Defining the Chronic Complexities of hEDS and HSD: A Global Survey of Diagnostic Challenges, Life-Long Comorbidities, and Unmet Needs
Abstract
1. Introduction
2. Materials and Methods
2.1. Ethics Approval
2.2. Survey Design
2.3. Statistical Analyses
3. Results
3.1. Study Cohort
3.1.1. Eligibility Criteria
3.1.2. Demographics
3.2. Diagnostic Journey
3.3. Multisystemic Clinical Presentation
3.3.1. Pain
3.3.2. Orthopedic
3.3.3. Neurological
3.3.4. Autonomic
3.3.5. Gastrointestinal
3.3.6. Cardiopulmonary
3.3.7. Endocrine
3.3.8. Hematologic
3.3.9. Reproductive
3.3.10. Urological
3.3.11. Dermatological
3.3.12. Allergic and Immunologic
3.3.13. Ocular
3.3.14. Dental
3.3.15. Mental Health and Sleep
3.3.16. Neurodivergence
3.3.17. Multimorbidity in hEDS
4. Discussion
4.1. Multisystemic Manifestations
4.2. hEDS, HSD, and Rare Diseases
4.3. Challenges of the Current Diagnostic Criteria
4.4. Triggering Events
4.5. Limitations and Future Directions
4.6. Reconsidering Etiology
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | |
---|---|---|---|
Yes, event preceded symptoms of hEDS/HSD | 2355 (70.1) | 355 (65) | 1.08 (1.01–1.15), ns |
No | 1005 (29.9) | 191 (35) | 0.86 (0.75–0.97), ns |
Puberty | 1009 (30) | 118 (21.6) | 1.39 (1.17–1.64), 0.0293 |
Viral or bacterial infection | 860 (25.6) | 126 (23.1) | 1.11 (0.94–1.31), ns |
Physical accident | 551 (16.4) | 75 (13.7) | 1.19 (0.95–1.49), ns |
Psychological or emotional event | 481 (14.3) | 86 (15.8) | 0.91 (0.74–1.12), ns |
Pregnancy | 477 (14.2) | 50 (9.2) | 1.55 (1.18–2.04), ns |
Other | 470 (14) | 68 (12.5) | 1.12 (0.89–1.42), ns |
Diagnosed with Long COVID | 221 (6.6) | 34 (6.2) | 1.06 (0.74–1.50), ns |
Diagnosed with Long COVID after hEDS/HSD | 142 (4.2) | 17 (3.1) | 1.36 (0.83–2.23), ns |
Diagnosed with Long COVID prior to hEDS/HSD | 79 (2.4) | 17 (3.1) | 0.76 (0.45–1.27), ns |
hEDS Most Severe Symptoms | hEDS | HSD Most Severe Symptoms | HSD |
---|---|---|---|
Chronic pain | 32.6% | Chronic pain | 34.2% |
Gastrointestinal Symptoms | 13.5% | Joint Manifestations | 14.1% |
Autonomic dysfunction | 12.8% | Autonomic dysfunction | 10.0% |
Joint Manifestations | 12.2% | Gastrointestinal Symptoms | 9.6% |
Neurological Symptoms | 7.2% | Neurological Symptoms | 7.1% |
Mental health | 4.1% | Mental health | 5.0% |
Allergic Symptoms | 3.5% | Sleep Issues | 4.0% |
Sleep Issues | 3.3% | Allergic Symptoms | 3.1% |
Other | 2.8% | Other | 2.8% |
Gynecological Symptoms | 1.7% | Gynecological Symptoms | 2.2% |
Neurodiversity | 0.9% | Neurodiversity | 1.3% |
Urinary Symptoms | 0.9% | Urinary Symptoms | 1.1% |
Dental Manifestations | 0.6% | Dental Manifestations | 0.9% |
Vision Dysfunction | 0.5% | Vision Dysfunction | 0.7% |
Dermatological Symptoms | 0.4% | Endocrine Dysfunction | 0.7% |
Endocrine Dysfunction | 0.4% | Dermatological Symptoms | 0.5% |
Medical Care | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † |
---|---|---|---|
Average hours per week coordinating care | |||
Less than 5 h | 1741 (51.8) | 365 (66.8) | 0.78 (0.72–0.83), <0.0001 |
5 to 10 h | 1068 (31.8) | 136 (24.9) | 1.28 (1.09–1.49), ns |
11 to 15 h | 305 (9.1) | 32 (5.9) | 1.55 (1.09–2.20), ns |
16 to 20 h | 121 (3.6) | 8 (1.5) | 2.46 (1.21–5.00), ns |
More than 20 h | 125 (3.7) | 5 (0.9) | 4.06 (1.67–9.89), ns |
Care Coordination | |||
Self | 3092 (92) | 494 (90.5) | 1.02 (0.99–1.05), ns |
Medical provider | 553 (16.5) | 83 (15.2) | 1.08 (0.88–1.34), ns |
Family member | 417 (12.4) | 63 (11.5) | 1.08 (0.84–1.38), ns |
Other | 19 (0.6) | 1 (0.2) | - |
Medical specialists seen in last year ‡ | 6.5 (±3.7) | 5.2 (±3.2) | (−1.64 to −1.04), <0.0001 |
Medical specialists seen in the past year | |||
Family medicine | 2150 (64) | 287 (52.6) | 1.22 (1.12–1.32), 0.0002 |
Cardiology | 1918 (57.1) | 221 (40.5) | 1.41 (1.27–1.57), <0.0001 |
Gastroenterology | 1500 (44.6) | 155 (28.4) | 1.57 (1.37–1.81), <0.0001 |
Neurology | 1418 (42.2) | 172 (31.5) | 1.34 (1.18–1.53), 0.0012 |
Emergency medicine | 1383 (41.2) | 140 (25.6) | 1.61 (1.38–1.86), <0.0001 |
Psychiatry | 1287 (38.3) | 190 (34.8) | 1.10 (0.97–1.24), ns |
Rheumatology | 1284 (38.2) | 205 (37.5) | 1.02 (0.91–1.14), ns |
Dermatology | 1129 (33.6) | 139 (25.5) | 1.32 (1.13–1.54), ns |
Ophthalmology | 1091 (32.5) | 120 (22) | 1.48 (1.25–1.74), 0.0005 |
Radiology | 1089 (32.4) | 110 (20.1) | 1.61 (1.35–1.91), <0.0001 |
Internal medicine | 956 (28.5) | 115 (21.1) | 1.35 (1.14–1.60), ns |
Sports medicine | 870 (25.9) | 140 (25.6) | 1.01 (0.87–1.18), ns |
Immunology | 673 (20) | 78 (14.3) | 1.40 (1.13–1.74), ns |
Endocrinology | 596 (17.7) | 94 (17.2) | 1.03 (0.85–1.26), ns |
Urology | 507 (15.1) | 39 (7.1) | 2.11 (1.54–2.89), 0.0004 |
Otolaryngology | 241 (7.2) | 36 (6.6) | 1.09 (0.78–1.53), ns |
Nephrology | 118 (3.5) | 11 (2) | 1.74 (0.95–3.21), ns |
Hepatology | 81 (2.4) | 5 (0.9) | 2.63 (1.07–6.47), ns |
Geriatric | 26 (0.8) | 1 (0.2) | - |
Other | 1503 (44.7) | 232 (42.5) | 1.05 (0.95–1.17), ns |
None of the above | 71 (2.1) | 19 (3.5) | 0.61 (0.37–1.00), ns |
