The EDS GP toolkit is provided by The Ehlers-Danlos Support UK

References

Please see below a list of the references used in the toolkit. The references have been broken down and numbered by section and are hyperlinked from the main text. You can use these links below to quickly navigate to a specific section.

Key pointsWhen to suspect EDS | Diagnosing hEDS in primary care | Emerging major associations | Indication for referral in EDS

Key Points

  1. Miklovic T, Sieg VC. Ehlers Danlos Syndrome. Treasure Island (FL): StatPearls Publishing; 2021.
  2. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers–Danlos syndromes. American journal of medical genetics. Part C, Seminars in medical genetics. 2017; 175(1):8-26. Available here.
  3. Tinkle B, Castori M, Berglund B, et al. Hypermobile Ehlers–Danlos syndrome (a.k.a. Ehlers–Danlos syndrome Type III and Ehlers–Danlos syndrome hypermobility type): Clinical description and natural history. American journal of medical genetics. Part C, Seminars in medical genetics. 2017;175(1):48–69. Available here.
  4. Gazit Y, Jacob G, Grahame R. Ehlers-Danlos Syndrome-Hypermobility Type: A Much Neglected Multisystemic Disorder. Rambam Maimonides Medical Journal. 2016;7(4): e0034. Available here.
  5. Song B, Yeh P, Harrell J. Systemic manifestations of Ehlers-Danlos syndrome. Proceedings (Baylor University. Medical Centre). 2020;34(1):49-53. Available here.
  6. Tinkle B, Malfait F, Francomano C, Byers P, et al. The Ehlers-Danlos Syndromes: Reports from the International Consortium on the Ehlers-Danlos Syndromes. American journal of medical genetics. Part C, Seminars in medical genetics. 2017;175(1):1-245.
  7. Berengere AR, Schwitzguebel A, Valerio, F, et al. Are patients with hypermobile Ehlers–Danlos syndrome or hypermobility spectrum disorder so different? Rheumatology International.2021;1785–1794(41) Available here.
  8. Demmler J, Atkinson M, Reinhold E, et al. Diagnosed prevalence of Ehlers-Danlos syndrome and hypermobility spectrum disorder in Wales, UK: a national electronic cohort study and case–control comparison. BMJ Open. 2019;9(11): e031365. Available here.
  9. Castori M, Dordoni C, Valiante M, et al. Nosology and inheritance pattern(s) of joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type: A study of intrafamilial and interfamilial variability in 23 Italian pedigrees. American Journal of Medical Genetics Part A. 2014;164A(12):3010–3020.
  10. Collins H. If you can’t connect the issues, think connective tissues” Connecting the Dots Between Ehlers-Danlos Syndrome and Related Conditions. Annual Conference. 2014
  11. Castori M, Celletti C, Camerota F. Ehlers–Danlos syndrome hypermobility type: a possible unifying concept for various functional somatic syndromes. Rheumatology International. 2013; 33(3): 819-21. Available here.
  12. Reinhold E. MUS or DEN. 2017 Editor’s Choice Letter. British Journal of General Practice British Journal of General Practice 2017; 67(657): 156. Available here.
  13. Hakim J. Rheumatology. 2012; 51(3): iii2 (I11). Available here.
  14. Engelbert R, Jull-Kristensen B, Pacey V, et al. The Evidence-Based Rationale for Physical Therapy Treatment of Children, Adolescents, and Adults Diagnosed with Joint Hypermobility Syndrome/Hypermobile Ehlers Danlos Syndrome. American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 2017;175(1):158–167.
  15. Bregant T, Spevak M. Ehlers–Danlos Syndrome: Not Just Joint Hypermobility. Case Reports in Medicine. 2018;5053825(2018): 3. Available here.
  16. Levy H, Adam M, Ardinger H, et al. Hypermobile Ehlers-Danlos Syndrome In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available here.
