 50
• ≥4 adults >50
If one point below cutoff, historical questions can help.
2
Criterion 2
Two or more of A / B / C
• A: ≥5 systemic features
• B: positive first-degree family history
• C: chronic musculoskeletal pain and/or instability
3
Criterion 3
All prerequisites must be met
• No unusual skin fragility
• Exclude other heritable or acquired CTDs
• Exclude alternative diagnoses that also cause hypermobility
3-Generation Pedigree
Differential Diagnosis
Hypermobility is a shared phenotype. Consider overlapping connective tissue disorders if severe cardiovascular or skeletal issues exist:
Red flags for vEDS and dangerous mimics
vEDS: reasons to escalate quickly
Vascular EDS vs. unaffected controls
Murdock D, Suresh A, Calderon Martinez E ...
Early diagnosis of vascular Ehlers-Danlos syndrome through AI-powered facial analysis: Results from the Montalcino Aortic Consortium. Genetics in Medicine Open, 2025; 3
Red flags for vEDS and dangerous mimics
Also escalate if the story suggests a higher-risk aortopathy:
POTS: what to evaluate first
POTS (POstural Tachycardia Syndrome) & dysautonomia
• Start with 10-minute standing test after 5 minutes supine; tilt-table if needed. Increase of heart rate by ≥30 (adults) within 10 minutes of standing without drop in BP confirms diagnosis. Orthostatic vitals used to document concurrent orthostasis.
• Basic evaluation may include ECG, CBC/hematocrit, thyroid testing, and echo when symptoms warrant it.
• First-line treatment: fluids, salt, compression, trigger avoidance, medication review, and graded recumbent exercise.
These associations may drive morbidity even though they are not part of the formal hEDS diagnostic criteria.
MCAS: what to evaluate first
MCAS / hereditary alpha-tryptasemia
• Think about it when recurrent urticaria, flushing, multiple allergies, or anaphylaxis cluster with hypermobility symptoms.
• Serum tryptase can be useful; in the Miami protocol, tryptase >11 ng/mL prompted TPSAB1 copy-number testing for hereditary alpha-tryptasemia.
• Common first-line symptom treatment is stepwise H1 + H2 antihistamines; some patients also use cromolyn, ketotifen, or leukotriene blockers; refer allergy / immunology if severe or unclear.
These associations may drive morbidity even though they are not part of the formal hEDS diagnostic criteria.
Practical management: PT
Physical therapy
• Start early and focus on strength, stabilization, movement control, and joint protection.
• Prefer low-joint-load activity; start low and go slow.
• Avoid aggressive stretching unless there is a specific functional goal.
Practical clinic pearl: “Stabilize first; stretch only with purpose.”
Practical management: bracing
Braces / supports
• Consider arch supports (orthoses), proprioceptive braces (like figure-8 ankle brace), compression garments, or off-the-shelf or custom fitted braces (e.g. knee orthoses).
• Use them to improve body awareness and reduce symptom burden — not instead of strengthening.
• Reassess function and avoid “permanent immobilization by default”.
Practical management: pain
Pain Management Approach
Genetic Testing Pearls
What testing can — and cannot — do
• hEDS has no confirmatory molecular test yet
• All other EDS subtypes rely on molecular confirmation for a final diagnosis
• In practice, testing is mainly used to exclude alternative diagnoses and identify conditions that change surveillance, surgery, pregnancy, and family screening
TNXB / clEDS caveat
• clEDS is associated with TNXB deficiency
• Testing is difficult because TNXB has a highly homologous pseudogene (TNXA)
• The challenging region is the 3′ end of TNXB, especially exons 32–44
• No method specifically detects TNXB CNVs across all homologous exons; make sure the ordered assay includes TNXB well
Who needs testing or referral?
Refer / test when the phenotype is not “clean hEDS”
• Arterial event, aortic disease, spontaneous pneumothorax, bowel rupture, or strong vascular family history
• Marfanoid or syndromic features: bifid uvula / cleft palate, hypertelorism, lens issues, severe scoliosis, clubfoot, brittle bones
• Developmental delay, facial dysmorphism, neuromuscular findings, or progressive unexplained course
• Objective connective-tissue signs but incomplete fit for hEDS — especially if management would change with a molecular diagnosis
Why testing matters
26.4%
of patients who met 2017 hEDS criteria in the Miami registry had an alternative or additional diagnosis.
• Connective tissue / skeletal disorders
• Neuromuscular disorders
• Chromosomal abnormalities / CNVs
• Immune disorders and hereditary alpha-tryptasemia
The primary use of genetic testing in hEDS evaluation is to exclude alternative diagnoses.
EDS Society Algorithm
Emerging Science Informed�Algorithm
Take-home Points
• Meeting the 2017 hEDS criteria does not rule out serious genetic conditions.
• Not meeting the 2017 hEDS criteria does not rule out serious genetic conditions.
• Patients with red flags are going to need referral or genetic testing.
• Don’t wait for genetics referral to manage what helps patients now: PT, pain strategy, orthostatic symptoms, mast-cell symptoms, and other targeted referrals.
• Order testing for the differential you need to exclude — especially when management would change.
Key references
1. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175:8-26.
2. Forghani I, See J, McGonigle WC. Hypermobile Ehlers–Danlos Syndrome: Diagnostic Challenges and the Role of Genetic Testing. Genes. 2025;16(5):530.
3. The Ehlers-Danlos Society: https://www.ehlers-danlos.com/
Detailed citations and image attributions are included in slide notes.
Key Resources
EDS Society — print and use at every encounter. Includes Beighton score guide.
EDS Society Paediatric Working Group — use for patients under 18 or before biological maturity.
Clinical guidance, CME, patient handouts, and specialist referral network.
Marfan screening tools, aortic management guidelines, cardiac referral resources.
Peer-reviewed clinical summaries for all EDS subtypes, Marfan, Loeys-Dietz.
Full open-access article — complete criteria for all 13 EDS subtypes, Beighton tables, skin measurements.