Admitted inpatient for hEDS/HSD or related condition | 1395 (41.5) | 108 (19.8) | 2.10 (1.76–2.50), <0.0001 |
Admissions in the last year | |||
0 | 581 (17.3) | 47 (8.6) | 2.01 (1.51–2.67), 0.0002 |
1 | 403 (12) | 27 (4.9) | 2.43 (1.66–3.54), 0.0006 |
2 | 185 (5.5) | 21 (3.8) | 1.43 (0.92–2.23), ns |
3+ | 226 (6.7) | 13 (2.4) | 2.83 (1.63–4.90), ns |
N/A | 1965 (58.5) | 438 (80.2) | - |
Farthest distance traveled for treatment | |||
Less than 300 miles | 2309 (68.7) | 458 (83.9) | 0.82 (0.78–0.86), <0.0001 |
300 to 599 miles | 503 (15) | 46 (8.4) | 1.78 (1.33–2.37), 0.0249 |
600 to 999 miles | 219 (6.5) | 13 (2.4) | 2.74 (1.58–4.75), ns |
1000 to 2000 miles | 169 (5) | 11 (2) | 2.50 (1.37–4.56), ns |
More than 2000 miles | 160 (4.8) | 18 (3.3) | 1.44 (0.89–2.33), ns |
Paid out-of-pocket for medical expenses | 2041 (60.7) | 245 (44.9) | 1.35 (1.23–1.49), 0.0103 |
Chronic Pain | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † |
---|---|---|---|
Experience chronic pain | 3318 (98.8) | 506 (92.7) | 1.07 (1.04–1.09), <0.0001 |
Chronic Pain Sites | |||
Neck | 2684 (79.9) | 367 (67.2) | 1.19 (1.12–1.26), <0.0001 |
Lower back | 2616 (77.9) | 359 (65.8) | 1.18 (1.11–1.26), <0.0001 |
Shoulder | 2578 (76.7) | 360 (65.9) | 1.16 (1.09–1.24), <0.0001 |
Hip | 2523 (75.1) | 342 (62.6) | 1.20 (1.12–1.28), <0.0001 |
Knee | 2397 (71.3) | 324 (59.3) | 1.20 (1.12–1.29), <0.0001 |
Fingers | 2162 (64.3) | 276 (50.5) | 1.27 (1.17–1.39), <0.0001 |
Upper back | 2132 (63.5) | 291 (53.3) | 1.19 (1.10–1.29), 0.0030 |
Wrist | 1959 (58.3) | 269 (49.3) | 1.18 (1.08–1.29), 0.0387 |
Head | 1894 (56.4) | 219 (40.1) | 1.41 (1.26–1.56), <0.0001 |
Jaw | 1880 (56) | 233 (42.7) | 1.31 (1.18–1.45), <0.0001 |
Ankle | 1861 (55.4) | 245 (44.9) | 1.23 (1.12–1.36), 0.0025 |
Widespread | 1842 (54.8) | 232 (42.5) | 1.29 (1.16–1.43), <0.0001 |
Abdominal | 1774 (52.8) | 188 (34.4) | 1.53 (1.36–1.73), <0.0001 |
Ribs | 1479 (44) | 153 (28) | 1.57 (1.37–1.81), <0.0001 |
Elbow | 1149 (34.2) | 145 (26.6) | 1.29 (1.11–1.49), ns |
Toes | 1079 (32.1) | 136 (24.9) | 1.29 (1.11–1.50), ns |
Other | 283 (8.4) | 47 (8.6) | 0.98 (0.73–1.31), ns |
Alternative Medicine | hEDS n (%) | HSD n (%) |
---|---|---|
Tried alternative medicine | 2858 (85.1) | 445 (81.5) |
Alternative medicine type | ||
Massage | 2366 (70.4) | 369 (67.6) |
Chiropractic | 1846 (54.9) | 250 (45.8) |
Meditation | 1553 (46.2) | 218 (39.9) |
Acupuncture | 1491 (44.4) | 232 (42.5) |
Functional medicine | 745 (22.2) | 99 (18.1) |
Naturopathy | 632 (18.8) | 77 (14.1) |
Homeopathy | 596 (17.7) | 76 (13.9) |
Chinese medicine | 423 (12.6) | 69 (12.6) |
Hypnosis | 220 (6.5) | 35 (6.4) |
Ayurveda | 167 (5) | 19 (3.5) |
Other | 239 (7.1) | 44 (8.1) |
Anesthesia Complications | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † |
---|---|---|---|
Anesthesia Complications | 1660 (49.4) | 155 (28.4) | 1.74 (1.52–2.00), <0.0001 |
Anesthesia type | |||
Local anesthesia only | 1287 (38.3) | 105 (19.2) | 1.99 (1.67–2.38), ns |
General anesthesia only | 1191 (35.4) | 95 (17.4) | 2.04 (1.69–2.46), ns |
Both general and local anesthesia | 844 (25.1) | 47 (8.6) | 2.92 (2.21–3.86), 0.0007 |
Complication Type | |||
Shortened effect | 1270 (37.8) | 103 (18.9) | 2.00 (1.67–2.40), ns |
Insufficient pain control | 1017 (30.3) | 62 (11.4) | 2.67 (2.10–3.39), 0.0002 |
Intubation complication | 193 (5.7) | 15 (2.7) | 2.09 (1.25–3.51), ns |
Anaphylaxis or allergic reaction | 137 (4.1) | 8 (1.5) | 2.78 (1.37–5.64), ns |
Other | 400 (11.9) | 46 (8.4) | 1.41 (1.06–1.89), ns |
Orthopedic Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Tendonitis | 1631 (48.5) | 215 (39.4) | 1.23 (1.10–1.38), 0.0352 | 23,000 (6.5) | 7.48 (7.21–7.76), <0.0001 |
Bursitis | 1199 (35.7) | 157 (28.8) | 1.24 (1.08–1.43), ns | 29,060 (8.2) | 4.35 (4.15–4.56), <0.0001 |
Ligament tear | 1090 (32.4) | 127 (23.3) | 1.39 (1.19–1.64), 0.0091 | 61,560 (17.4) | 1.87 (1.78–1.96), <0.0001 |
Tendon rupture | 543 (16.2) | 63 (11.5) | 1.40 (1.10–1.79), ns | 1320 (0.4) | 43.39 (39.50–47.66), <0.0001 |
Slipping rib syndrome | 383 (11.4) | 22 (4) | 2.83 (1.86–4.31), 0.0001 | 7040 (2) | 5.74 (5.21–6.32), <0.0001 |
Congenital hip dislocation | 161 (4.8) | 12 (2.2) | 2.18 (1.22–3.89), ns | 100 (0) | 169.82 (132.62–217.45), <0.0001 |
Bowing of legs | 159 (4.7) | 17 (3.1) | 1.52 (0.93–2.49), ns | 940 (0.3) | 17.84 (15.13–21.03), <0.0001 |
Osgood-Schlatter disease | 155 (4.6) | 19 (3.5) | 1.33 (0.83–2.12), ns | - | - |
Pectus excavatum | 125 (3.7) | 10 (1.8) | 2.03 (1.07–3.84), ns | 340 (0.1) | 38.78 (31.68–47.47), <0.0001 |
Joint contracture | 70 (2.1) | 7 (1.3) | 1.63 (0.75–3.52), ns | 180 (0.1) | 41.02 (31.19–53.95), <0.0001 |
Club foot | 70 (2.1) | 5 (0.9) | 2.28 (0.92–5.61), ns | 40 (0) | 184.58 (125.35–271.81), <0.0001 |
Congenital muscle hypotonia | 42 (1.3) | 3 (0.5) | - | - | - |
None of the above | 885 (26.3) | 205 (37.5) | 0.70 (0.62–0.79), <0.0001 | - | - |
Orthopedic Symptoms | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † |
---|---|---|---|
