THE CRITICAL ROLE OF EARLY DIAGNOSIS IN EHLERS-DANLOS SYNDROME: A COMPREHENSIVE REVIEW
Abstract
Introduction and purpose: Ehlers- Danlos syndrome (EDS) is a group of genetic connective tissue disorders with 13 distinguished subtypes. Approximately, 1 in 5000 people receive a diagnosis; however, this number is likely underestimated due to frequent misdiagnosis and delayed identification. The aim of this literature review is to provide a comprehensive overview of EDS, with focus on diagnostic process, common comorbidities and consequences of delayed diagnosis.
State of knowledge: Among the 13 recognized EDS subtypes hypermobile EDS (hEDS), classical EDS (cEDS), and vascular EDS (vEDS) are the most prevalent. Most subtypes can be confirmed through genetic testing, however hEDS lacks a known genetic marker and is diagnosed solely on clinical criteria. This prolongs the diagnostic process-frequently exceeding a decade- leading to psychological distress and increased risk of complications in surgery or pregnancy. Comorbidities such as POTS, MCAS, and gastrointestinal dysmotility are prevalent and further complicate clinical management.
Conclusion: Early detection and accurate diagnosis are crucial for improving patient outcomes and quality of life. It reduces the risk of complications, enables tailored treatment plans and helps with psychological distress of medical uncertainty. Healthcare professionals must have higher awareness about EDS in order to provide integrated, comprehensive care.
References
Basem, J. I., Lin, T., & Mehta, N. D. (2022). A comprehensive review: Chronic pain sequelae in the presence of Ehlers–Danlos syndrome. Current Pain and Headache Reports, 26(12), 871–876. https://doi.org/10.1007/s11916-022-01093-z
Benrashid, E., & Ohman, J. W. (2020). Current management of the vascular subtype of Ehlers–Danlos syndrome. Current Opinion in Cardiology. Advance online publication. https://doi.org/10.1097/hco.0000000000000797
Caliogna, L., Guerrieri, V., Annunziata, S., et al. (2021). Biomarkers for Ehlers–Danlos syndromes: There is a role? International Journal of Molecular Sciences, 22(18), 10149. https://doi.org/10.3390/ijms221810149
Colman, M., Castori, M., Micale, L., et al. (2022). Atypical variants in COL1A1 and COL3A1 associated with classical and vascular Ehlers–Danlos syndrome overlap phenotypes: Expanding the clinical phenotype based on additional case reports. Clinical and Experimental Rheumatology, 40(Suppl. 134, 5), 46–62. https://doi.org/10.55563/clinexprheumatol/kzkq6y
Demirdas, S., Lechner, R., et al. (2024). Vascular Ehlers–Danlos syndrome: A comprehensive natural history study in a Dutch national cohort of 142 patients. Circulation: Genomic and Precision Medicine, 17(3). https://doi.org/10.1161/circgen.122.003978
Fuqua, A. A., Worden, J. A., Bonsu, J. M., Ross, B. J., & Premkumar, A. (2024). Outcomes of total knee arthroplasty in patients who have Ehlers–Danlos syndrome: A matched cohort study. The Journal of Arthroplasty, 39(11), 2755–2760. https://doi.org/10.1016/j.arth.2024.05.069
Gagnon, H., Lunde, C. E., Wu, Z., Novais, E. N., Borsook, D., & Sieberg, C. B. (2023). Exploring comorbidities in adolescent and young adults with hypermobile Ehlers–Danlos syndrome with and without a surgical history: A preliminary investigation. Children, 10(9), 1562. https://doi.org/10.3390/children10091562
Gensemer, C., Burks, R., Kautz, S., Judge, D. P., Lavallee, M., & Norris, R. A. (2020). Hypermobile Ehlers–Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes. Developmental Dynamics, 250(3), 318–344. https://doi.org/10.1002/dvdy.220
Gensemer, C., Daylor, V., Nix, J., Norris, R. A., & Patel, S. (2024). Co-occurrence of tethered cord syndrome and cervical spine instability in hypermobile Ehlers–Danlos syndrome. Frontiers in Neurology, 15. https://doi.org/10.3389/fneur.2024.1441866
Haem, T., Benson, B., Dernoncourt, A., Gondry, J., Schmidt, J., & Foulon, A. (2024). Vascular Ehlers–Danlos syndrome and pregnancy: A systematic review. BJOG: An International Journal of Obstetrics & Gynaecology. Advance online publication. https://doi.org/10.1111/1471-0528.17893
Halverson, C. M. E., Cao, S., Perkins, S. M., & Francomano, C. A. (2023). Comorbidity, misdiagnoses, and the diagnostic odyssey in patients with hypermobile Ehlers–Danlos syndrome. Genetics in Medicine Open, 1(1), 100812. https://doi.org/10.1016/j.gimo.2023.100812
Islam, M., Chang, C., & Gershwin, M. E. (2021). Ehlers–Danlos syndrome: Immunologic contrasts and connective tissue comparisons. Journal of Translational Autoimmunity, 4, 100077. https://doi.org/10.1016/j.jtauto.2020.100077
