Background: Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSDs) are prevalent, complex conditions marked by chronic pain, joint instability, and multisystem involvement. Despite affecting an estimated 1 in 500 individuals, these conditions remain poorly understood and inconsistently diagnosed. This study aimed to define their clinical burden through a large-scale, international survey. Methods: A cross-sectional, anonymous survey was distributed globally from September 2023 to March 2024. Of 9258 responses, 3906 met inclusion criteria (hEDS: n = 3360; HSD: n = 546). The 418-item questionnaire assessed symptoms, comorbidities, healthcare utilization, and quality of life. The 95% confidence intervals (CIs) were calculated for comparison. Results: Participants with hEDS reported a mean of 24 comorbid conditions and an average diagnostic delay of 22.1 years. Common diagnoses included gastrointestinal disorders (84.3% [95% CI: 98.3–99.2%]), dysautonomia (71.4% [95% CI: 69.9–72.9%]), and chronic pain (98.9% [95% CI: 98.3–99.2%]). In contrast, HSD respondents reported a mean of 17 comorbidities, a 17.5-year time to diagnosis, and lower rates of key complications. Triggering events, such as puberty and infections were commonly reported preceding hEDS or HSD symptom onset. Comparison to the All of Us dataset revealed significantly elevated prevalence ratios of neurological, immune, and autonomic diagnoses. Conclusions: This global survey highlights the extensive multisystemic burden and diagnostic delays faced by individuals with hEDS and HSDs. The high prevalence of immune, neurological, gastrointestinal, and autonomic dysfunctions challenges the notion of these conditions as isolated connective tissue disorders. These findings highlight the need for updated diagnostic frameworks and mechanistic studies that explore multifactorial etiologies beyond the connective tissue paradigm.

Hypermobile Ehlers–Danlos Syndrome (hEDS) is a poorly understood connective tissue disorder that lacks molecular diagnostic markers. This study aimed to identify proteomic signatures associated with hEDS to define underlying pathophysiology and to inform objective diagnostic strategies with therapeutic potential. An unbiased mass spectrometry–based proteomic analysis of serum from female hEDS patients (n = 29) and matched controls (n = 29) was conducted. Differentially abundant proteins were analyzed through pathway enrichment and gene ontology pipelines. Prioritized candidate biomarker proteins were verified in expanded patient and control cohorts via ELISA. Cytokine array profiling was conducted to assess immune signaling patterns. Proteomic analysis revealed 35 differentially expressed proteins in hEDS, with 43% involved in the complement cascade and 80% linked to immune, coagulation, or inflammatory pathways. Pathway analyses confirmed enrichment in complement activation, coagulation, and stress responses. ELISA validation showed significant reductions in C1QA, C3, C8A, C8B, and C9 in hEDS patients, consistent across age and sex. Cytokine profiling revealed alterations in nodal immune cell mediators in hEDS patients, supporting a model of dysregulated inflammatory response. Our findings indicate a systemic immune dysregulation, particularly involving the complement system and profibrotic cytokines, as a common feature in hEDS pathophysiology. These findings challenge the traditional view of hEDS as solely a connective tissue disorder and support a revised paradigm that includes innate immune dysfunction. This immune involvement may contribute to disease pathophysiology and inform the development of biologically based diagnostic tools, enabling earlier diagnosis and guiding future therapeutic strategies.

Background/Objectives: Dermatosparaxis Ehlers–Danlos syndrome (dEDS) is a rare autosomal recessive connective tissue disorder caused by biallelic pathogenic variants in ADAMTS2, which encodes the primary N-proteinase responsible for fibrillar procollagen processing. Although defective procollagen cleavage is the defining molecular feature of dEDS, how ADAMTS2 deficiency disrupts extracellular matrix (ECM) organization and tissue integrity remains incompletely understood. Here we characterized the structural, molecular, and cellular consequences of a knock-in Adamts2 mouse model harboring a disease-associated variant and assessed its phenotypic and mechanistic resemblance to human dEDS. Methods: We generated Adamts2^Q226* mice carrying a variant analogous to a human dEDS-causing mutation. Skin from homozygous, heterozygous, and control animals was evaluated using histologic, ultrastructural, biochemical, digital pathology, and single-nucleus RNA-sequencing approaches. Pathway enrichment analyses and the computational tool CellChat were used to infer altered molecular programs and changes in intercellular communication. Results: Homozygous knock-in mice exhibited near-complete loss of dermal ADAMTS2 protein expression, impaired type I procollagen processing, disrupted dermal architecture, and irregular hieroglyphic collagen fibrils characteristic of dEDS. Digital pathology demonstrated reduced collagen bulk, diminished assembled and total collagen, increased fine collagen, and loss of mature collagen architecture, with intermediate changes in heterozygous animals. Single-nucleus RNA sequencing identified fibroblasts as the most affected population, with coordinated downregulation of collagen, microfibrillar, and other ECM-associated genes. Pathway analyses implicated altered ECM organization, receptor-linked signaling, cytoskeletal regulation, protein processing, and metabolism, while CellChat inferred widespread reductions in intercellular communication. Conclusions: ADAMTS2 deficiency causes fibroblast-enriched transcriptional remodeling, impaired collagen processing and ECM maturation, and disrupted tissue-wide cellular communication. This model provides a translational platform for studying dEDS pathogenesis and strategies to restore ECM homeostasis.