| Domain | Phenotype / comorbidity | Current understanding for hEDS/HSD disease entry | Quantitative statistic(s) | Evidence type | Supporting citations |
|---|---|---|---|---|---|
| Musculoskeletal | Generalized joint hypermobility (GJH) | Core defining feature of hEDS; also common in HSD and therefore not disease-specific by itself. Often accompanied by impaired proprioception/motion coordination and recurrent injury. | In a systematic review of EDS extracutaneous features, joint hypermobility was reported in 153/160 hypermobile EDS cases (95.6%). | Systematic review; diagnostic review | (pqac-00000001, pqac-00000004) |
| Musculoskeletal | Joint instability, subluxations, dislocations | Common and clinically central in both hEDS and HSD; recurrent atraumatic dislocations/instability are part of musculoskeletal diagnostic features. | Mayo clinic cohort: subluxations self-reported in 71.2% of hEDS and 72.6% of HSD patients. | Large cohort; diagnostic review | (pqac-00000001, pqac-00000004) |
| Musculoskeletal / pain | Chronic pain | Very common, often chronic and disabling; pain should be considered a major clinical burden rather than a specific diagnostic biomarker. | Systematic review of EDS complications: chronic pain in hypermobile EDS 139/157 (88.5%); joint pain across EDS cases 217/270 (80.4%). Mayo cohort: joint pain 82.0% in hEDS and 88.9% in HSD. | Systematic review; cohort; pain review | (pqac-00000004, pqac-00000010) |
| Skin / connective tissue | Soft/velvety skin, mild hyperextensibility | Typical but usually milder than in classical EDS; included among systemic connective-tissue features in adult criteria summaries. | No robust pooled prevalence identified in retrieved recent sources; repeatedly listed as Feature A systemic signs. | Diagnostic review; clinical review | (pqac-00000005, pqac-00000019) |
| Skin / connective tissue | Easy bruising, striae, mild tissue fragility | Frequently reported in hEDS descriptions, but less specific than major skin fragility seen in other EDS subtypes; unusual skin fragility argues against hEDS and should prompt alternative diagnosis review. | Quantitative prevalence not reliably established in retrieved sources. | Diagnostic review; genetics/diagnosis review | (pqac-00000001, pqac-00000003, pqac-00000005) |
| Skin / connective tissue | Hernias, pelvic organ prolapse, related tissue signs | Considered part of systemic connective-tissue manifestations and may help distinguish hEDS from HSD when present in aggregate. | No pooled prevalence from retrieved high-level sources; hernias/rectal prolapse were reported more often in hEDS than HSD in a 2024 cohort. | Cohort; diagnostic review | (pqac-00000004, pqac-00000005) |
| Fatigue | Chronic fatigue / exercise intolerance | Common across hEDS/HSD, often interacting with pain, dysautonomia, sleep issues, and deconditioning; causality remains multifactorial and not fully resolved. | Systematic review: chronic fatigue in hypermobile EDS 61/63 (96.8%). Tertiary-center cohort summarized in 2024 review: >40% reported fatigue. | Systematic review; comparative review | (pqac-00000006, pqac-00000010) |
| Autonomic | Dysautonomia / orthostatic intolerance / POTS | Strong clinical association, but mechanism remains uncertain; may aggravate fatigue, presyncope, palpitations, nausea, and exercise intolerance. | Review cited autonomic dysfunction in ~30% of hypermobility-disorder patients; GI review states POTS occurs in up to 40% of hypermobility disorders and hypermobility is present in ~25% of POTS cohorts. | Review; GI management review | (pqac-00000008, pqac-00000010) |
| Gastrointestinal | Functional GI symptoms overall | GI symptoms are common and often attributed to disorders of gut–brain interaction; true prevalence of structural dysmotility is unknown. | GI symptom prevalence across hypermobility disorders reported as 30%–96%. | GI review / management review | (pqac-00000009, pqac-00000010) |
| Gastrointestinal | Functional dyspepsia, dysphagia, nausea, constipation, IBS-C | Frequently reported in hEDS/HSD; dysphagia, nausea, bloating, constipation, and IBS-C are among the recurring symptom clusters. | Functional dyspepsia occurs in up to 50% of secondary-care hypermobility patients; slow colonic transit reported in 10%–20%. Mayo cohort: nausea 54.6% in hEDS vs 59.5% in HSD; constipation 53.0% vs 57.2%. | GI review; comparative cohort | (pqac-00000004, pqac-00000008, pqac-00000009) |
| Neurologic / cognitive | Headache, migraine, brain fog | Common extra-articular manifestations; likely multifactorial and overlapping with dysautonomia, pain, sleep disturbance, and mood symptoms. | Mayo cohort: headache 68.1% in hEDS vs 69.1% in HSD; migraine 53.7% vs 52.5%; brain fog 70.0% vs 74.7%. | Large cohort | (pqac-00000004) |
| Immune / allergy | Allergy / atopy | Frequently self-reported in both hEDS and HSD, but not specific and not yet tied to a validated unifying mechanism. | Mayo cohort: allergy reported in 77.0% of hEDS and 77.0% of HSD patients. | Large cohort | (pqac-00000004) |
| Mast-cell / inflammatory | Mast-cell activation associations | MCAS/mast-cell involvement is commonly discussed clinically, but current evidence does not establish it as a proven causal mechanism for hEDS/HSD or associated GI/autonomic symptoms. | Tertiary-center cohort summarized in 2024 comparative review reported >40% with mast-cell activation symptoms/comorbidity, but GI review explicitly states mechanistic links are unclear/unproven. | Review; comparative review | (pqac-00000006, pqac-00000008, pqac-00000010) |
| Psychosocial | Anxiety, depression, psychiatric comorbidity | Psychosocial comorbidity is common and should not be used to dismiss somatic disease burden; pain and diagnostic ambiguity may worsen distress. | In one cohort of 106 hypermobile EDS patients, 42.5% had a psychiatric disorder; anxiety 23.6%, depression 25.5%. Mayo cohort: anxiety 60.3% in hEDS vs 69.3% in HSD; depression 52.2% vs 58.0%. | Scoping review; cohort | (pqac-00000004, pqac-00000015) |
| Psychosocial | Illness uncertainty | Illness uncertainty is increasingly recognized because of delayed diagnosis, unclear etiology, multisystem symptoms, and prior dismissal/misattribution. | No validated prevalence estimate identified in retrieved sources. | Narrative review | (pqac-00000013) |
| Reproductive / pregnancy | Pregnancy and childbearing considerations | Pregnancy-related care should be individualized and multidisciplinary; attention is warranted for tissue fragility, pain, dysautonomia/POTS, GI issues, mental health, and postpartum recovery. | International survey: 947 respondents, 1338 pregnancies; reported higher-than-general-population incidences of pre-eclampsia, preterm birth, postpartum hemorrhage, hyperemesis gravidarum, precipitate labor, PTSD, and other complications. Guideline scoping review synthesized 35 studies/case studies totaling 1,260,317 participants. | Large survey; scoping review + expert guideline | (pqac-00000009, pqac-00000014) |


*Table: This table summarizes core clinical phenotypes and associated comorbidities relevant to a disease entry for hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders. It emphasizes what is common, what remains uncertain, and where quantitative estimates are available from recent reviews and cohorts.*