Jayarajan, S. N., Downing, B. D., Sanchez, L. A., & Jim, J. (2020). Trends of vascular surgery procedures in Marfan syndrome and Ehlers–Danlos syndrome. Vascular, 28(6), 834–841. https://doi.org/10.1177/1708538120925597
Johansen, H., Velvin, G., Fugl-Meyer, K., & Lidal, I. B. (2021). Adults with Loeys-Dietz syndrome and vascular Ehlers–Danlos syndrome: A cross-sectional study of life satisfaction. Journal of Rehabilitation Medicine. Advance online publication. https://doi.org/10.2340/jrm.v53.572
Kang, J., Hanif, M., Mirza, E., & Jaleel, S. (2020). Ehlers–Danlos syndrome in pregnancy: A review. European Journal of Obstetrics & Gynecology and Reproductive Biology, 255, 118–123. https://doi.org/10.1016/j.ejogrb.2020.10.033
Knight, D. R. T., Confiado, S. M., Bruno, K. A., et al. (2022). Establishing an Ehlers–Danlos syndrome clinic: Lessons learned. SN Comprehensive Clinical Medicine, 4(1), 138. https://doi.org/10.1007/s42399-022-01218-w
Kohn, A., & Chang, C. (2019). The relationship between hypermobile Ehlers–Danlos syndrome (hEDS), postural orthostatic tachycardia syndrome (POTS), and mast cell activation syndrome (MCAS). Clinical Reviews in Allergy & Immunology, 58(3). https://doi.org/10.1007/s12016-019-08755-8
Malfait, F., Castori, M., Francomano, C. A., Giunta, C., Kosho, T., & Byers, P. H. (2020). The Ehlers–Danlos syndromes. Nature Reviews Disease Primers, 6(1). https://doi.org/10.1038/s41572-020-0194-9
Miklovic, T., & Sieg, V. C. (2023). Ehlers–Danlos syndrome. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK549814/
Neto, R., Pereira, I. A., Sztajnbok, F. R., & Azevedo, V. F. (2024). Unraveling the genetic collagen connection: Clinical and therapeutic insights on genetic connective tissue disorders. Advances in Rheumatology, 64(1). https://doi.org/10.1186/s42358-024-00373-z
Reina-Gutiérrez, S., Caty, G., Torres-Costoso, A., Pitance, L., Manicourt, D. H., & Reychler, G. (2023). Assessment of functional respiratory complaints and related factors in people with hypermobile Ehlers–Danlos syndrome: Cross-sectional study. Respiratory Medicine and Research, 83, 101017. https://doi.org/10.1016/j.resmer.2023.101017
Ritelli, M., Venturini, M., Cinquina, V., Chiarelli, N., & Colombi, M. (2020). Multisystemic manifestations in a cohort of 75 classical Ehlers–Danlos syndrome patients: Natural history and nosological perspectives. Orphanet Journal of Rare Diseases, 15(1). https://doi.org/10.1186/s13023-020-01470-0
Rocchetti, M., Bassotti, A., Corradi, J., et al. (2021). Is the pain just physical? The role of psychological distress, quality of life, and autistic traits in Ehlers–Danlos syndrome: An internet-based survey in Italy. Healthcare, 9(11), 1472. https://doi.org/10.3390/healthcare9111472
Song, B., Yeh, P., Nguyen, D., Ikpeama, U., Epstein, M., & Harrell, J. (2020). Ehlers–Danlos syndrome: An analysis of the current treatment options. Pain Physician, 23(4), 429–438. https://pubmed.ncbi.nlm.nih.gov/32709178/
Thwaites, P. A., Gibson, P. R., & Burgell, R. E. (2022). Hypermobile Ehlers–Danlos syndrome and disorders of the gastrointestinal tract: What the gastroenterologist needs to know. Journal of Gastroenterology and Hepatology, 37(9). https://doi.org/10.1111/jgh.15927
Tofts, L. J., Simmonds, J., Schwartz, S. B., et al. (2023). Pediatric joint hypermobility: A diagnostic framework and narrative review. Orphanet Journal of Rare Diseases, 18(1). https://doi.org/10.1186/s13023-023-02717-2
Udugampolage, N., Taurino, J., Bassotti, A., et al. (2025). Exploring fatigue in Marfan and hypermobile Ehlers–Danlos syndromes: An analytical cross-sectional study in two Italian healthcare centres. BMJ Open, 15(1), e087298. https://doi.org/10.1136/bmjopen-2024-087298
van Dijk, F. S., Ghali, N., & Chandratheva, A. (2023). Ehlers–Danlos syndromes: Importance of defining the type. Practical Neurology, 24(2), pn-2023-003703. https://doi.org/10.1136/pn-2023-003703
Yekkalam, N., Sipilä, K., Novo, M., Reissmann, D., Hanisch, M., & Oelerich, O. (2024). Oral health–related quality of life among women with temporomandibular disorders and hypermobile Ehlers–Danlos syndrome or hypermobility spectrum disorder. The Journal of the American Dental Association. Advance online publication. https://doi.org/10.1016/j.adaj.2024.08.013
De Paepe, A., Malfait, F., & Wenstrup, R. J. (2018). Classic Ehlers–Danlos syndrome. In GeneReviews. University of Washington, Seattle. https://www.ncbi.nlm.nih.gov/books/NBK1244/
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