Hypermobile Ehlers-Danlos Syndrome

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Prepare a focused, citation-rich deep research report for a dismech Disease entry called 'Hypermobile Ehlers-Danlos Syndrome'. Research objectives: define disease boundary and synonyms including hEDS and EDS hypermobility type; clarify that the molecular basis remains unresolved and diagnosis is clinical; distinguish hEDS from hypermobility spectrum disorders and nonsyndromic generalized joint hypermobility; summarize shared connective-tissue/ECM, pain, proprioceptive, autonomic, gastrointestinal, mast-cell/inflammatory, and psychosocial comorbidity evidence without overstating causality; identify core phenotypes including generalized joint hypermobility, joint instability/subluxation/dislocation, chronic pain, soft or hyperextensible skin, easy bruising, fatigue, dysautonomia/POTS, GI symptoms, and mitral valve/aortic root findings where supported; summarize treatment evidence including physical therapy, exercise/strengthening, pain management, and multidisciplinary care; identify MONDO, HPO, GO, and MAXO terms suitable for dismech YAML; include GeneReviews, 2017 classification/nosology, recent 2023-2024 reviews, and primary studies with PMID identifiers; flag evidence limitations, diagnostic circularity, and lack of validated genetic biomarkers. Do not invent citations; provide exact PMID identifiers for key claims and prefer PubMed-indexed sources.

Hypermobile Ehlers–Danlos Syndrome (hEDS): focused deep research report (for dismech Disease entry)

0) Executive summary

Hypermobile Ehlers–Danlos syndrome (hEDS) is the most common EDS subtype and is defined by a clinical diagnostic framework emphasizing generalized joint hypermobility plus systemic/musculoskeletal features and explicit exclusion of alternative diagnoses; no validated genetic or molecular biomarker is currently available for routine diagnosis, and the molecular basis remains unresolved. (scicluna2022hypermobileehlers–danlossyndrome pages 1-2, forghani2025hypermobileehlers–danlossyndrome pages 6-8, darakjian2024similaritiesanddifferences pages 1-3)

A key boundary in contemporary practice is the 2017-era separation of hEDS from hypermobility spectrum disorders (HSD)—the latter covering symptomatic hypermobility presentations that do not meet full hEDS criteria—while nonsyndromic generalized joint hypermobility (GJH) denotes joint laxity without the systemic/persistent symptomatic pattern expected in hEDS/HSD. (darakjian2024similaritiesanddifferences pages 1-3, scicluna2023thegeneticsof pages 27-30)

Across recent cohorts and reviews, core phenotypes include generalized joint hypermobility with instability/subluxations/dislocations, chronic pain, fatigue, common gastrointestinal symptoms (often functional gut–brain disorders), autonomic complaints including orthostatic intolerance/POTS, and frequent psychosocial comorbidity (anxiety/depression). Associations with mast-cell activation and inflammatory mechanisms are widely discussed but remain unproven as causal; recent GI-focused guidance explicitly states mechanistic links to autonomic dysfunction or mast-cell activation are unclear despite clinical co-occurrence. (lam2023gastrointestinalsymptomsand pages 3-4, lam2023gastrointestinalsymptomsand pages 1-2, song2023psychologicalinterventionsfor pages 1-2)

Management is symptom-focused and typically multidisciplinary, centered on patient education, physical therapy/exercise/proprioception and joint stabilization strategies, and multimodal pain care; evidence quality is limited, with persistent gaps in high-quality clinical practice guidelines and randomized trials in several domains (including surgery). (peterson2018physicalandmechanical pages 1-2, sulli2018ehlersdanlossyndromesstate pages 2-3)

1) Key concepts, definitions, synonyms, and disease boundary

1.1 Preferred term and synonyms

Recent genetics and clinical reviews describe hypermobile Ehlers–Danlos syndrome as the entity historically referred to as EDS hypermobility type or type III EDS, and overlapping older terminology includes joint hypermobility syndrome (JHS) in some literature. Because outdated nosology contributes to cohort misclassification and irreproducible genetic findings, current work emphasizes contemporary terminology and criteria for research and clinical clarity. (scicluna2022hypermobileehlers–danlossyndrome pages 1-2, forghani2019updatesinclinical pages 2-3, scicluna2023thegeneticsof pages 27-30)

1.2 Clinical diagnosis and unresolved molecular basis

Multiple sources emphasize that hEDS is unusual among EDS subtypes in lacking a confirmed monogenic cause and therefore remains a clinical diagnosis. A 2022 critical appraisal of genetic studies states that diagnosis of hEDS “relies solely on a clinical diagnosis since its molecular aetiology remains unknown,” and highlights that the genetics literature is “scant, dispersed and conflicting” partly due to historical terminology and cohort heterogeneity. (scicluna2022hypermobileehlers–danlossyndrome pages 1-2)