  17. Sutcliff J. Gastrointestinal problems in children with Ehlers-Danlos syndrome – The Ehlers-Danlos Support UK. [Internet]. EDS UK; [reviewed 2016 March 01]. Available here.
  18. de Kort LM, Verhulst J, Engelbert R, Uiterwaal C, et al. Lower urinary tract dysfunction in children with generalized hypermobility of joints. J Urol. 2003;170(5):1971–1974.
  19. Adib N, Davies K, Grahame R, et al. Joint hypermobility syndrome in childhood. A not so benign multisystem disorder? Rheumatology. 2005;44(6):744–750.
  20. Reilly D, Chase J, Hutson J, et al. Connective tissue disorder—A new subgroup of boys with slow transit constipation? J Pediatr Surg. 2008;43(6):1111–1114.
  21. Pacey V, Adams R, Tofts L, et al. Joint hypermobility syndrome subclassification in paediatrics: A factor analytic approach. Arch Dis Child.2015;100(1):8–13.
  22. Kovacic K, Chelimsky T, Sood M, et al. Joint hypermobility: A common association with complex functional gastrointestinal disorders. J Pediatr. 2014;165(5):973–978. Available here.
  23. Hasija R, Khubchandani R, Shenoi S. Joint hypermobility in Indian children. Clin Exp Rheumatol. 2008;26(1):146–150.
  24. Fikree A, Chelimsky G, Collins H, Kovacic K, et al. Gastrointestinal involvement in the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):181–7.
  25. Alomari M, Hitawala A, Chadalavada P, et al. Prevalence and Predictors of Gastrointestinal Dysmotility in Patients with Hypermobile Ehlers-Danlos Syndrome: A Tertiary Care Center Experience. Cureus. 2020;12(4): e7881. Available here.
  26. Murray K, Woo P. Benign joint hypermobility in childhood. Rheumatology. 2001;40(5):489–491. Available here.
  27. Glans M, Thelin N, Humble M, Elwin M, et al. Association between adult attention-deficit hyperactivity disorder and generalised joint hypermobility: A cross-sectional case control comparison. Journal of Psychiatric Research. 2021;143:334-340. Available here.
  28. Ghibellini G, Brancati F, Castori M. Neurodevelopmental attributes of joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type: Update and perspectives. Am J Med Genet C Semin Med Genet. 2015;169C(1):107-16. Available here.
  29. Savage G, Csecs J, Davies G, et al. #3085 Relationship between variant connective tissue (hypermobility) and autism sensory processing: externally oriented thinking as a mediator. Journal of Neurology, Neurosurgery & Psychiatry. 2021;92:A7-A8.
  30. Casanova E, Baeza-Velasco C, Buchanan C, Casanova M. The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders. J Pers Med. 2020;10(4):260. Available here.
  31. Skalny A V, Skalny A A, Lobanova Y, et al. Serum amino acid spectrum in children with autism spectrum disorder (ASD). Research in Autism Spectrum Disorders. 2020;77:101605. Available here.
  32. Gaisi T, Giunta C, Bratton D, et al. Obstructive sleep apnoea and quality of life in Ehlers-Danlos syndrome: a parallel cohort study. 2017;72(8):729-735. Available here.
  33. Domany K, Hatragool S, Smith D, et al. Sleep Disorders and Their Management in Children With Ehlers-Danlos Syndrome Referred to Sleep Clinics. J Clin Sleep Med. 2018;14(4):623-629.
  34. Stöberl A, Gaisl T, Giunta C, et al. Obstructive Sleep Apnoea in Children and Adolescents with Ehlers-Danlos Syndrome. Respiration. 2019;97(4):284-291. Available here.
  35. Moss C, Fernandez-Mendoza J, Schubart J, et al. 0924 Nighttime Sleep and Daytime Functioning in Ehlers-Danlos Syndrome: A Cohort Study of Syndrome Subtypes. Sleep. 2018;41(1):A343-A343. Available here.
  36. Baeza-Velasco C, Bossche T, Grossin D, Hamonet C. Difficulty eating and significant weight loss in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.  Eat Weight Disord. 2016;21(2):175-83. Available here.