Joint subluxations | 3254 (96.8) | 467 (85.5) | 1.13 (1.09–1.17), <0.0001 |
Joint dislocations | 2159 (64.3) | 196 (35.9) | 1.79 (1.60–2.01), <0.0001 |
Unexplained fractures | 666 (19.8) | 52 (9.5) | 2.08 (1.59–2.72), <0.0001 |
None of the above | 75 (2.2) | 64 (11.7) | 0.19 (0.14–0.26), <0.0001 |
Joints Affected | |||
Shoulder | 2704 (80.5) | 328 (60.1) | 1.34 (1.25–1.44), <0.0001 |
Hip | 2428 (72.3) | 256 (46.9) | 1.54 (1.41–1.69), <0.0001 |
Knee | 2345 (69.8) | 275 (50.4) | 1.39 (1.27–1.51), <0.0001 |
Fingers | 2313 (68.8) | 258 (47.3) | 1.46 (1.33–1.60), <0.0001 |
Ribs | 2022 (60.2) | 198 (36.3) | 1.66 (1.48–1.86), <0.0001 |
Ankle | 2003 (59.6) | 221 (40.5) | 1.47 (1.33–1.64), <0.0001 |
Wrist | 1872 (55.7) | 180 (33) | 1.69 (1.49–1.91), <0.0001 |
Toes | 1387 (41.3) | 124 (22.7) | 1.82 (1.55–2.13), <0.0001 |
Elbow | 1315 (39.1) | 139 (25.5) | 1.54 (1.32–1.79), <0.0001 |
Spine | 1288 (38.3) | 129 (23.6) | 1.62 (1.39–1.90), <0.0001 |
Other | 454 (13.5) | 47 (8.6) | 1.57 (1.18–2.09), ns |
Anatomical Abnormalities | hEDS n = 3360 n (%) |
---|---|
Uterus | 549 (16.3) |
Ribs | 40 (1.2) |
Lumbar/sacral | 38 (1.1) |
Extra or missing vertebrae | 9 (0.3) |
Neurological Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Migraine | 2162 (64.3) | 255 (46.7) | 1.38 (1.26–1.51), <0.0001 | 49,740 (14) | 4.58 (4.46–4.71), <0.0001 |
Scoliosis | 1145 (34.1) | 114 (20.9) | 1.63 (1.38–1.93), <0.0001 | 11,680 (3.3) | 10.34 (9.83–10.87), <0.0001 |
Raynaud’s phenomenon | 1130 (33.6) | 104 (19) | 1.77 (1.48–2.11), <0.0001 | 3060 (0.9) | 38.95 (36.71–41.32), <0.0001 |
Tinnitus | 1046 (31.1) | 121 (22.2) | 1.40 (1.19–1.66), 0.0113 | 26,620 (7.5) | 4.14 (3.94–4.36), <0.0001 |
Other nerve entrapments | 910 (27.1) | 100 (18.3) | 1.48 (1.23–1.78), 0.0076 | - | - |
Herniated disk(s) | 882 (26.3) | 97 (17.8) | 1.48 (1.22–1.79), 0.0117 | 37,360 (10.5) | 2.49 (2.35–2.64), <0.0001 |
CCI/AAI | 742 (22.1) | 41 (7.5) | 2.94 (2.18–3.97), <0.0001 | 180 (0.1) | 434.80 (370.78–509.86), <0.0001 |
ME/CFS | 568 (16.9) | 78 (14.3) | 1.18 (0.95–1.47), ns | 12,920 (3.6) | 4.64 (4.29–5.01), <0.0001 |
Spinal stenosis | 443 (13.2) | 36 (6.6) | 2.00 (1.44–2.77), 0.0077 | 37,140 (10.5) | 1.26 (1.15–1.37), <0.0001 |
Other spinal instability | 396 (11.8) | 42 (7.7) | 1.53 (1.13–2.08), ns | 15,640 (4.4) | 2.67 (2.43–2.93), <0.0001 |
Occipital neuralgia | 394 (11.7) | 23 (4.2) | 2.78 (1.85–4.20), <0.0001 | 3160 (0.9) | 13.15 (11.91–14.52), <0.0001 |
SFN | 337 (10) | 24 (4.4) | 2.28 (1.52–3.42), 0.0148 | 80 (0) | 444.32 (349.03–565.62), <0.0001 |
Thoracic outlet syndrome | 292 (8.7) | 30 (5.5) | 1.58 (1.10–2.28), ns | 160 (0) | 192.49 (159.22–232.72), <0.0001 |
Hearing impairment | 291 (8.7) | 33 (6) | 1.43 (1.01–2.03), ns | 52,120 (14.7) | 0.59 (0.53–0.66), <0.0001 |
CRPS | 236 (7) | 17 (3.1) | 2.26 (1.39–3.66), ns | 1660 (0.5) | 15.00 (13.14–17.11), <0.0001 |
Trigeminal neuralgia | 228 (6.8) | 18 (3.3) | 2.06 (1.28–3.30), ns | 2360 (0.7) | 10.19 (8.93–11.62), <0.0001 |
Chiari malformation | 211 (6.3) | 5 (0.9) | 6.86 (2.84–16.57), 0.0003 | 360 (0.1) | 61.82 (52.34–73.02), <0.0001 |
Dystonia | 208 (6.2) | 16 (2.9) | 2.11 (1.28–3.48), ns | 3080 (0.9) | 7.12 (6.22–8.16), <0.0001 |
Kyphoscoliosis | 199 (5.9) | 9 (1.6) | 3.59 (1.85–6.96), 0.0240 | 240 (0.1) | 87.46 (72.70–105.21), <0.0001 |
CSF leak | 177 (5.3) | 13 (2.4) | 2.21 (1.27–3.86), ns | 60 (0) | 311.15 (232.63–416.18), <0.0001 |
TCS | 154 (4.6) | 5 (0.9) | 5.01 (2.06–12.14), 0.0393 | 40 (0) | 406.08 (287.26–574.05), <0.0001 |
Voice disorder | 134 (4) | 6 (1.1) | 3.63 (1.61–8.18), ns | 11,320 (3.2) | 1.25 (1.06–1.48), ns |
Intracranial hypotension | 126 (3.8) | 9 (1.6) | 2.28 (1.16–4.45), ns | - | - |
Syringomyelia | 53 (1.6) | 3 (0.5) | - | - | - |
Transverse sinus stenosis | 24 (0.7) | 5 (0.9) | 0.78 (0.30–2.04), ns | - | - |
Multiple sclerosis | 23 (0.7) | 0 (0) | - | - | - |
Myasthenia gravis | 14 (0.4) | 0 (0) | - | - | - |
None of the above | 341 (10.1) | 131 (24) | 0.42 (0.35–0.51), <0.0001 | - | - |
Neurological Symptoms | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † |
---|---|---|---|
Weakness | 2676 (79.6) | 391 (71.6) | 1.11 (1.05–1.18), 0.0121 |
Muscle spasm | 2632 (78.3) | 367 (67.2) | 1.17 (1.10–1.24), <0.0001 |
Tingling | 2555 (76) | 366 (67) | 1.13 (1.07–1.21), 0.0037 |
Numbness | 2365 (70.4) | 288 (52.7) | 1.33 (1.23–1.45), <0.0001 |
None of the above | 122 (3.6) | 37 (6.8) | 0.54 (0.38–0.77), ns |
Autonomic Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
POTS | 1772 (52.7) | 142 (26) | 2.03 (1.75–2.34), <0.0001 | 660 (0.2) | 283.19 (260.72–307.59), <0.0001 |
General dysautonomia | 906 (27) | 80 (14.7) | 1.84 (1.49–2.27), <0.0001 | 5080 (1.4) | 18.81 (17.68–20.01), <0.0001 |
Orthostatic hypotension | 545 (16.2) | 44 (8.1) | 2.01 (1.50–2.70), 0.0004 | 10,840 (3.1) | 5.30 (4.90–5.74), <0.0001 |
Orthostatic intolerance | 512 (15.2) | 43 (7.9) | 1.93 (1.44–2.61), 0.0028 | - | - |
Autonomic neuropathy | 247 (7.4) | 13 (2.4) | 3.09 (1.78–5.35), 0.0098 | 2520 (0.7) | 10.34 (9.11–11.73), <0.0001 |