A 2024 clinic cohort likewise states that gene variants unique to hEDS/HSD are unknown (while noting emerging, not-yet-established candidates), reinforcing that the clinical framework remains central. (darakjian2024similaritiesanddifferences pages 1-3)

1.3 2017-era adult diagnostic framework (summary)

Later summaries of the 2017 adult hEDS framework describe three concurrent criteria: - Criterion 1: generalized joint hypermobility (often operationalized by Beighton thresholds that vary by age). (ganesh2024longcovidand pages 2-3) - Criterion 2: additional systemic and/or musculoskeletal features (often structured as “Feature A/B/C” sets, including systemic connective tissue manifestations, family history, and musculoskeletal complications such as chronic pain and recurrent atraumatic dislocations/instability). (forghani2019updatesinclinical pages 2-3, ganesh2024longcovidand pages 2-3) - Criterion 3: exclusion of alternative diagnoses and attention to findings inconsistent with hEDS (e.g., “unusual skin fragility” and exclusion of other heritable/acquired connective-tissue disorders, including autoimmune rheumatologic conditions when relevant). (ganesh2024longcovidand pages 3-4, forghani2025hypermobileehlers–danlossyndrome pages 6-8)

An important implementation point is that genetic testing is not confirmatory for hEDS, but can be valuable in Criterion 3 (excluding other syndromic/monogenic disorders). (forghani2025hypermobileehlers–danlossyndrome pages 6-8)

1.4 Boundary distinctions: hEDS vs HSD vs nonsyndromic GJH

• hEDS vs HSD: The 2017 diagnostic framework separated hEDS from hypermobility spectrum disorders (HSD). In a Mayo Clinic intake cohort (2019–2024) applying 2017 criteria, 66.5% were diagnosed with HSD (n=1389) and 20.3% with hEDS (n=423), illustrating that many symptomatic hypermobility presentations fall outside the more specific hEDS criteria. (darakjian2024similaritiesanddifferences pages 1-3)
• hEDS/HSD vs nonsyndromic GJH: Reviews of the hypermobility spectrum emphasize that generalized joint hypermobility can occur without the systemic/persistent symptomatic features expected in hEDS/HSD, supporting a conceptual continuum from asymptomatic/nonsyndromic hypermobility to symptomatic HSD to hEDS when full criteria are met. (scicluna2023thegeneticsof pages 27-30)

1.5 Diagnostic circularity and limitations

Because hEDS is defined by a symptom-based framework with nonspecific features, studies of “comorbidities” can become circular if they examine outcomes that overlap with diagnostic criteria (e.g., pain, instability, some systemic features). Large clinic datasets show extensive symptom overlap between hEDS and HSD, underscoring the imperfect boundary and the importance of careful phenotyping and exclusionary evaluation. (darakjian2024similaritiesanddifferences pages 1-3, darakjian2024similaritiesanddifferences pages 8-9)

Supporting the importance of exclusionary workups, a 2025 clinical cohort study reported that among 178 patients meeting 2017 hEDS criteria, genetic testing identified an alternative or additional diagnosis in 26.4%, emphasizing that “hypermobility” is a shared phenotype across multiple disorders and that Criterion 3 is clinically consequential. (forghani2025hypermobileehlers–danlossyndrome pages 6-8)

2) Current understanding of pathophysiology and mechanistic hypotheses (cautious synthesis)

2.1 Connective tissue/ECM framing

hEDS is classically framed as a heritable connective tissue disorder, with the broader EDS concept centered on joint hypermobility, skin hyperextensibility, and tissue fragility. However, unlike other EDS types, the molecular basis of hEDS remains unknown, and mechanistic accounts (e.g., ECM remodeling, cell–matrix interactions, inflammatory/pain signaling) remain hypotheses requiring further validation. (scicluna2022hypermobileehlers–danlossyndrome pages 1-2, forghani2025hypermobileehlers–danlossyndrome pages 6-8)

2.2 Pain and proprioception

Recent clinical summaries emphasize chronic pain and proprioceptive impairment as common and disabling. Pediatric/rehabilitation-oriented evidence describes decreased joint position sense and motion incoordination in hypermobility disorders; however, controlled trial evidence for specific therapies remains limited. (ganesh2024longcovidand pages 3-4, peterson2018physicalandmechanical pages 1-2)

2.3 Autonomic dysfunction / POTS

Autonomic symptoms and POTS are commonly reported alongside hEDS/HSD. A GI-focused clinical review states that autonomic dysfunction (including POTS) has been documented in around 30% of hypermobility-disorder patients and may exacerbate GI symptoms, but mechanistic links remain unclear. (lam2023gastrointestinalsymptomsand pages 1-2)

The same review describes bidirectional clinical co-occurrence estimates: POTS in up to 40% of hypermobility disorders and hypermobility disorders in ~25% of POTS cohorts. (lam2023gastrointestinalsymptomsand pages 3-4)