  37. Cutts R, Meyer R, Thapar N, et al. Gastrointestinal food allergies in children with Ehlers Danlos type 3 syndrome. The Journal of Allergy and Clinical Immunology. 2012;129(2):AB34. Available here.
  38. Baeza-Velasco C, Lorente S, Tasa-Vinyals E, et al. Gastrointestinal and eating problems in women with Ehlers–Danlos syndromes. Eat Weight Disord. 2021;26(8):2645-2656. Available here.
  39. Hunter A, Morgan A, Bird H. A survey of Ehlers-Danlos syndrome: Hearing, voice, speech and swallowing difficulties. Is there an underlying relationship? Br J Rheumatol1998;37(7):803–804. Available here.
  40. Hunter A. Speech, language, voice and swallowing in the Ehlers-Danlos syndromes – Chewing and swallowing section. 2017. Available here. (accessed 25/11/2021)
  41. Bulbena A, Baeza-Velasco C, Bulbena-Cabré, et al. Psychiatric and psychological aspects in the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):237–245. Available here.
  42. Collins H. Ehlers-Danlos Syndrome’s Effect on Gastrointestinal Function. 2013. Available here.
  43. Collins H. Diet and Supplementation Guide for EDS. 2015. Available here.
  44. Csecs J, Dowell N, Savage G, et al. Variant connective tissue (joint hypermobility) and dysautonomia are associated with multimorbidity at the intersection between physical and psychological health. Am J Med Genet C Semin Med Genet.2021;187(4):500-509. Available here.
  45. Eccles J, Beacher F, Gray M, et al. Brain structure and joint hypermobility: relevance to the expression of psychiatric symptoms. Br J Psychiatry. 2012;200(6):508-509. Available here.
  46. Singh H, McKay M, Baldwin J, et al. Beighton scores and cut-offs across the lifespan: cross-sectional study of an Australian population. Rheumatology. 2017;56(11):1857–1864. Available here.
  47. Castori M, Sperduti I, Celletti C, et al. Symptom and joint mobility progression in the joint hypermobility syndrome (Ehlers–Danlos syndrome, hypermobility type). Clin Exp Rheumatol. 2011;29(6):998– 1005.
  48. Hakim A, O’Callaghan C, De Wandele I, et al. Cardiovascular autonomic dysfunction in Ehlers–Danlos syndrome—Hypermobile type. Am J Med Genet C Semin Med Genet. 2017;175(1):168–174. Available here.
  49. Mathias C, Owens A, Iodice V, et al. Dysautonomia in the Ehlers–Danlos syndromes and hypermobility spectrum disorders—With a focus on the postural tachycardia syndrome. Am J Med Genet C Semin Med Genet. 2021;187(4):510-519. Available here.
  50. Seneviratne S, Maitland A, Afrin L. Mast cell disorders in Ehlers–Danlos syndrome. Am J Med Genet C Semin Med Genet. 2017;175:226–36
  51. Afrin L. Some cases of hypermobile Ehlers–Danlos syndrome may be rooted in mast cell activation syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2021;187(4):466-472. Available here.
  52. Brock I, Prendergast W, Maitland A. Mast cell activation disease and immunoglobulin deficiency in patients with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorder. Am J Genet C Semin Med Genet. 2021;187(4):473-481. Available here.
  53. Fikree A, Aktar R, Grahame R, et al. Functional gastrointestinal disorders are associated with the joint hypermobility syndrome in secondary care: A case-control study. Neurogastroenterol Moti. 2015;27(4):569–579. Available here.
  54. Castori M. Tinkle B, Levy H, et al. A Framework for the Classification of Joint Hypermobility and Related Conditions. Am J Med Genet Part C Semin Med Genet. 2017;175(1):148–157. Available here.
  55. Beckers A, Keszthelyi D, Fikree A, et al. Gastrointestinal disorders in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type: A review for the gastroenterologist. Neurogastroenterol Motil. 2017;29(8):e13013. Available here.