Hyperadrenergic POTS | 178 (5.3) | 14 (2.6) | 2.07 (1.21–3.53), ns | - | - |
Hypovolemic POTS | 82 (2.4) | 7 (1.3) | 1.90 (0.88–4.10), ns | 6500 (1.8) | 1.33 (1.07–1.65), <0.0001 |
Pure autonomic failure | 14 (0.4) | 0 (0) | - | - | - |
None of the above | 962 (28.6) | 326 (59.7) | 0.48 (0.44–0.52), <0.0001 | - | - |
Autonomic Symptoms | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † |
---|---|---|---|
Fatigue | 3312 (98.6) | 516 (94.5) | 1.04 (1.02–1.06), <0.0001 |
Dizziness | 3216 (95.7) | 482 (88.3) | 1.08 (1.05–1.12), <0.0001 |
Brain fog | 3211 (95.6) | 491 (89.9) | 1.06 (1.03–1.09), <0.0001 |
Heart palpitations | 3177 (94.6) | 468 (85.7) | 1.10 (1.06–1.14), <0.0001 |
Thermoregulatory dysfunction | 3090 (92) | 440 (80.6) | 1.14 (1.09–1.19), <0.0001 |
Vertigo | 2782 (82.8) | 371 (67.9) | 1.22 (1.15–1.29), <0.0001 |
Trouble swallowing | 2171 (64.6) | 251 (46) | 1.41 (1.28–1.54), <0.0001 |
Fainting | 2166 (64.5) | 239 (43.8) | 1.47 (1.33–1.62), <0.0001 |
None of the above | 3 (0.1) | 6 (1.1) | - |
Gastrointestinal Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Irritable bowel syndrome (IBS) | 1627 (48.4) | 201 (36.8) | 1.32 (1.17–1.48), 0.0002 | 21,220 (6) | 8.09 (7.79–8.39), <0.0001 |
Gastroesophageal reflux disease (GERD) | 1601 (47.6) | 168 (30.8) | 1.55 (1.36–1.76), <0.0001 | 110,180 (31.1) | 1.53 (1.48–1.59), <0.0001 |
Constipation | 1467 (43.7) | 153 (28) | 1.56 (1.35–1.79), <0.0001 | 63,800 (18) | 2.43 (2.33–2.52), <0.0001 |
Dysmotility | 880 (26.2) | 57 (10.4) | 2.51 (1.95–3.23), <0.0001 | - | - |
Gastritis | 818 (24.3) | 81 (14.8) | 1.64 (1.33–2.02), 0.0005 | 35,320 (10) | 2.44 (2.30–2.59), <0.0001 |
Obesity | 730 (21.7) | 106 (19.4) | 1.12 (0.93–1.34), ns | 111,560 (31.5) | 0.69 (0.65–0.74), <0.0001 |
Non-celiac gluten sensitivity | 514 (15.3) | 60 (11) | 1.39 (1.08–1.79), ns | - | - |
Hiatal hernia | 501 (14.9) | 43 (7.9) | 1.89 (1.41–2.55), 0.0060 | 700 (0.2) | 75.49 (67.66–84.23), <0.0001 |
Abdominal hernia | 341 (10.1) | 18 (3.3) | 3.08 (1.93–4.90), 0.0002 | 48,640 (13.7) | 0.74 (0.67–0.82), <0.0001 |
Gastric ulcer | 330 (9.8) | 18 (3.3) | 2.98 (1.87–4.75), 0.0004 | 7420 (2.1) | 4.69 (4.22–5.21), <0.0001 |
Appendicitis | 322 (9.6) | 45 (8.2) | 1.16 (0.86–1.57), ns | 4200 (1.2) | 8.09 (7.26–9.01), <0.0001 |
Small intestine bacterial overgrowth (SIBO) | 312 (9.3) | 31 (5.7) | 1.64 (1.14–2.34), ns | - | - |
Colorectal polyp(s) | 283 (8.4) | 30 (5.5) | 1.53 (1.06–2.21), ns | 26,580 (7.5) | 1.12 (1.00–1.26), ns |
Diverticulosis/diverticulitis | 262 (7.8) | 18 (3.3) | 2.37 (1.48–3.78), ns | 9320 (2.6) | 2.97 (2.64–3.34), <0.0001 |
Functional dyspepsia | 190 (5.7) | 17 (3.1) | 1.82 (1.12–2.96), ns | 4860 (1.4) | 4.12 (3.58–4.75), <0.0001 |
Celiac disease | 150 (4.5) | 14 (2.6) | 1.74 (1.01–2.99), ns | 2760 (0.8) | 5.73 (4.88–6.73), <0.0001 |
Feeding intolerance | 125 (3.7) | 8 (1.5) | 2.54 (1.25–5.16), ns | 1360 (0.4) | 9.69 (8.10–11.61), <0.0001 |
Cholelithiasis | 118 (3.5) | 9 (1.6) | 2.13 (1.09–4.17), ns | 22,980 (6.5) | 0.54 (0.45–0.65), <0.0001 |
Liver disease | 105 (3.1) | 10 (1.8) | 1.71 (0.90–3.24), ns | 60,580 (17.1) | 0.18 (0.15–0.22), <0.0001 |
Eosinophilic esophagitis (EoE) | 102 (3) | 10 (1.8) | 1.66 (0.87–3.15), ns | 1300 (0.4) | 8.28 (6.78–10.09), <0.0001 |
Median arcuate ligament syndrome (MALS) | 96 (2.9) | 4 (0.7) | - | - | - |
Duodenal ulcer | 78 (2.3) | 3 (0.5) | - | - | - |
Superior mesenteric artery syndrome (SMAS) | 62 (1.8) | 2 (0.4) | - | - | - |
Ulcerative colitis | 59 (1.8) | 6 (1.1) | 1.60 (0.69–3.68), ns | 4060 (1.1) | 1.53 (1.19–1.98), ns |
Crohn’s disease | 43 (1.3) | 5 (0.9) | 1.40 (0.56–3.51), ns | 4040 (1.1) | 1.12 (0.83–1.51), <0.0001 |
Visceroptosis | 26 (0.8) | 1 (0.2) | - | - | - |
Intestinal malrotation | 22 (0.7) | 1 (0.2) | - | - | - |
Gastrointestinal organ rupture | 17 (0.5) | 1 (0.2) | - | - | - |
None of the above | 529 (15.7) | 169 (31) | 0.51 (0.44–0.59), ns | - | - |
Types of dysmotility | |||||
Gastric | 711 (21.2) | 43 (7.9) | 2.69 (2.00–3.61), <0.0001 | 5260 (1.5) | 14.26 (13.29–15.30), <0.0001 |
Esophageal | 232 (6.9) | 13 (2.4) | 2.90 (1.67–5.03), 0.0329 | - | - |
Colon | 230 (6.8) | 17 (3.1) | 2.20 (1.35–3.57), ns | 4000 (1.1) | 6.06 (5.33–6.90), <0.0001 |
Small bowel | 202 (6) | 8 (1.5) | 4.10 (2.04–8.27), 0.0083 | - | - |
Types of IBS | |||||
Mixed | 911 (27.1) | 89 (16.3) | 1.66 (1.36–2.03), <0.0001 | - | - |
Constipation | 435 (12.9) | 46 (8.4) | 1.54 (1.15–2.05), ns | - | - |
Diarrhea | 357 (10.6) | 48 (8.8) | 1.21 (0.91–1.61), ns | - | - |
Undifferentiated | 233 (6.9) | 42 (7.7) | 0.90 (0.66–1.24), ns | - | - |
Gastrointestinal Symptoms | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † |
---|---|---|---|
Abdominal pain | 3120 (92.9) | 439 (80.4) | 1.15 (1.11–1.20), <0.0001 |
Nausea | 3044 (90.6) | 425 (77.8) | 1.16 (1.11–1.22), <0.0001 |
Bloating | 3012 (89.6) | 439 (80.4) | 1.11 (1.07–1.16), <0.0001 |
Constipation | 2925 (87.1) | 412 (75.5) | 1.15 (1.10–1.21), <0.0001 |
Diarrhea | 2778 (82.7) | 391 (71.6) | 1.15 (1.09–1.22), <0.0001 |