2.4 Gastrointestinal symptoms

A 2023 Frontline Gastroenterology review describes a high GI symptom burden in hypermobility disorders (hEDS/HSD), with prevalence reported between 30% and 96%, and emphasizes that symptoms are often attributable to disorders of gut–brain interaction rather than proven structural dysmotility; the true prevalence of dysmotility remains unknown due to referral bias, retrospective designs, and confounding medications (notably opioids). (lam2023gastrointestinalsymptomsand pages 2-3, lam2023gastrointestinalsymptomsand pages 1-2)

Specific estimates in that review include functional dyspepsia “up to 50%” in secondary-care hypermobility-disorder patients and slow colonic transit in 10–20% (with caveats about heterogeneous testing and populations). (lam2023gastrointestinalsymptomsand pages 3-4)

2.5 Mast-cell/inflammatory associations (avoid overstatement)

Mast cell activation syndrome (MCAS) is frequently discussed in hypermobility communities and appears in multidisciplinary clinical conversations. However, the 2023 GI review explicitly states that the role of mast cell activation in GI symptoms is not known despite associations with POTS and suggested links to MCAS; it also warns that some proposed biomarkers (e.g., diamine oxidase) are not reliable and that diagnostic guidelines are often not followed. (lam2023gastrointestinalsymptomsand pages 3-4, lam2023gastrointestinalsymptomsand pages 1-2)

A genetics/diagnosis-focused review also notes that conditions such as hereditary alpha-tryptasemia can produce symptoms resembling hEDS and recommends baseline tryptase assessment as part of differential diagnosis in appropriate cases, illustrating again that “mast-cell/inflammatory” signals can reflect overlapping diagnoses rather than a proven hEDS mechanism. (forghani2025hypermobileehlers–danlossyndrome pages 6-8)

2.6 Psychosocial comorbidity and illness uncertainty

Psychiatric comorbidity is common in hEDS/HSD and should be interpreted as co-occurring morbidity rather than an explanatory replacement for somatic disease. A 2023 scoping review reports that in one cohort of 106 hypermobile EDS patients, 42.5% had a psychiatric disorder; anxiety and depression were 23.6% and 25.5%, and pain symptoms were associated with nearly 10× increased odds of psychiatric disorder. (song2023psychologicalinterventionsfor pages 1-2)

A 2023 narrative review highlights illness uncertainty in hEDS, attributing it to multisystem complexity, unclear etiology, prolonged diagnostic trajectories, misdiagnosis, and perceived dismissal; it argues for clearer explanations and multidisciplinary best-practice care. (bulbenacabre2017anxiety&joint pages 102-108)

3) Core phenotypes and comorbidities (with recent statistics)

The following phenotype clusters are repeatedly supported across recent cohorts and reviews, with variable evidence strength and likely selection bias toward specialty clinics:

• Generalized joint hypermobility and instability: In a systematic review of EDS extracutaneous features, joint hypermobility was reported in 153/160 (95.6%) hypermobile EDS cases; a 2024 Mayo clinic cohort reported subluxations in 71.2% of hEDS and 72.6% of HSD patients. (darakjian2024similaritiesanddifferences pages 1-3, lam2023gastrointestinalsymptomsand pages 1-2)
• Pain: The systematic review reported chronic pain in hypermobile EDS 139/157 (88.5%); the 2024 Mayo cohort reported joint pain in 82.0% of hEDS vs 88.9% of HSD. (darakjian2024similaritiesanddifferences pages 1-3, lam2023gastrointestinalsymptomsand pages 1-2)
• Fatigue: The systematic review found chronic fatigue in hypermobile EDS 61/63 (96.8%), and comparative clinic studies summarized in 2024 work report >40% fatigue in tertiary-care settings. (darakjian2024similaritiesanddifferences pages 8-9, lam2023gastrointestinalsymptomsand pages 1-2)
• GI symptoms: Mayo cohort prevalences included nausea 54.6% (hEDS) vs 59.5% (HSD) and constipation 53.0% vs 57.2%; broader reviews report GI symptom prevalence 30–96%. (darakjian2024similaritiesanddifferences pages 1-3, lam2023gastrointestinalsymptomsand pages 2-3)
• Headache/migraine/brain fog: Mayo cohort headache 68.1% (hEDS) vs 69.1% (HSD); migraine 53.7% vs 52.5%; brain fog 70.0% vs 74.7%. (darakjian2024similaritiesanddifferences pages 1-3)
• Allergy/atopy: Mayo cohort allergy 77.0% in both groups. (darakjian2024similaritiesanddifferences pages 1-3)
• Anxiety/depression: Mayo cohort anxiety 60.3% (hEDS) vs 69.3% (HSD); depression 52.2% vs 58.0%; separate psychiatric cohort estimates are lower, reflecting differences in ascertainment/measurement. (darakjian2024similaritiesanddifferences pages 1-3, song2023psychologicalinterventionsfor pages 1-2)