When to suspect EDS

  1. Rombaut L, Malfait F, Cools A, et al. Musculoskeletal complaints, physical activity and health-related quality of life among patients with the Ehlers–Danlos syndrome hypermobility type. Disabil Rehabil.2010;32(16):1339–1345. Available here.
  2. Castori M, Dordoni C, Valiante M, et al. Nosology and inheritance pattern(s) of joint hypermobility syndrome and Ehlers–Danlos syndrome, hypermobility type: A study of intrafamilial and interfamilial variability in 23 Italian pedigrees. Am J Med Genet A. 2014;164A(12):3010–3020. Available here.
  3. Scheper M, Juul-Kristensen B, Rombaut L, et al. Disability in adolescents and adults diagnosed with hypermobility related disorders: A meta-analysis. Arch Phys Med Rehabil. 2016;97(12):2174–2187. Available here.
  4. Juul-Kristensen B, Schmedling K, Rombaut L, et al. Measurement properties of clinical assessment methods for classifying generalized joint hypermobility—A systematic review. Am J Med Genet C Semin Med Genet. 2017;175(1):116-147. Available here.
  5. Tinkle B, Castori M, Berglund B, et al. Hypermobile Ehlers–Danlos syndrome (a.k.a. Ehlers–Danlos syndrome Type III and Ehlers–Danlos syndrome hypermobility type): Clinical description and natural history. Am J Med Genet C Semin Med Genet. 2017;175(1):48–69. Available here.
  6. Alomari M, Hitawala A, Chadalavada P et al. Prevalence and Predictors of Gastrointestinal Dysmotility in Patients with Hypermobile Ehlers-Danlos Syndrome: A Tertiary Care Center Experience. 2020;12(4):e7881. Available here.
  7. Fikree A, Aktar A, Grahame R, et al. Functional gastrointestinal disorders are associated with the joint hypermobility syndrome in secondary care: A case-control study. Neurogastroenterol Motil2015;27(4):569–579.
  8. Cheung I, & Vedas P. A New Disease Cluster: Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome, and Ehlers-Danlos Syndrome. Journal of Allergy and Clinical Immunology. 2015;135(2):AB65. Available here.
  9. Seneviratne S L, Maitland A, Afrin L. Mast cell disorders in Ehlers–Danlos syndrome. Am J Med Genet C Semin Med Genet. 2017;175:226–36. Available here.
  10. Afrin L B. Some cases of hypermobile Ehlers–Danlos syndrome may be rooted in mast cell activation syndrome. Am J Med Genet C Semin Med Genet. 2021;187(4):466-472. Available here.
  11. Brock I, Prendergast W, Maitland A. Mast cell activation disease and immunoglobulin deficiency in patients with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorder. Am J Med Genet C Semin Med Genet. 2021;187(4):473-481. Available here.
  12. Hakim A, O’Callaghan C, De Wandele I, et al. Cardiovascular autonomic dysfunction in Ehlers–Danlos syndrome—Hypermobile type. Am J Med Genet C Semin Med Genet. 2017;175(1):168–74. Available here.
  13. De Wandele I, Rombaut L, Backer T, et al. Orthostatic intolerance and fatigue in the hypermobility type of 14 Ehlers-Danlos Syndrome. 2016;55(8)8:1412-1420. Available here.
  14. Hakim A, Wandele I, O’Callaghan C, et al. Chronic fatigue in Ehlers–Danlos syndrome—Hypermobile type. Am J Med Genet Part C Semin Med Genet. 2017;175(1):175–80. Available here.
  15. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet.2017;175(1):8-26. Available here.
  16. Levy H. Hypermobile Ehlers-Danlos Syndrome. Seattle (WA): University of Washington; 2004.
  17. Donohue P, Chavirmootoo S, Ramakrishnan S. AB1411-HPR Hypermobility and fibromyalgia: coexistence or mistaken identity? Annals of the Rheumatic Diseases.2018;77:1840-1841.
  18. Lam C Y, Palsson O S, Whitehead W E, et al. Rome IV Functional Gastrointestinal Disorders and Health Impairment in Subjects With Hypermobility Spectrum Disorders or Hypermobile Ehlers-Danlos Syndrome. Clin Gastroenterol Hepatol. 2021 Feb;19(2):277-287.e3. Available here.
  19. Sulli A, Talarico R, Sciré C, et al. Ehlers-Danlos syndromes: state of the art on clinical practice guidelines. RMD Open.2018;4(1):e000790. Available here.
  20. Beckers A B, Keszthelyi D, Fikree A, et al. Gastrointestinal disorders in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type: a review for the gastroenterologist. Neurogastroenterol Motil. 2017;29(8):e13013.