Reflux | 2640 (78.6) | 350 (64.1) | 1.23 (1.15–1.31), <0.0001 |
Heartburn | 2488 (74) | 337 (61.7) | 1.20 (1.12–1.29), <0.0001 |
Vomiting | 1968 (58.6) | 211 (38.6) | 1.52 (1.36–1.69), <0.0001 |
Rectal bleeding | 1523 (45.3) | 166 (30.4) | 1.49 (1.31–1.70), <0.0001 |
None of the above | 20 (0.6) | 8 (1.5) | 0.41 (0.18–0.92), ns |
Feeding Devices and Ostomies | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † |
---|---|---|---|
Have used a feeding device | 240 (7.1) | 11 (2) | 3.55 (1.95–6.44), 0.0038 |
Type of Feeding Device | |||
Nasogastric (NG) tube | 130 (3.9) | 4 (0.7) | - |
Nasojejunal (NJ) tube | 110 (3.3) | 4 (0.7) | - |
Gastrojejunostomy (GJ) tube | 74 (2.2) | 3 (0.5) | - |
Total parenteral nutrition (TPN) | 74 (2.2) | 2 (0.4) | - |
Jejunostomy (JEJ, PEJ, or RIJ) tube | 55 (1.6) | 0 (0) | - |
Gastric (G) tube | 48 (1.4) | 3 (0.5) | - |
Peripheral parenteral nutrition (PPN) | 28 (0.8) | 0 (0) | - |
Nasoduodenal (ND) tube | 26 (0.8) | 1 (0.2) | - |
Orogastric (OG) tube | 3 (0.1) | 0 (0) | - |
Oroenteric tube | 0 (0) | 0 (0) | - |
Ostomies | |||
Colostomy | 51 (1.5) | 10 (1.8) | - |
Ileostomy | 38 (1.1) | 2 (0.4) | - |
None of the above | 3287 (97.8) | 535 (98) | - |
Cardiopulmonary Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Mitral valve defect | 547 (16.3) | 30 (5.5) | 2.96 (2.07–4.23), <0.0001 | 2880 (0.8) | 20.03 (18.40–21.81), <0.0001 |
Other arrhythmia | 485 (14.4) | 53 (9.7) | 1.49 (1.14–1.95), ns | - | - |
Supraventricular tachycardia (SVT) | 263 (7.8) | 20 (3.7) | 2.14 (1.37–3.34), ns | 32,080 (9.1) | 0.86 (0.77–0.97), ns |
Tricuspid valve defect | 201 (6) | 13 (2.4) | 2.51 (1.44–4.37), ns | 15,340 (4.3) | 1.38 (1.21–1.58), 0.0005 |
Aortic valve defect | 111 (3.3) | 3 (0.5) | - | - | - |
Lung disease | 99 (2.9) | 11 (2) | 1.46 (0.79–2.71), ns | 83,600 (23.6) | 0.12 (0.10–0.15), <0.0001 |
Atrial fibrillation | 99 (2.9) | 7 (1.3) | 2.30 (1.07–4.92), ns | 26,160 (7.4) | 0.40 (0.33–0.48), <0.0001 |
Stroke | 80 (2.4) | 5 (0.9) | 2.60 (1.06–6.39), ns | 160 (0) | 52.74 (40.41–68.82), <0.0001 |
May-Thurner syndrome | 62 (1.8) | 6 (1.1) | 1.68 (0.73–3.86), ns | - | - |
Nutcracker syndrome | 61 (1.8) | 4 (0.7) | - | - | - |
Pulmonary valve defect | 60 (1.8) | 3 (0.5) | - | - | - |
Patent foramen ovale (PFO) | 51 (1.5) | 4 (0.7) | - | - | - |
Heart failure | 44 (1.3) | 2 (0.4) | - | - | - |
Coronary artery disease | 36 (1.1) | 2 (0.4) | - | - | - |
Aortic aneurysm | 32 (1) | 0 (0) | - | - | - |
Atrial septal defect (ASD) (not PFO) | 24 (0.7) | 1 (0.2) | - | - | - |
Myocardial infarction | 17 (0.5) | 2 (0.4) | - | - | - |
Hypertrophic cardiomyopathy | 15 (0.4) | 2 (0.4) | - | - | - |
Rheumatic heart disease | 5 (0.1) | 0 (0) | - | - | - |
Spontaneous Coronary Artery Dissection (SCAD) | 4 (0.1) | 0 (0) | - | - | - |
Ebstein’s anomaly | 2 (0.1) | 1 (0.2) | - | - | - |
None of the above | 2083 (62) | 431 (78.9) | 0.79 (0.75–0.83), <0.0001 | - | - |
Endocrinological Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Hypothyroidism (non-autoimmune) | 389 (11.6) | 49 (9) | 1.29 (0.97–1.71), ns | 36,920 (10.4) | 1.11 (1.01–1.22), ns |
Osteopenia | 354 (10.5) | 42 (7.7) | 1.37 (1.01–1.86), ns | 3220 (0.9) | 11.60 (10.45–12.87), <0.0001 |
Hashimoto’s disease | 231 (6.9) | 30 (5.5) | 1.25 (0.86–1.81), ns | 2880 (0.8) | 8.46 (7.43–9.63), <0.0001 |
Osteoporosis | 189 (5.6) | 18 (3.3) | 1.71 (1.06–2.74), ns | 32,160 (9.1) | 0.62 (0.54–0.71), <0.0001 |
Adrenal insufficiency (non-autoimmune) | 104 (3.1) | 18 (3.3) | 0.94 (0.57–1.54), ns | 2240 (0.6) | 4.90 (4.03–5.94), <0.0001 |
Hyperthyroidism (non-autoimmune) | 83 (2.5) | 6 (1.1) | 2.25 (0.99–5.12), ns | 740 (0.2) | 11.83 (9.45–14.81), <0.0001 |
Diabetes, type 2 | 82 (2.4) | 14 (2.6) | 0.95 (0.54–1.67), ns | 74,920 (21.1) | 0.12 (0.09–0.14), <0.0001 |
Diabetes, gestational | 77 (2.3) | 7 (1.3) | 1.79 (0.83–3.85), ns | 3180 (0.9) | 2.55 (2.04–3.19), <0.0001 |
Pineal cyst | 62 (1.8) | 5 (0.9) | 2.02 (0.81–4.99), ns | 40 (0) | 163.49 (110.02–242.93), <0.0001 |
Pituitary tumor/adenoma | 56 (1.7) | 6 (1.1) | 1.52 (0.66–3.50), ns | 200 (0.1) | 29.53 (22.00–39.64), <0.0001 |
Grave’s disease | 33 (1) | 6 (1.1) | 0.89 (0.38–2.12), ns | 300 (0.1) | 11.60 (8.11–16.59), <0.0001 |
Hyperparathyroidism | 27 (0.8) | 5 (0.9) | 0.88 (0.34–2.27), ns | 10,560 (3) | 0.27 (0.19–0.39), <0.0001 |
Diabetes, type 1 | 23 (0.7) | 1 (0.2) | - | - | - |
Cushing disease | 22 (0.7) | 1 (0.2) | - | - | - |
Addison’s disease | 12 (0.4) | 1 (0.2) | - | - | - |
Congenital adrenal hyperplasia | 9 (0.3) | 1 (0.2) | - | - | - |
Multiple endocrine neoplasia | 2 (0.1) | 0 (0) | - | - | - |
None of the above | 2485 (74) | 435 (79.7) | - | - | - |
Hematological Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Pernicious anemia | 155 (4.6) | 14 (2.6) | 1.80 (1.05–3.09), ns | 1180 (0.3) | 13.85 (11.76–16.32), <0.0001 |
Deep vein thrombosis (DVT) | 116 (3.5) | 6 (1.1) | 3.14 (1.39–7.10), ns | 11,440 (3.2) | 1.07 (0.89–1.28), ns |
Pulmonary embolism (PE) | 71 (2.1) | 8 (1.5) | 1.44 (0.70–2.98), ns | 9940 (2.8) | 0.75 (0.60–0.95), ns |