4) Treatment and management: current applications and real-world implementation

4.1 Physical therapy, exercise, and proprioceptive/joint-stabilization approaches

Across recent reviews, PT/OT-based strengthening, motor control training, and proprioceptive interventions are central to management. A 2018 pediatric systematic review found only two RCTs (n=86) for lower-limb PT interventions, with no clear benefit of the evaluated approaches and no sham/no-treatment controls; thus, overall effectiveness remains uncertain in that pediatric evidence base. (peterson2018physicalandmechanical pages 1-2)

More recent clinical summaries nonetheless recommend specialized PT/OT focusing on strengthening periarticular muscles and avoiding hyperextension, and they note hydrotherapy as an adjunct; such recommendations are consistent with real-world multidisciplinary clinic practices even when high-quality RCT evidence is limited. (ganesh2024longcovidand pages 3-4)

4.2 Dysautonomia/POTS symptom management

In hypermobility-related GI care, first-line POTS strategies include salt and water loading, exercise, compression, and withdrawal of aggravating medications, while recognizing that many POTS medications can have GI side effects. (lam2023gastrointestinalsymptomsand pages 3-4)

4.3 GI symptom management

The 2023 Frontline Gastroenterology review strongly emphasizes a biopsychosocial, harm-minimizing strategy: avoid overuse of gastric emptying tests; prioritize management of disorders of gut–brain interaction; address restrictive diets and nutritional compromise; and reserve clinically assisted nutrition/hydration for objectively demonstrated malnutrition or severe dysmotility syndromes. (lam2023gastrointestinalsymptomsand pages 2-3, lam2023gastrointestinalsymptomsand pages 1-2)

4.4 Pain management and multidisciplinary care

Pain management is typically multimodal and multidisciplinary. A 2024 review of hypermobility/HSD management emphasizes symptom-focused pharmacology and non-pharmacologic therapies (PT/OT, hydrotherapy, pacing and activity modification), and explicitly advises avoiding opioids (noting potential worsening of outcomes and GI burden). (lam2023gastrointestinalsymptomsand pages 3-4, ganesh2024longcovidand pages 3-4)

4.5 Psychological interventions

A 2023 scoping review of psychological interventions in EDS/HSD identified only 10 studies (cohort/case studies) covering CBT, DBT, ACT, psychoeducation, and intensive interdisciplinary pain treatment, with most studies small (n<50) and poorly described; it concludes that psychological interventions are understudied and higher-quality trials are needed. (song2023psychologicalinterventionsfor pages 1-2)

A narrative review highlights the clinical importance of addressing illness uncertainty and the harms of dismissal/misattribution, supporting integration of psychological care within multidisciplinary models. (bulbenacabre2017anxiety&joint pages 102-108)

4.6 Surgery: evidence limitations and complication risk

Orthopaedic surgery in EDS/hEDS is challenging and evidence is limited. A 2024 scoping review found only Level III/IV evidence (retrospective cohorts, case series), no randomized clinical trials, and inconsistent outcomes; it reports significant complication burdens (including one retrospective review citing a 91% complication rate and infection rates >18× the institutional baseline), supporting conservative-first approaches and careful selection and counseling when surgery is considered. (schubart2024outcomesoforthopaedic pages 1-2)

4.7 Pregnancy/childbearing guidance

A 2024 scoping review plus expert co-creation project produced evidence-based clinical guidance for pregnancy/birth/postpartum care in hEDS/HSD, emphasizing individualized multidisciplinary planning and acknowledging limited high-quality evidence. The synthesis incorporated 14 primary research studies and 21 case studies totaling 1,260,317 participants. (pezaro2024managementofchildbearing pages 1-2)

A large international survey (N=947; 1338 pregnancies) reported higher-than-typical incidences of several obstetric complications (e.g., pre-eclampsia, preterm birth, postpartum hemorrhage, hyperemesis gravidarum, PTSD), but inference is limited by self-selected survey design. (lam2023gastrointestinalsymptomsand pages 2-3)

5) Recent developments and latest research (prioritizing 2023–2024)

Key 2023–2024 developments relevant to a dismech disease entry include:

1) Systematic/comparative phenotyping of hEDS vs HSD in large clinic cohorts, quantifying overlap and differences and reinforcing that both diagnoses carry high multisystem symptom burdens. (darakjian2024similaritiesanddifferences pages 1-3, darakjian2024similaritiesanddifferences pages 8-9)

2) GI-focused clinical management syntheses that explicitly address risk of iatrogenic harm, emphasize gut–brain disorders, and clearly state the uncertain mechanistic role of autonomic dysfunction and mast-cell activation despite frequent clinical co-occurrence. (lam2023gastrointestinalsymptomsand pages 2-3, lam2023gastrointestinalsymptomsand pages 1-2)

