Connective tissue disease
The anchor question: hypermobile EDS or a hypermobility spectrum disorder, or a genetic connective tissue disorder that changes management? The 2017 criteria make hEDS a diagnosis of exclusion,1 and the exclusion matters: in one registry it turned up an alternative or additional diagnosis in 26.4% of those who met criteria.2
Who this cohort covers
Adults with generalized joint hypermobility and systemic features: chronic pain, fatigue, orthostatic intolerance, GI symptoms, easy bruising, skin findings, and a family history that is usually there and rarely documented. Also the differentials to exclude before calling it hEDS: classical and vascular EDS, Marfan syndrome, Loeys-Dietz syndrome and the heritable thoracic aortic diseases.
Why the exclusion matters, in numbers: in one registry of 907 patients referred for hEDS evaluation, 178 met the 2017 criteria, and genetic testing found an alternative or additional diagnosis with distinct management in 47 of them (26.4%).2
Vascular EDS is a different disease. Lumping the Ehlers-Danlos syndromes under one name does clinical harm: the vascular form shares almost nothing with the rest except joint laxity. COL3A1 encodes the collagen of arterial media, bowel and uterus, so its structural failure means spontaneous rupture of those organs. Marfan-style surveillance doesn't transfer: vEDS vessels rupture at normal caliber. Any suspicion of vEDS calls for urgent molecular testing, because management diverges completely. Don't diagnose vEDS on hypermobility alone.
Adapted from the Atlas at allaboutgenetics.com, entry mtx02.
Care map
| Role | Year 1, Establish | Year 2, Treat | Year 3, Sustain |
|---|---|---|---|
| Anchor | Full history with a three-generation pedigree. Beighton score and 2017 hEDS criteria assessment, documented item by item.1 Problem list across systems. | Coordinate specialists; medication review with attention to opioids and NSAIDs; written plan the patient carries. | Annual review. Re-score symptoms, reprioritize, and revisit the diagnosis if the picture has changed. |
| Genetics | Exclude the differentials when features suggest them: vascular, classical and other EDS types, Marfan, Loeys-Dietz, heritable aortic disease. A connective tissue panel or genome sequencing, not single-gene testing.1 2 | Cascade testing for relatives if a pathogenic variant is found. Counsel on what a negative panel means in hEDS, which has no molecular test. | Reanalyze sequencing data at 24 to 36 months. VUS reclassification. |
| Specialists | Cardiology if the echocardiogram is abnormal. Autonomic evaluation for orthostatic symptoms once hydration, salt and exercise have been tried.3 Gastroenterology for motility symptoms or red flags.3 4 | Rheumatology or pain medicine as needed. Urogynecology for pelvic floor dysfunction. Allergy or a mast cell center only when a generalized mast cell disorder is clinically supported.3 | Follow positive findings only. No open-ended referral cycle. |
| Diagnostics | Baseline echocardiogram with aortic root measurement and Z-score. Postural vital signs; tilt table if indicated. Celiac testing early in those with GI symptoms.3 | Targeted imaging for joint or spine problems. Gastric emptying or anorectal testing when symptoms and the AGA criteria call for it.3 | Repeat echo at the interval the baseline findings call for; no routine serial imaging if the root is normal and no syndromic diagnosis was made. |
| Therapies | Physical therapy with a clinician experienced in hypermobility: joint protection and graded strengthening. | Ongoing PT; occupational therapy for hand and daily function; pelvic floor therapy as needed. | Maintenance home program with a periodic check-in. |
| Behavioral health and nutrition | Screen for anxiety, depression and pain burden. Ask about sleep. | Pain psychology. Dietitian for GI symptoms, with care to avoid restrictive eating when elimination diets are tried.3 | As needed. |
| Community | Introduce reputable patient organizations and the emergency card for anyone with a vascular diagnosis. |
Visit one
The map is the evidence. This is the patient in the room: one long visit or two shorter ones. Every line comes from the Year 1 column and carries its citations.
| Ask | Three-generation pedigree: joint problems, aortic disease, sudden death, organ rupture, easy bruising, poor wound healing. Orthostatic symptoms, GI symptoms, sleep, pain burden, prior diagnoses given and by whom. |
| Examine | Beighton score and every item of the 2017 hEDS criteria, documented item by item, including the systemic features and the family history criterion.1 Skin, scars, arm span, palate, chest wall. Postural vital signs. |
| Order | Echocardiogram with aortic root measurement and Z-score (ask the center for the Z-score explicitly). Celiac serology if GI symptoms.3 A connective tissue panel or genome sequencing when any feature suggests a differential: vascular, classical or other EDS types, Marfan, Loeys-Dietz, heritable aortic disease.1 2 Not single-gene testing. |
| Refer | Physical therapy with hypermobility experience now. Cardiology only if the echo is abnormal. Autonomic evaluation only after hydration, salt and exercise have been tried.3 Where: the imaging and specialist rosters, and the therapists roster as it forms. |
| Tell the patient | What hEDS is and isn't; that a negative panel doesn't rule it out, because hEDS has no molecular test; what the echo result will mean. If a vascular diagnosis is possible, the emergency card and urgent molecular testing. |
| Document | The criteria assessment item by item, the pedigree, the Z-score, the plan the patient carries, and the date for the Year 1 review. |
Roster for this cohort
Drawn from the advanced imaging and specialist rosters: echo with aortic root reporting, autonomic testing, GI with a motility interest, cardiology, rheumatology, pain medicine, and physical therapists who treat hypermobility routinely. Forming; members propose and vet entries in the cohort's Slack channel.
Readings
- GeneReviews: Hypermobile Ehlers-Danlos Syndrome, University of Washington, updated 2024.
- The Atlas at allaboutgenetics.com: Ehlers-Danlos syndromes, Marfan syndrome, Loeys-Dietz syndrome, heritable thoracic aortic disease.
- The references below. Start with the 2025 AGA clinical practice update: the most useful single document on GI, POTS and mast cell questions in this population.
References
- 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(1):8-26. doi:10.1002/ajmg.c.31552
- Forghani I, See J, McGonigle WC. Hypermobile Ehlers-Danlos syndrome: diagnostic challenges and the role of genetic testing. Genes (Basel). 2025;16(5). doi:10.3390/genes16050530
- Aziz Q, Harris LA, Goodman BP, Simrén M, Shin A. AGA clinical practice update on GI manifestations and autonomic or immune dysfunction in hypermobile Ehlers-Danlos syndrome: expert review. Clin Gastroenterol Hepatol. 2025;23(8):1291-1302. doi:10.1016/j.cgh.2025.02.015
- Thwaites PA, Gibson PR, Burgell RE. Hypermobile Ehlers-Danlos syndrome and disorders of the gastrointestinal tract: what the gastroenterologist needs to know. J Gastroenterol Hepatol. 2022;37(9):1693-1709. doi:10.1111/jgh.15927
References retrieved from PubMed on 2026-10-30. Care maps are peer-authored clinical frameworks for network members, not individualized medical advice, and are reviewed at each yearly cycle.