{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:39:54Z","timestamp":1791409194284,"version":"4.3.3"},"reference-count":30,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T00:00:00Z","timestamp":1760227200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"institutional international funds of the university of Verona","award":["FUR 2025"],"award-info":[{"award-number":["FUR 2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Lipedema is a chronic, progressive disorder of the adipo-fascial tissue characterized by abnormal subcutaneous fat accumulation, inflammation, fibrosis, pain, and edema. Despite its considerable impact on patients\u2019 quality of life, it remains underdiagnosed. Recent studies have suggested a potential overlap between lipedema and hypermobility spectrum disorders (HSDs), both involving connective tissue dysfunction. This work explores the shared pathophysiological features of lipedema and HSD, highlighting clinical correlations, comorbidities, and the need for integrated diagnostic and therapeutic approaches. Methods: A cross-sectional observational study was conducted through an online survey targeting individuals with lipedema and a control group with lymphedema. The questionnaire assessed symptoms typically associated with HSD, including musculoskeletal, gastrointestinal, urogynecological, vascular, and neuropsychological manifestations. Descriptive statistics were used to evaluate clinical patterns in both groups. Results: Among the lipedema patients, 44% reported joint hypermobility and 60% recalled being hypermobile during childhood. High rates of pediatric overweight (50%), low muscle tone (55%), and exercise-induced fatigue (70%) were observed. Adult symptoms included joint pain (notably in the ankles, knees, cervical spine, sacrum, and feet), digestive issues (50%), and thyroid disorders (24.4%). Compared with the control group, patients with lipedema showed significantly more connective tissue-related motor deficits and systemic symptoms. Conclusions: Connective tissue laxity may play a critical role in the pathogenesis of lipedema, contributing to multisystemic manifestations through vascular, lymphatic, gastrointestinal, and musculoskeletal involvement. The high prevalence of HSD-like features calls for a paradigm shift in the understanding of lipedema as a systemic disorder. Early identification of connective tissue alterations, especially in children with familial predisposition, could enable timely interventions, potentially mitigating disease progression. A multidisciplinary, evidence-based approach is essential for accurate diagnosis and effective management.<\/jats:p>","DOI":"10.3390\/jcm14207195","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T10:12:29Z","timestamp":1760523149000},"page":"7195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Lipedema and Hypermobility Spectrum Disorders Sharing Pathophysiology: A Cross-Sectional Observational Study"],"prefix":"10.3390","volume":"14","author":[{"given":"Elettra","family":"Fiengo","sequence":"first","affiliation":[{"name":"Studio Iris, Pomezia, 00071 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0954-2119","authenticated-orcid":false,"given":"Andrea","family":"Sbarbati","sequence":"additional","affiliation":[{"name":"Department of Neurological, Biomedical and Movement Sciences, Section of Anatomy and Histology, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Michelini, S., Chiurazzi, P., Marino, V., Dell\u2019Orco, D., Manara, E., Baglivo, M., Fiorentino, A., Maltese, P.E., Pinelli, M., and Herbst, K.L. (2020). Aldo-Keto Reductase 1C1 (AKR1C1) as the First Mutated Gene in a Family with Nonsyndromic Primary Lipedema. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176264"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Al-Ghadban, S., Isern, S.U., Herbst, K.L., and Bunnell, B.A. (2024). The Expression of Adipogenic Marker Is Significantly Increased in Estrogen-Treated Lipedema Adipocytes Differentiated from Adipose Stem Cells In Vitro. Biomedicines, 12.","DOI":"10.3390\/biomedicines12051042"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1089\/lrb.2019.0011","article-title":"Lipedema and Dercum\u2019s Disease: A New Application of Bioimpedance","volume":"17","author":"Crescenzi","year":"2019","journal-title":"Lymphat. Res. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Kruppa, P., Gohlke, S., \u0141api\u0144ski, K., Garcia-Carrizo, F., Soultoukis, G.A., Infanger, M., Schulz, T.J., and Ghods, M. (2023). Lipedema stage affects adipocyte hypertrophy, subcutaneous adipose tissue inflammation and interstitial fibrosis. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1223264"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1002\/oby.24244","article-title":"Endothelial cell alterations in capillaries of adipose tissue from patients affected by lipedema","volume":"33","author":"Michelini","year":"2025","journal-title":"Obesity"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1089\/whr.2020.0086","article-title":"Interstitial Fluid in Lipedema and Control Skin","volume":"1","author":"Allen","year":"2020","journal-title":"Women\u2019s Health Rep."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Executive Committee of the International Society of Lymphology (2023). The Diagnosis and Treatment of Peripheral Lymphedema: 2023 Consensum document of the International Society of Lymphology. Lymphology, 56, 133\u2013151.","DOI":"10.2458\/lymph.6372"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1161\/CIRCRESAHA.121.318307","article-title":"Advances in Lymphedema","volume":"128","author":"Rockson","year":"2021","journal-title":"Circ. Res."},{"key":"ref_9","first-page":"481","article-title":"Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders","volume":"103","author":"Yew","year":"2021","journal-title":"Am. Fam. Physician"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ajmg.c.31552","article-title":"The 2017 international classification of the Ehlers\u2013Danlos syndromes","volume":"175","author":"Malfait","year":"2017","journal-title":"Am. J. Med. Genet. Part C Semin. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Daylor, V., Griggs, M., Weintraub, A., Byrd, R., Petrucci, T., Huff, M., Byerly, K., Fenner, R., Severance, S., and Griggs, C. (2025). Defining the Chronic Complexities of hEDS and HSD: A Global Survey of Diagnostic Challenges, Life-Long Comorbidities, and Unmet Needs. J. Clin. Med., 14.","DOI":"10.1101\/2025.06.05.25329074"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1002\/ajmg.c.31935","article-title":"Patients with Ehlers\u2013Danlos syndrome on the diagnostic odyssey: Rethinking complexity and difficulty as a hero\u2019s journey","volume":"187","author":"Halverson","year":"2021","journal-title":"Am. J. Med. Genet. Part C Semin. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.mcna.2019.08.002","article-title":"Symptomatic Joint Hypermobility: The Hypermobile Type of Ehlers-Danlos Syndrome and the Hypermobility Spectrum Disorders","volume":"103","author":"Tinkle","year":"2019","journal-title":"Med. Clin. N. Am."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1002\/dvdy.220","article-title":"Hypermobile Ehlers-Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes","volume":"250","author":"Gensemer","year":"2021","journal-title":"Dev. Dyn."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Torre, Y.S., Wadeea, R., Rosas, V., and Herbst, K.L. (2018). Lipedema: Friend and foe. Horm. Mol. Biol. Clin. Investig., 33.","DOI":"10.1515\/hmbci-2017-0076"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1177\/02683555211015887","article-title":"Standard of care for lipedema in the United States","volume":"36","author":"Herbst","year":"2021","journal-title":"Phlebology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/ijo.2016.205","article-title":"Differentiating lipedema and Dercum\u2019s disease","volume":"41","author":"Beltran","year":"2017","journal-title":"Int. J. Obes."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1177\/1358863X231202769","article-title":"National survey of patient symptoms and therapies among 707 women with a lipedema phenotype in the United States","volume":"29","author":"Aday","year":"2024","journal-title":"Vasc. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e5436","DOI":"10.1097\/GOX.0000000000005436","article-title":"Lipedema Reduction Surgery Improves Pain, Mobility, Physical Function, and Quality of Life: Case Series Report","volume":"11","author":"Wright","year":"2023","journal-title":"Plast. Reconstr. Surg. Glob. Open"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11957","DOI":"10.3390\/cimb46110710","article-title":"Identification of Specific microRNAs in Adipose Tissue Affected by Lipedema","volume":"46","author":"Cione","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e135109","DOI":"10.1172\/jci.insight.135109","article-title":"Platelet factor 4 is a biomarker for lymphatic-promoted disorders","volume":"5","author":"Ma","year":"2020","journal-title":"JCI Insight"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2931","DOI":"10.2147\/JPR.S315736","article-title":"Common and Contrasting Characteristics of the Chronic Soft-Tissue Pain Conditions Fibromyalgia and Lipedema","volume":"14","author":"Angst","year":"2021","journal-title":"J. Pain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1177\/02683555251321042","article-title":"Lipedema awareness in fibromyalgia","volume":"40","author":"Ay","year":"2025","journal-title":"Phlebology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1089\/lrb.2023.0038","article-title":"Prevalence of Fibromyalgia Syndrome in Women with Lipedema and Its Effect on Anxiety, Depression, and Quality of Life","volume":"22","author":"Erden","year":"2024","journal-title":"Lymphat. Res. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Patton, L., Ricolfi, L., Bortolon, M., Gabriele, G., Zolesio, P., Cione, E., and Cannataro, R. (2024). Observational Study on a Large Italian Population with Lipedema: Biochemical and Hormonal Profile, Anatomical and Clinical Evaluation, Self-Reported History. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25031599"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.jss.2020.03.055","article-title":"Adipose Tissue Hypertrophy, An Aberrant Biochemical Profile and Distinct Gene Expression in Lipedema","volume":"253","author":"Felmerer","year":"2020","journal-title":"J. Surg. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2726","DOI":"10.1111\/jocd.16314","article-title":"Gluteal femoral subcutaneous and dermal adipose tissue in female","volume":"23","author":"Conti","year":"2024","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e48","DOI":"10.4081\/ejh.2010.e48","article-title":"Subcutaneous adipose tissue classification","volume":"54","author":"Sbarbati","year":"2010","journal-title":"Eur. J. Histochem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Chiarelli, N., Ritelli, M., Zoppi, N., and Colombi, M. (2019). Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers\u2014Danlos Syndromes. Genes, 10.","DOI":"10.3390\/genes10080609"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Veronese, S., Zoccante, L., Smania, N., and Sbarbati, A. (2023). Stretch marks: A visible expression of connective\u2019s involvement in autism spectrum disorders. Front. Psychiatry, 14.","DOI":"10.3389\/fpsyt.2023.1155854"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/20\/7195\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T10:39:51Z","timestamp":1760524791000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/20\/7195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,12]]},"references-count":30,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["jcm14207195"],"URL":"https:\/\/doi.org\/10.3390\/jcm14207195","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,12]]}}}