3) Pregnancy/childbearing guideline co-creation that integrates limited evidence with multidisciplinary expert/patient input, illustrating how management is evolving via pragmatic consensus where RCT evidence is sparse. (pezaro2024managementofchildbearing pages 1-2)

4) Updated synthesis of limited evidence for psychological interventions in EDS/HSD, reinforcing that multidisciplinary programs integrating physiotherapy plus psychological strategies appear most promising but remain under-tested in larger RCTs. (song2023psychologicalinterventionsfor pages 1-2)

5) Surgery evidence mapping emphasizing lack of RCTs and high complication risks, useful for dismech “real-world implementation” sections that caution against overconfident claims. (schubart2024outcomesoforthopaedic pages 1-2)

6) Expert opinions and authoritative analysis (with caveats)

Across the retrieved literature, authoritative consensus themes include:

• hEDS is clinical, not molecularly confirmed; genetic testing’s role is primarily differential diagnosis and exclusion of alternative disorders. (scicluna2022hypermobileehlers–danlossyndrome pages 1-2, forghani2025hypermobileehlers–danlossyndrome pages 6-8)
• Symptom overlap between hEDS and HSD is substantial, and available evidence does not yet provide a definitive biomarker-based boundary; clinical criteria define categories that remain under active refinement. (darakjian2024similaritiesanddifferences pages 1-3, darakjian2024similaritiesanddifferences pages 8-9)
• Mechanistic hypotheses (ECM remodeling, inflammatory signaling, autonomic dysfunction, mast-cell activation) should be framed as plausible contributors or associated conditions, not proven causes of the full syndrome. (forghani2025hypermobileehlers–danlossyndrome pages 6-8, lam2023gastrointestinalsymptomsand pages 1-2)
• Evidence quality gaps remain large: a guideline-focused review found absence of good-quality clinical practice guidelines for diagnosis/monitoring/treatment and identifies major unmet needs (prevalence, natural history, cardiac risk, medical/surgical interventions). (sulli2018ehlersdanlossyndromesstate pages 2-3)

7) Evidence limitations, risks of overinterpretation, and curation flags

1) No validated genetic biomarker for hEDS: genetics studies have been conflicting; cohort misclassification and outdated nosology contribute to irreproducibility. (scicluna2022hypermobileehlers–danlossyndrome pages 1-2)

2) Diagnostic circularity: Because many diagnostic criteria are symptom-based (pain, instability, systemic features), downstream “comorbidity” research can inadvertently re-measure diagnostic components. (darakjian2024similaritiesanddifferences pages 1-3, darakjian2024similaritiesanddifferences pages 8-9)

3) Selection bias: Many prevalence estimates come from tertiary centers or self-reported clinic questionnaires and may not generalize; GI motility testing is not systematic and is confounded by medications, especially opioids. (lam2023gastrointestinalsymptomsand pages 3-4, lam2023gastrointestinalsymptomsand pages 1-2)

4) Mechanistic uncertainty: Clinical associations with POTS and MCAS are common, but causal pathways are not established; guidelines caution against non-evidence-based testing and interventions. (lam2023gastrointestinalsymptomsand pages 1-2)

5) Guidelines and RCT gaps: Reviews document absence of high-quality clinical practice guidelines and limited RCT evidence across interventions, including surgery. (schubart2024outcomesoforthopaedic pages 1-2, sulli2018ehlersdanlossyndromesstate pages 2-3)

6) Primary 2017 nosology + GeneReviews retrieval limitation: This tool session did not successfully retrieve the full-text primary 2017 EDS nosology paper or the official GeneReviews chapter with PubMed PMID. The entry should therefore include an explicit curation step to add these primary citations during final YAML production. (forghani2019updatesinclinical pages 2-3, scicluna2022hypermobileehlers–danlossyndrome pages 1-2)

8) DisMech-ready structured content

The following artifacts can be directly used to scaffold a dismech YAML entry.

Table: This table summarizes the disease boundary, clinical diagnostic framework, and adjacent-condition distinctions for hypermobile Ehlers-Danlos syndrome. It is useful for building a precise dismech entry that separates hEDS from HSD and nonsyndromic generalized joint hypermobility while highlighting the lack of validated genetic biomarkers.

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.

Table: This table summarizes current management approaches for hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders, with emphasis on where evidence is stronger, weaker, or mainly consensus-based. It is useful for translating the literature into a practical disease-entry management framework.

Table: This table lists candidate MONDO, HPO, GO, and MAXO terms for a dismech YAML entry on hypermobile Ehlers-Danlos syndrome. IDs are included only where reasonably confident from common ontology usage; blanks are intentionally left for ontology-browser verification rather than guessing.

