Defining the Clinical Complexity of hEDS and HSD: A Global Survey of Diagnostic Challenge, Comorbidities, and Unmet Needs

BackgroundHypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are connective tissue disorders marked by chronic pain, joint instability, and extensive multisystem involvement. Despite affecting an estimated 1 in 500 individuals, these conditions remain poorly understood, and current diagnostic categories lack clarity and consistency. This study aimed to characterize the clinical presentation, comorbidities, and healthcare burden of individuals with hEDS and HSD through a large-scale international survey. Methods and FindingsA cross-sectional, anonymous online survey was distributed globally between September 2023 and March 2024. Of 9,258 responses, 3,906 participants met inclusion criteria and were included in analysis. The 418-item questionnaire covered symptom domains, diagnoses, healthcare access, and quality of life. Responses were statistically analyzed using chi-square and Mann-Whitney U tests with Bonferroni correction and compared to the All of Us dataset (n=354,400). Participants reported high rates of gastrointestinal disorders (84.3% hEDS, 69.0% HSD), with 21.2% of hEDS participants diagnosed with gastroparesis and 7.1% requiring feeding devices. Dysautonomia was common, affecting 71.4% of those with hEDS and 40.3% with HSD (p<0.0001), with postural orthostatic tachycardia syndrome (POTS) as the most frequently reported subtype. Neurological complications were also prevalent, with hEDS participants reporting significantly higher rates of tethered cord syndrome (4.6%, 0.9%), Chiari malformation (6.3%, 0.9%), and small fiber neuropathy (10.0%, 4.4%) compared to those with HSD. Chronic pain was nearly universal (98.8% hEDS, 92.7% HSD). On average, hEDS participants reported 24 comorbid diagnoses and HSD participants 17, with diagnostic delays averaging over 20 years. Notably, 50% of those reporting HSD met hEDS criteria, while 26% of those reporting hEDS did not meet full criteria, underscoring persistent diagnostic uncertainty. ConclusionsThis global survey underscores the profound multisystemic burden, diagnostic ambiguity, and unmet clinical needs faced by individuals with hEDS and HSD. The high prevalence of immune-mediated, neurological, gastrointestinal, and autonomic dysfunctions, alongside the frequent identification of triggering events such as infections and hormonal transitions, challenges the conventional framework that defines these disorders as purely connective tissue in origin. Instead, our findings support the hypothesis that hEDS and/or HSD may represent complex syndromes in which connective tissue fragility may be a downstream consequence rather than the primary cause. This reframing has critical implications for diagnosis, pathophysiology, and therapeutic development, and highlights the need for mechanistic studies that explore distinct etiologies beyond the connective tissue paradigm.