Diagnosing hEDS in primary care

  1. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet2017;175(1):8-26. Available here.
  2. Castori M, Tinkle B, Levy H, et al. A Framework for the Classification of Joint Hypermobility and Related Conditions. Am J Med Genet Part C Semin Med Genet. 2017;175(1):148–157. Available here.
  3. Atwell K, Michael W, Dubey J, et al. Diagnosis and Management of Hypermobility Spectrum Disorders in Primary Care. The Journal of the American Board of Family Medicine Jul 2021;34(4);838-848. Available here.
  4. Demmler JC, Atkinson MD, Reinhold EJ, et al. Diagnosed prevalence of Ehlers-Danlos syndrome and hypermobility spectrum disorder in Wales, UK: a national electronic cohort study and case–control comparison. BMJ Journals 2019;9:e031365. Available here.
  5. Grahame R, Hakim A, Tofts L et al. Treatment and prognosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder [internet] com [14/12/2021). Available here.
  6. ICD- 10 Coded. ICD Code for Hypermobile Ehlers-Danlos Syndrome [14/12/21].

Emerging major associations

  1. Hakim A, O’Callaghan C, De Wandele I, et al. Cardiovascular autonomic dysfunction in Ehlers–Danlos syndrome—Hypermobile type. Am J Med Genet C Semin Med Genet. 2017;175(1):168–74. Available here.
  2. Celletti C, Camerota F, Castori M, et al. Orthostatic intolerance and postural orthostatic tachycardia syndrome in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type: Neurovegetative dysregulation or autonomic failure? BioMed Res Int. 2017;2017:9161865. Available here.
  3. Tinkle B, Castori M, Berglund B, et al. Hypermobile Ehlers–Danlos syndrome (a.k.a. Ehlers–Danlos syndrome Type III and Ehlers–Danlos syndrome hypermobility type): Clinical description and natural history. Am J Med Genet C Semin Med Genet. 2017;175(1):48–69. Available here.
  4. Mathias C, Owens A, Iodice V, et al. Dysautonomia in the Ehlers–Danlos syndromes and hypermobility spectrum disorders—With a focus on the postural tachycardia syndrome. Am J Med Genet C Semin Med Genet. 2021;187(4):510-519. Available here.
  5. De Wandele I, Rombaut L, Backer T, et al. Orthostatic intolerance and fatigue in the hypermobility type of Ehlers-Danlos Syndrome. Rheumatology. 2016;55(8):1412–1420. Available here.
  6. Kanjwal K, Saeed B, Karabin B, et al. Comparative clinical profile of postural orthostatic tachycardia patients with and without joint hypermobility syndrome. Indian Pacing Electrophysiol J. 2010;10(4):173-178.
  7. Zaldumbide-Alcocer L, Jiménez-Ruiz, & Estaňol-Vidal B. BS05. Orthostatic hypotension and syncope in patients with ehlers-danlos syndrome. Clinical Neurophysiology. 2018;129(1):e214-e215. Available here.
  8. Rowe P, Barron D, Calkins H, et al. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers Danlos syndrome. J Pediatr. 1999:135(4):494–499. Available here.
  9. Hakim AJ & Grahame R. Non-musculoskeletal symptoms in Joint Hypermobility syndrome: Indirect evidence for autonomic dysfunction. 2004;43(9):1194–1195. Available here.
  10. Mathias C, Low D, Iodice V, et al. Postural tachycardia syndrome—Current experience and concepts. Nat Rev Neurol. 2011;8(1):22–34. Available here.
  11. De Wandele I, Calders P, Peersman W, et al. Autonomic symptom burden in the hypermobility type of Ehlers–Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism. 2014;44(3):353-361. Available here.
  12. Freeman R, Wieling W, Axelrod F, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011;21(2):69-72. Available here.
  13. Afrin LB. Some cases of hypermobile Ehlers–Danlos syndrome may be rooted in mast cell activation syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2021:187(4):466 – 472. Available here.

Indication for referral in EDS

  1. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8-26. Available here. PMID: 28306229.
  2. Byers P, Belmont J, Black J, et al. Diagnosis, natural history, and management in vascular Ehlers–Danlos syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):40-47.
  3. Ehlers-Danlos syndrome. Section: Getting medical advice (Accessed 22/12/2021) Available here.