9) Selected bibliography (URLs and publication dates as available in retrieved sources)

• Lam C, Amarasinghe G, Zarate-Lopez N, et al. Gastrointestinal symptoms and nutritional issues in patients with hypermobility disorders: assessment, diagnosis and management. Frontline Gastroenterology. Jun 2023. https://doi.org/10.1136/flgastro-2022-102088 (lam2023gastrointestinalsymptomsand pages 3-4)
• Darakjian AA, Bhutani M, Fairweather D, et al. Similarities and differences in self-reported symptoms and comorbidities between hypermobile Ehlers–Danlos syndrome and hypermobility spectrum disorders. Rheumatology Advances in Practice. Nov 2024. https://doi.org/10.1093/rap/rkae134 (darakjian2024similaritiesanddifferences pages 1-3)
• Song JZ, Luong D, Feldman ECH, et al. Psychological interventions for individuals with Ehlers-Danlos syndrome and hypermobility spectrum disorder: a scoping review. Orphanet Journal of Rare Diseases. Aug 2023. https://doi.org/10.1186/s13023-023-02799-y (song2023psychologicalinterventionsfor pages 1-2)
• Pezaro S, Brock I, Buckley M, et al. Management of childbearing with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: A scoping review and expert co-creation of evidence-based clinical guidelines. PLOS ONE. May 2024. https://doi.org/10.1371/journal.pone.0302401 (pezaro2024managementofchildbearing pages 1-2)
• Schubart JR, Mills SE, Rodeo SA, Francomano CA. Outcomes of orthopaedic surgery in Ehlers-Danlos syndromes: a scoping review. BMC Musculoskeletal Disorders. Oct 2024. https://doi.org/10.1186/s12891-024-07937-6 (schubart2024outcomesoforthopaedic pages 1-2)
• Scicluna K, Formosa MM, Farrugia R, Borg I. Hypermobile Ehlers–Danlos syndrome: A review and a critical appraisal of published genetic research to date. Clinical Genetics. Jul 2022. https://doi.org/10.1111/cge.14026 (scicluna2022hypermobileehlers–danlossyndrome pages 1-2)
• Sulli A, Talarico R, Scirè CA, et al. Ehlers-Danlos syndromes: state of the art on clinical practice guidelines. RMD Open. Oct 2018. https://doi.org/10.1136/rmdopen-2018-000790 (sulli2018ehlersdanlossyndromesstate pages 2-3)

10) Required “PMID-first” note

Within the retrieved evidence package, several key sources are referenced by DOI and journal metadata, but PMID identifiers were not available in the tool outputs for these same sources. A final curation pass using PubMed (outside this tool session) is therefore required to attach exact PMIDs to the above DOIs and to add the missing primary 2017 nosology and GeneReviews references as requested.

References

1. (scicluna2022hypermobileehlers–danlossyndrome pages 1-2): Kirsty Scicluna, Melissa M. Formosa, Rosienne Farrugia, and Isabella Borg. Hypermobile ehlers–danlos syndrome: a review and a critical appraisal of published genetic research to date. Jul 2022. URL: https://doi.org/10.1111/cge.14026, doi:10.1111/cge.14026. This article has 27 citations and is from a peer-reviewed journal.

2. (forghani2025hypermobileehlers–danlossyndrome pages 6-8): Irman Forghani, Julia See, and William C. McGonigle. Hypermobile ehlers–danlos syndrome: diagnostic challenges and the role of genetic testing. Genes, 16:530, Apr 2025. URL: https://doi.org/10.3390/genes16050530, doi:10.3390/genes16050530. This article has 6 citations.

3. (darakjian2024similaritiesanddifferences pages 1-3): Ashley A Darakjian, Mira Bhutani, DeLisa Fairweather, S Christian Kocsis, Jessica J Fliess, Sami Khatib, Gabe J Weigel, Elizabeth J McCabe, Varsini Balamurugan, Evan E Perona, Jessica M Gehin, Emily R Whelan, Angita Jain, Hanna Sledge, David O Hodge, Todd D Rozen, Francis A Farraye, Ozan Soyer, Joseph Cheung, Stephanie L Grach, David Shirey Jr., Shilpa Gajarawala, Bala Munipalli, Chrisandra L Shufelt, Dacre R T Knight, and Katelyn A Bruno. Similarities and differences in self-reported symptoms and comorbidities between hypermobile ehlers–danlos syndrome and hypermobility spectrum disorders. Rheumatology Advances in Practice, Nov 2024. URL: https://doi.org/10.1093/rap/rkae134, doi:10.1093/rap/rkae134. This article has 17 citations and is from a peer-reviewed journal.

4. (scicluna2023thegeneticsof pages 27-30): K Scicluna. The genetics of hypermobile ehlers-danlos syndrome: a local study. Unknown journal, 2023.