Lymphedema | 63 (1.9) | 6 (1.1) | 1.71 (0.74–3.92), ns | 6560 (1.9) | 1.01 (0.79–1.30), ns |
Thrombocytosis | 41 (1.2) | 5 (0.9) | 1.33 (0.53–3.36), ns | 3700 (1) | 1.17 (0.86–1.59), ns |
Antiphospholipid antibody syndrome (APLS) | 37 (1.1) | 1 (0.2) | - | - | - |
Von Willebrand disease | 33 (1) | 4 (0.7) | - | - | - |
Hemophilia | 15 (0.4) | 2 (0.4) | - | - | - |
Arterial thrombosis | 6 (0.2) | 0 (0) | - | - | - |
None of the above | 2971 (88.4) | 510 (93.4) | - | - | - |
Easy or severe bruising | 2696 (80.2) | 337 (61.7) | 1.30 (1.21–1.39), <0.0001 | - | - |
Reproductive Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Endometriosis | 622 (18.5) | 66 (12.1) | 1.53 (1.21–1.94), ns | 7620 (2.2) | 8.61 (7.99–9.27), <0.0001 |
Polycystic ovary syndrome (PCOS) | 571 (17) | 80 (14.7) | 1.16 (0.93–1.44), ns | 5000 (1.4) | 12.05 (11.12–13.04), <0.0001 |
Pelvic organ prolapse | 455 (13.5) | 19 (3.5) | 3.89 (2.48–6.10), <0.0001 | 10,020 (2.8) | 4.79 (4.39–5.23), <0.0001 |
Vaginismus | 246 (7.3) | 28 (5.1) | 1.43 (0.98–2.09), ns | 320 (0.1) | 81.08 (68.91–95.41), <0.0001 |
Vulvodynia | 231 (6.9) | 30 (5.5) | 1.25 (0.86–1.81), ns | 620 (0.2) | 39.30 (33.92–45.53), <0.0001 |
Infertility | 198 (5.9) | 36 (6.6) | 0.89 (0.63–1.26), ns | 7340 (2.1) | 2.85 (2.48–3.26), <0.0001 |
Pelvic congestion syndrome | 101 (3) | 10 (1.8) | 1.64 (0.86–3.12), ns | 260 (0.1) | 40.97 (32.64–51.43), <0.0001 |
Hypogonadism | 11 (0.3) | 3 (0.5) | - | - | - |
Erectile dysfunction | 10 (0.3) | 3 (0.5) | - | - | - |
Enlarged prostate gland | 7 (0.2) | 0 (0) | - | - | - |
Premature ejaculation | 3 (0.1) | 2 (0.4) | - | - | - |
Peyronie’s disease | 1 (0) | 0 (0) | - | - | - |
Testicular torsion | 1 (0) | 0 (0) | - | - | - |
Penile fracture | 1 (0) | 0 (0) | - | - | - |
Cryptorchidism | 0 (0) | 1 (0.2) | - | - | - |
Reproductive Symptoms, Menstruation, and Pregnancy | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † |
---|---|---|---|
Pelvic pain | 2701 (80.4) | 361 (66.1) | 1.22 (1.14–1.29), <0.0001 |
Irregular periods | 2363 (70.3) | 310 (56.8) | 1.24 (1.15–1.34), <0.0001 |
Pain during sex | 2130 (63.4) | 274 (50.2) | 1.26 (1.16–1.38), <0.0001 |
Bleeding during sex | 1285 (38.2) | 139 (25.5) | 1.50 (1.29–1.75), <0.0001 |
Genital overstimulation | 594 (17.7) | 65 (11.9) | 1.49 (1.17–1.89), ns |
Tight foreskin | 17 (0.5) | 4 (0.7) | - |
None of the above | 247 (7.4) | 81 (14.8) | 0.50 (0.39–0.63), <0.0001 |
Age of first menstrual period *‡ | 12.3 (±1.7) | 12.4 (±1.5) | (−0.11–0.18), ns |
Have been pregnant * | 1463 (44.5) | 186 (35.1) | - |
Average number of pregnancies ** | 2.5 (±1.4) | 2.3 (±1.2) | - |
Had pregnancy complications ** | 983 (67.2) | 102 (54.8) | 1.23 (1.07–1.40), <0.0001 |
Pregnancy complication types ** | |||
Preterm labor | 339 (23.2) | 24 (12.9) | 1.80 (1.22–2.64), 0.0111 |
Spontaneous abortion | 583 (39.8) | 57 (30.6) | 1.30 (1.04–1.63), 0.0247 |
Prelabor membrane rupture | 178 (23.2) | 20 (10.8) | 1.13 (0.73–1.75), ns |
Failure to progress in labor | 320 (21.9) | 38 (20.4) | 1.07 (0.79–1.44), <0.0001 |
Stillbirth | 40 (2.7) | 4 (2.2) | - |
None of the above | 480 (32.8) | 84 (45.2) | 0.73 (0.61–0.87), <0.0001 |
Average number of spontaneous abortions *** | 1.5 (±0.7) | 1.4 (±0.7) | (−0.28–0.10), ns |
Urinary Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Recurrent urinary tract infections (UTIs) | 980 (29.2) | 98 (17.9) | 1.63 (1.35–1.96), <0.0001 | 740 (0.2) | 139.68 (127.76–152.72), <0.0001 |
Urinary incontinence | 711 (21.2) | 61 (11.2) | 1.89 (1.48–2.42), <0.0001 | 38,020 (10.7) | 1.97 (1.85–2.11), <0.0001 |
Voiding dysfunction | 500 (14.9) | 43 (7.9) | 1.89 (1.40–2.55), 0.0065 | 60 (0) | 878.97 (673.93–1146.39), <0.0001 |
Kidney stone(s) | 450 (13.4) | 39 (7.1) | 1.88 (1.37–2.57), 0.0240 | 25,060 (7.1) | 1.89 (1.74–2.07), <0.0001 |
Overactive bladder syndrome | 441 (13.1) | 39 (7.1) | 1.84 (1.34–2.52), 0.0439 | 8580 (2.4) | 5.42 (4.96–5.93), <0.0001 |
Bladder pain syndrome | 215 (6.4) | 20 (3.7) | 1.75 (1.11–2.74), ns | 1520 (0.4) | 14.92 (12.99–17.14), <0.0001 |
Urinary hesitancy | 196 (5.8) | 18 (3.3) | 1.77 (1.10–2.84), ns | 3500 (1) | 5.91 (5.14–6.79), <0.0001 |
Kidney disease | 85 (2.5) | 9 (1.6) | 1.53 (0.78–3.03), ns | 87,560 (24.7) | 0.10 (0.08–0.13), <0.0001 |
Vesicoureteral reflux | 27 (0.8) | 1 (0.2) | - | - | - |
None of the above | 1597 (47.5) | 353 (64.7) | 0.74 (0.68–0.79), <0.0001 | - | - |
Dermatological Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Atopic dermatitis (eczema) | 1052 (31.3) | 158 (28.9) | 1.08 (0.94–1.25), ns | 9540 (2.7) | 11.63 (11.02–12.27), <0.0001 |
Hyperhidrosis | 223 (6.6) | 21 (3.8) | 1.73 (1.11–2.67), ns | 12,280 (3.5) | 1.92 (1.69–2.18), <0.0001 |
Hidradenitis suppurativa | 93 (2.8) | 10 (1.8) | 1.51 (0.79–2.88), ns | 2640 (0.7) | 3.72 (3.03–4.56), <0.0001 |
Hypohidrosis | 36 (1.1) | 3 (0.5) | - | - | - |
Acrogeria | 1 (0) | 0 (0) | - | - | - |
None of the above | 1993 (59.3) | 352 (64.5) | 0.92 (0.86–0.99), ns | - | - |