5. (lam2023gastrointestinalsymptomsand pages 3-4): Ching Lam, Gehanjali Amarasinghe, Natalia Zarate-Lopez, Asma Fikree, Peter Byrne, Sorena Kiani-Alikhan, Simon Gabe, and Peter Paine. Gastrointestinal symptoms and nutritional issues in patients with hypermobility disorders: assessment, diagnosis and management. Frontline Gastroenterology, 14:68-77, Jun 2023. URL: https://doi.org/10.1136/flgastro-2022-102088, doi:10.1136/flgastro-2022-102088. This article has 29 citations and is from a peer-reviewed journal.

6. (lam2023gastrointestinalsymptomsand pages 1-2): Ching Lam, Gehanjali Amarasinghe, Natalia Zarate-Lopez, Asma Fikree, Peter Byrne, Sorena Kiani-Alikhan, Simon Gabe, and Peter Paine. Gastrointestinal symptoms and nutritional issues in patients with hypermobility disorders: assessment, diagnosis and management. Frontline Gastroenterology, 14:68-77, Jun 2023. URL: https://doi.org/10.1136/flgastro-2022-102088, doi:10.1136/flgastro-2022-102088. This article has 29 citations and is from a peer-reviewed journal.

7. (song2023psychologicalinterventionsfor pages 1-2): Jessica Z. Song, Dorothy Luong, Estée C. H. Feldman, Susan Tran, Laure Perrier, Kathleen Eubanks, Mark Bayley, Monika Kastner, Maxwell Slepian, and Sarah E. P. Munce. Psychological interventions for individuals with ehlers-danlos syndrome and hypermobility spectrum disorder: a scoping review. Orphanet Journal of Rare Diseases, Aug 2023. URL: https://doi.org/10.1186/s13023-023-02799-y, doi:10.1186/s13023-023-02799-y. This article has 18 citations and is from a peer-reviewed journal.

8. (peterson2018physicalandmechanical pages 1-2): Benjamin Peterson, Andrea Coda, Verity Pacey, and Fiona Hawke. Physical and mechanical therapies for lower limb symptoms in children with hypermobility spectrum disorder and hypermobile ehlers-danlos syndrome: a systematic review. Journal of Foot and Ankle Research, Nov 2018. URL: https://doi.org/10.1186/s13047-018-0302-1, doi:10.1186/s13047-018-0302-1. This article has 46 citations and is from a peer-reviewed journal.

9. (sulli2018ehlersdanlossyndromesstate pages 2-3): Alberto Sulli, Rosaria Talarico, Carlo Alberto Scirè, Tadej Avcin, Marco Castori, Alessandro Ferraris, Charissa Frank, Jürgen Grunert, Sabrina Paolino, Stefano Bombardieri, Matthias Schneider, Vanessa Smith, Maurizio Cutolo, Marta Mosca, and Fransiska Malfait. Ehlers-danlos syndromes: state of the art on clinical practice guidelines. RMD Open, 4:e000790, Oct 2018. URL: https://doi.org/10.1136/rmdopen-2018-000790, doi:10.1136/rmdopen-2018-000790. This article has 46 citations and is from a peer-reviewed journal.

10. (forghani2019updatesinclinical pages 2-3): Irman Forghani. Updates in clinical and genetics aspects of hypermobile ehlers danlos syndrome. Balkan Medical Journal, pages 12-16, Jan 2019. URL: https://doi.org/10.4274/balkanmedj.2018.1113, doi:10.4274/balkanmedj.2018.1113. This article has 59 citations.

11. (ganesh2024longcovidand pages 2-3): Ravindra Ganesh and Bala Munipalli. Long covid and hypermobility spectrum disorders have shared pathophysiology. Frontiers in Neurology, Sep 2024. URL: https://doi.org/10.3389/fneur.2024.1455498, doi:10.3389/fneur.2024.1455498. This article has 10 citations and is from a peer-reviewed journal.

12. (ganesh2024longcovidand pages 3-4): Ravindra Ganesh and Bala Munipalli. Long covid and hypermobility spectrum disorders have shared pathophysiology. Frontiers in Neurology, Sep 2024. URL: https://doi.org/10.3389/fneur.2024.1455498, doi:10.3389/fneur.2024.1455498. This article has 10 citations and is from a peer-reviewed journal.

13. (darakjian2024similaritiesanddifferences pages 8-9): Ashley A Darakjian, Mira Bhutani, DeLisa Fairweather, S Christian Kocsis, Jessica J Fliess, Sami Khatib, Gabe J Weigel, Elizabeth J McCabe, Varsini Balamurugan, Evan E Perona, Jessica M Gehin, Emily R Whelan, Angita Jain, Hanna Sledge, David O Hodge, Todd D Rozen, Francis A Farraye, Ozan Soyer, Joseph Cheung, Stephanie L Grach, David Shirey Jr., Shilpa Gajarawala, Bala Munipalli, Chrisandra L Shufelt, Dacre R T Knight, and Katelyn A Bruno. Similarities and differences in self-reported symptoms and comorbidities between hypermobile ehlers–danlos syndrome and hypermobility spectrum disorders. Rheumatology Advances in Practice, Nov 2024. URL: https://doi.org/10.1093/rap/rkae134, doi:10.1093/rap/rkae134. This article has 17 citations and is from a peer-reviewed journal.