Dermatological Symptoms | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † |
---|---|---|---|
Soft and velvety skin | 3059 (91) | 332 (60.8) | 1.50 (1.40–1.60), <0.0001 |
Abnormally stretchy skin | 2602 (77.4) | 178 (32.6) | 2.38 (2.10–2.68), <0.0001 |
Unexplained stretch marks | 2473 (73.6) | 205 (37.5) | 1.96 (1.76–2.19), <0.0001 |
Poor wound healing | 2445 (72.8) | 266 (48.7) | 1.49 (1.37–1.63), <0.0001 |
Atrophic scarring | 2114 (62.9) | 149 (27.3) | 2.31 (2.01–2.65), <0.0001 |
Keratosis pilaris | 1820 (54.2) | 250 (45.8) | 1.18 (1.07–1.30), ns |
Recurrent Hives (urticaria) | 1636 (48.7) | 182 (33.3) | 1.46 (1.29–1.65), <0.0001 |
Hypertrophic scarring | 1331 (39.6) | 147 (26.9) | 1.47 (1.27–1.70), <0.0001 |
Recurrent folliculitis or abscesses | 1212 (36.1) | 132 (24.2) | 1.49 (1.28–1.74), <0.0001 |
Acne (if 30+ years old) | 979 (29.1) | 133 (24.4) | 1.20 (1.02–1.40), ns |
Keloid scarring | 751 (22.4) | 67 (12.3) | 1.82 (1.44–2.30), <0.0001 |
None of the above | 12 (0.4) | 20 (3.7) | 0.10 (0.05–0.20), <0.0001 |
Allergy and Immune-Related Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Allergies | 2707 (80.6) | 379 (69.4) | 1.16 (1.10–1.23), <0.0001 | 24,160 (6.8) | 11.82 (11.58–12.06), <0.0001 |
Asthma | 1415 (42.1) | 163 (29.9) | 1.41 (1.23–1.61), <0.0001 | 65,180 (18.4) | 2.29 (2.20–2.38), <0.0001 |
Mast cell activation syndrome (MCAS) | 1003 (29.9) | 66 (12.1) | 2.47 (1.96–3.11), <0.0001 | 100 (0) | 1057.93 (863.81–1295.66), <0.0001 |
Chronic sinusitis | 899 (26.8) | 94 (17.2) | 1.55 (1.28–1.88), 0.0011 | 40,320 (11.4) | 2.35 (2.22–2.49), <0.0001 |
Chronic urticaria | 493 (14.7) | 26 (4.8) | 3.08 (2.10–4.52), <0.0001 | 220 (0.1) | 236.36 (202.38–276.06), <0.0001 |
Histamine intolerance | 365 (10.9) | 36 (6.6) | 1.65 (1.18–2.29), ns | - | - |
Immune deficiency | 243 (7.2) | 24 (4.4) | 1.65 (1.09–2.48), ns | - | - |
Nasal polyps | 236 (7) | 20 (3.7) | 1.92 (1.23–3.00), ns | 880 (0.2) | 28.29 (24.60–32.52), <0.0001 |
Cold urticaria | 170 (5.1) | 10 (1.8) | 2.76 (1.47–5.19), ns | 160 (0) | 112.07 (90.55–138.70), <0.0001 |
Systemic mastocytosis | 19 (0.6) | 1 (0.2) | - | - | - |
None of the above | 346 (10.3) | 120 (22) | 0.47 (0.39–0.56), <0.0001 | - | - |
Types of Allergies | - | - | |||
Seasonal | 1938 (57.7) | 248 (45.4) | 1.27 (1.15–1.40), <0.0001 | - | - |
Drug | 1529 (45.5) | 166 (30.4) | 1.50 (1.31–1.71), <0.0001 | - | - |
Environmental | 1435 (42.7) | 174 (31.9) | 1.34 (1.18–1.52), 0.0010 | - | - |
Food | 1169 (34.8) | 142 (26) | 1.34 (1.15–1.55), 0.0285 | - | - |
Metal | 510 (15.2) | 42 (7.7) | 1.97 (1.46–2.67), 0.0018 | - | - |
Latex | 477 (14.2) | 40 (7.3) | 1.94 (1.42–2.64), 0.0064 | - | - |
Anaphylaxis Episodes | 986 (29.3) | 84 (15.4) | 1.91 (1.56–2.34), <0.0001 | - | - |
Psoriasis | 221 (6.6) | 21 (3.8) | 1.71 (1.10–2.65), ns | 10,780 (3) | 2.16 (1.90–2.46), <0.0001 |
Lyme disease | 154 (4.6) | 20 (3.7) | 1.25 (0.79–1.98), ns | 3120 (0.9) | 5.21 (4.44–6.10), <0.0001 |
Cancer | 143 (4.3) | 16 (2.9) | 1.45 (0.87–2.42), ns | 65,980 (18.6) | 0.23 (0.19–0.27), <0.0001 |
Rheumatoid arthritis (RA) | 137 (4.1) | 19 (3.5) | 1.17 (0.73–1.88), ns | 11,380 (3.2) | 1.27 (1.08–1.50), ns |
Sjögren syndrome | 127 (3.8) | 14 (2.6) | 1.47 (0.86–2.54), ns | 5600 (1.6) | 2.39 (2.01–2.84), <0.0001 |
Ankylosing spondylitis | 73 (2.2) | 11 (2) | 1.08 (0.58–2.02), ns | 1360 (0.4) | 5.66 (4.48–7.15), <0.0001 |
Systemic lupus erythematosus (SLE) | 62 (1.8) | 6 (1.1) | 1.68 (0.73–3.86), ns | 5020 (1.4) | 1.30 (1.02–1.67), ns |
Scleroderma | 15 (0.4) | 2 (0.4) | - | - | - |
Other | 168 (5) | 25 (4.6) | 1.09 (0.72–1.65), ns | - | - |
None of the above | 2608 (77.6) | 452 (82.8) | 0.94 (0.90–0.98), ns | - | - |
Ocular Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Astigmatism | 2139 (63.7) | 280 (51.3) | 1.24 (1.14–1.35), <0.0001 | 30,440 (8.6) | 7.41 (7.21–7.62), <0.0001 |
Myopia | 1904 (56.7) | 276 (50.5) | 1.12 (1.03–1.22), ns | 29,380 (8.3) | 6.84 (6.62–7.05), <0.0001 |
Hyperopia | 669 (19.9) | 75 (13.7) | 1.45 (1.16–1.81), ns | 14,840 (4.2) | 4.75 (4.44–5.10), <0.0001 |
Macular degeneration | 69 (2.1) | 6 (1.1) | 1.87 (0.82–4.28), ns | 3160 (0.9) | 2.30 (1.82–2.92), <0.0001 |
Keratoconus | 42 (1.3) | 5 (0.9) | 1.37 (0.54–3.43), ns | 760 (0.2) | 5.83 (4.28–7.94), <0.0001 |
Retinal detachment | 43 (1.3) | 6 (1.1) | 1.16 (0.50–2.72), ns | 4900 (1.4) | 0.93 (0.69–1.25), ns |
Blue sclerae | 554 (16.5) | 19 (3.5) | - | - | - |
Lens subluxation | 21 (0.6) | 1 (0.2) | - | - | - |
Lens dislocation | 5 (0.1) | 0 (0) | - | - | - |
None of the above | 600 (17.9) | 149 (27.3) | - | - | - |
Ocular Symptoms | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † |
---|---|---|---|
Light sensitivity | 2971 (88.4) | 434 (79.5) | 1.11 (1.06–1.16), <0.0001 |
Visual disturbances | 2802 (83.4) | 400 (73.3) | 1.14 (1.08–1.20), <0.0001 |
Dry eyes | 2307 (68.7) | 338 (61.9) | 1.11 (1.03–1.19), ns |
Double vision | 1606 (47.8) | 163 (29.9) | 1.60 (1.40–1.83), <0.0001 |
Loss of peripheral vision | 709 (21.1) | 59 (10.8) | 1.95 (1.52–2.51), <0.0001 |
None of the above | 106 (3.2) | 37 (6.8) | 0.47 (0.32–0.67), 0.0208 |
Dental Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Temporomandibular joint disorder (TMJ disorder) | 1660 (49.4) | 177 (32.4) | 1.52 (1.34–1.73), <0.0001 | 11,120 (3.1) | 15.75 (15.15–16.37), <0.0001 |
Enamel defects | 661 (19.7) | 68 (12.5) | 1.58 (1.25–1.99), 0.0319 | 300 (0.1) | 232.40 (203.63–265.23), <0.0001 |
Early onset periodontitis | 580 (17.3) | 64 (11.7) | 1.47 (1.16–1.88), ns | 340 (0.1) | 179.93 (158.08–204.81), <0.0001 |
None of the above | 1302 (38.8) | 310 (56.8) | 0.68 (0.63–0.74), <0.0001 | - | - |
Dental Symptoms | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † |
---|---|---|---|
Jaw pain | 2753 (81.9) | 375 (68.7) | 1.19 (1.12–1.27), <0.0001 |
Dental crowding | 2358 (70.2) | 232 (42.5) | 1.65 (1.49–1.83), <0.0001 |
Subluxation or dislocation of TMJ | 2321 (69.1) | 261 (47.8) | 1.45 (1.32–1.58), <0.0001 |
Tooth sensitivity without other cause | 2169 (64.6) | 272 (49.8) | 1.30 (1.19–1.41), <0.0001 |
High or narrow palate | 2000 (59.5) | 152 (27.8) | 2.14 (1.86–2.45), <0.0001 |
Frequent cavities | 1547 (46) | 172 (31.5) | 1.46 (1.28–1.66), <0.0001 |
None of the above | 41 (1.2) | 37 (6.8) | 0.18 (0.12–0.28), <0.0001 |
Mental Health and Sleep Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Anxiety | 2512 (74.8) | 395 (72.3) | 1.03 (0.98–1.09), ns | 112,320 (31.7) | 2.36 (2.31–2.41), <0.0001 |
Depression | 2285 (68) | 352 (64.5) | 1.05 (0.99–1.13), ns | 112,440 (31.7) | 2.14 (2.09–2.19), <0.0001 |
Post-traumatic stress disorder (PTSD) | 1388 (41.3) | 150 (27.5) | 1.50 (1.30–1.73), <0.0001 | 21,540 (6.1) | 6.80 (6.51–7.09), <0.0001 |
Insomnia | 1281 (38.1) | 148 (27.1) | 1.41 (1.22–1.62), 0.0004 | 56,320 (15.9) | 2.40 (2.30–2.51), <0.0001 |
Panic disorder | 602 (17.9) | 74 (13.6) | 1.32 (1.06–1.65), ns | 14,260 (4) | 4.45 (4.13–4.80), <0.0001 |
Eating disorder | 592 (17.6) | 77 (14.1) | 1.25 (1.00–1.56), ns | 4820 (1.4) | 12.95 (11.98–14.01), <0.0001 |
Restless leg syndrome | 553 (16.5) | 56 (10.3) | 1.60 (1.24–2.08), ns | 10,860 (3.1) | 5.37 (4.97–5.81), <0.0001 |
Obstructive sleep apnea | 427 (12.7) | 51 (9.3) | 1.36 (1.03–1.79), ns | 60,340 (17) | 0.75 (0.68–0.82), <0.0001 |
Bipolar disorder | 230 (6.8) | 13 (2.4) | 2.88 (1.66–4.99), 0.0386 | 20,540 (5.8) | 1.18 (1.04–1.34), ns |
Substance use disorder | 96 (2.9) | 15 (2.7) | 1.04 (0.61–1.78), ns | 57,920 (16.3) | 0.17 (0.14–0.21), <0.0001 |
None of the above | 409 (12.2) | 95 (17.4) | 0.70 (0.57–0.86), ns | - | - |
Neurodiversity-Related Disorders | hEDS n (%) | HSD n (%) | hEDS vs. HSD RR (95% CI), p-Value † | All of Us n (%) | hEDS vs. All of Us RR (95% CI), p-Value † |
---|---|---|---|---|---|
Attention deficit hyperactivity disorder (ADHD/ADD) | 1172 (34.9) | 156 (28.6) | 1.22 (1.06–1.40), ns | 13,740 (3.9) | 9.00 (8.57–9.45), <0.0001 |
Autism spectrum disorder (ASD) | 466 (13.9) | 58 (10.6) | 1.31 (1.01–1.69), ns | 1060 (0.3) | 46.37 (41.81–51.43), <0.0001 |
Obsessive–compulsive disorder (OCD) | 466 (13.9) | 45 (8.2) | 1.68 (1.26–2.25), ns | 2860 (0.8) | 17.19 (15.68–18.84), <0.0001 |
Sensory processing disorder | 306 (9.1) | 34 (6.2) | - | - | - |
Learning disorder | 299 (8.9) | 37 (6.8) | 1.31 (0.94–1.83), ns | 880 (0.2) | 35.84 (31.57–40.68), <0.0001 |
Tourette’s syndrome | 38 (1.1) | 4 (0.7) | - | - | - |
None of the above | 1710 (50.9) | 329 (60.3) | 0.84 (0.78–0.91), 0.0247 | - | - |
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Daylor, V.; Griggs, M.; Weintraub, A.; Byrd, R.; Petrucci, T.; Huff, M.; Byerly, K.; Fenner, R.; Severance, S.; Griggs, C.; et al. Defining the Chronic Complexities of hEDS and HSD: A Global Survey of Diagnostic Challenges, Life-Long Comorbidities, and Unmet Needs. J. Clin. Med. 2025, 14, 5636. https://doi.org/10.3390/jcm14165636
Daylor V, Griggs M, Weintraub A, Byrd R, Petrucci T, Huff M, Byerly K, Fenner R, Severance S, Griggs C, et al. Defining the Chronic Complexities of hEDS and HSD: A Global Survey of Diagnostic Challenges, Life-Long Comorbidities, and Unmet Needs. Journal of Clinical Medicine. 2025; 14(16):5636. https://doi.org/10.3390/jcm14165636
Chicago/Turabian StyleDaylor, Victoria, Molly Griggs, Amy Weintraub, Rebecca Byrd, Taylor Petrucci, Matthew Huff, Kathryn Byerly, Roman Fenner, Sydney Severance, Charlotte Griggs, and et al. 2025. "Defining the Chronic Complexities of hEDS and HSD: A Global Survey of Diagnostic Challenges, Life-Long Comorbidities, and Unmet Needs" Journal of Clinical Medicine 14, no. 16: 5636. https://doi.org/10.3390/jcm14165636
APA StyleDaylor, V., Griggs, M., Weintraub, A., Byrd, R., Petrucci, T., Huff, M., Byerly, K., Fenner, R., Severance, S., Griggs, C., Sharma, A., Atwal, P., Kautz, S. A., Shapiro, S., Youkhana, K., Lavallee, M., Wilkerson, A., Nichols, M., Snyder, A., ... Norris, R. A. (2025). Defining the Chronic Complexities of hEDS and HSD: A Global Survey of Diagnostic Challenges, Life-Long Comorbidities, and Unmet Needs. Journal of Clinical Medicine, 14(16), 5636. https://doi.org/10.3390/jcm14165636