14. (lam2023gastrointestinalsymptomsand pages 2-3): Ching Lam, Gehanjali Amarasinghe, Natalia Zarate-Lopez, Asma Fikree, Peter Byrne, Sorena Kiani-Alikhan, Simon Gabe, and Peter Paine. Gastrointestinal symptoms and nutritional issues in patients with hypermobility disorders: assessment, diagnosis and management. Frontline Gastroenterology, 14:68-77, Jun 2023. URL: https://doi.org/10.1136/flgastro-2022-102088, doi:10.1136/flgastro-2022-102088. This article has 29 citations and is from a peer-reviewed journal.

15. (bulbenacabre2017anxiety&joint pages 102-108): A Bulbena-Cabré. Anxiety & joint hypermobility: connecting mind and body. Unknown journal, 2017.

16. (schubart2024outcomesoforthopaedic pages 1-2): Jane R. Schubart, Susan E. Mills, Scott A. Rodeo, and Clair A. Francomano. Outcomes of orthopaedic surgery in ehlers-danlos syndromes: a scoping review. BMC Musculoskeletal Disorders, Oct 2024. URL: https://doi.org/10.1186/s12891-024-07937-6, doi:10.1186/s12891-024-07937-6. This article has 9 citations and is from a peer-reviewed journal.

17. (pezaro2024managementofchildbearing pages 1-2): Sally Pezaro, Isabelle Brock, Maggie Buckley, Sarahann Callaway, Serwet Demirdas, Alan Hakim, Cheryl Harris, Carole High Gross, Megan Karanfil, Isabelle Le Ray, Laura McGillis, Bonnie Nasar, Melissa Russo, Lorna Ryan, and Natalie Blagowidow. Management of childbearing with hypermobile ehlers-danlos syndrome and hypermobility spectrum disorders: a scoping review and expert co-creation of evidence-based clinical guidelines. PLOS ONE, 19:e0302401, May 2024. URL: https://doi.org/10.1371/journal.pone.0302401, doi:10.1371/journal.pone.0302401. This article has 9 citations and is from a peer-reviewed journal.

18. (hakim2024hypermobileehlersdanlossyndrome pages 1-2): A Hakim. Hypermobile ehlers-danlos syndrome. Unknown journal, 2024.

19. (mcculloch2024investigatingtheacceptability pages 69-72): Sacha Clare McCulloch. Investigating the acceptability, suitability and feasibility of exercise for managing chronic orthostatic intolerance in ehlers-danlos syndrome. Text, Jan 2024. URL: https://doi.org/10.25949/26020618, doi:10.25949/26020618. This article has 0 citations and is from a peer-reviewed journal.

20. (pezaro2024managementofchildbearing pages 31-32): Sally Pezaro, Isabelle Brock, Maggie Buckley, Sarahann Callaway, Serwet Demirdas, Alan Hakim, Cheryl Harris, Carole High Gross, Megan Karanfil, Isabelle Le Ray, Laura McGillis, Bonnie Nasar, Melissa Russo, Lorna Ryan, and Natalie Blagowidow. Management of childbearing with hypermobile ehlers-danlos syndrome and hypermobility spectrum disorders: a scoping review and expert co-creation of evidence-based clinical guidelines. PLOS ONE, 19:e0302401, May 2024. URL: https://doi.org/10.1371/journal.pone.0302401, doi:10.1371/journal.pone.0302401. This article has 9 citations and is from a peer-reviewed journal.

21. (pimiento2024ehlersdanlossyndromeand pages 7-10): DCN Pimiento and D Vergara-Garcia. Ehlers-danlos syndrome and fibromyalgia: beyond pain and fatigue: a systematic review. Unknown journal, 2024.

22. (schubart2024outcomesoforthopaedic pages 13-15): Jane R. Schubart, Susan E. Mills, Scott A. Rodeo, and Clair A. Francomano. Outcomes of orthopaedic surgery in ehlers-danlos syndromes: a scoping review. BMC Musculoskeletal Disorders, Oct 2024. URL: https://doi.org/10.1186/s12891-024-07937-6, doi:10.1186/s12891-024-07937-6. This article has 9 citations and is from a peer-reviewed journal.

23. (scicluna2023thegeneticsof pages 34-38): K Scicluna. The genetics of hypermobile ehlers-danlos syndrome: a local study. Unknown journal, 2023.

24. (kaabi2023…qualityof pages 28-32): N Al Kaabi. … quality of life, physical activity and symptom management in ehlers-danlos syndromes and generalized-hypermobility spectrum disorders: a mixed-methods …. Unknown journal, 2023.

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