The Ehlers—Danlos Syndrome

  • Fransiska Malfait
  • Anne De Paepe


The Ehlers—Danlos syndrome (EDS) comprises a clinically heterogeneous group of connective tissue diseases, the principal features of which result from generalized but variable tissue fragility. EDS is a congenital disorder, but the age of onset of symptoms varies from birth to the fifth or even sixth decade of life. The major characteristics of EDS are, to a varying degree, present in all EDS subtypes. These include skin hyperextensibility (see Fig. 47.1), poor wound healing causing wide, thin, atrophic scars (“cigarette paper scars”) (see Fig. 47.2), easy bruising, joint hypermobil-ity (see Fig. 47.3) with recurrent dislocations, and generalized tissue fragility. During childhood, patients may present to the pediatrician with complaints as diverse as hypotonia or delayed neuromotor development, easy bruising, or abnormal wound healing. Later in life, patients may present to the hematologist due to unexplained bleeding diathesis; to the rheuma-tologist with complaints of joint hyperlaxity and arth-ralgias; to the orthopedic surgeon due to recurrent dislocations; or to the (vascular) surgeon with arterial or bowel rupture.


Chronic Fatigue Syndrome Collagen Fibril Preimplantation Genetic Diagnosis Mitral Valve Prolapse Postural Orthostatic Tachycardia Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ameye L, Young MF. Mice deficient in small leucine-rich proteogly-cans: novel in vivo models for osteoporosis, osteoarthritis, Ehlers— Danlos syndrome, muscular dystrophy, and corneal diseases. Glycobiology 2002;12:107R–16RPubMedCrossRefGoogle Scholar
  2. Arendt-Nielsen L, Kaalund S, Hogsaa B, et al The response to local anaesthetics (EMLA-cream) as a clinical test to diagnose between hypermo-bility and Ehlers Danlos type III syndrome. Scand J Rheumatol. 1991;20:190–5PubMedCrossRefGoogle Scholar
  3. Beighton P. The Ehlers–Danlos syndrome. London: William Heinemann Medical Books; 1970Google Scholar
  4. Beighton P, De Paepe A, Danks D, et al International nosology of heritable disorders of connective tissue, Berlin, 1986. Am J Med Genet. 1988;29:581–94PubMedCrossRefGoogle Scholar
  5. Beighton P, De Paepe A, Steinmann B, et al Ehlers—Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers—Danlos National Foundation (USA) and Ehlers—Danlos Support Group (UK). Am J Med Genet. 1998;77:31–7PubMedCrossRefGoogle Scholar
  6. Bristow J, Carey W, Egging D, et al Tenascin-X, collagen, elastin, and the Ehlers–Danlos syndrome. Am J Med Genet C Semin Med Genet. 2005;139:24–30Google Scholar
  7. Bulbena A, Duro JC, Porta M, et al Anxiety disorders in the joint hyper-mobility syndrome. Psychiatry Res. 1993;46:59–68PubMedCrossRefGoogle Scholar
  8. Burch GH, Gong Y, Liu W, et al Tenascin-X deficiency is associated with Ehlers—Danlos syndrome. Nat Genet. 1997;17:104–8PubMedCrossRefGoogle Scholar
  9. Byers P. Disorders of collagen biosynthesis and structure. In: Scriver CR, Beaudet AR, Sly WS and Valle D, editors. The metabolic and molecular bases of inherited disease. 2nd ed. Edinbugrh: Churchill Livingstone; 2001. p. 1065–81Google Scholar
  10. Cabral WA, Makareeva E, Colige A, et al Mutations near amino end of alpha 1(I) collagen cause combined OI/EDS by interference with N-propeptide processing. J Biol Chem. 2005;280:19259–69PubMedCrossRefGoogle Scholar
  11. Cikrit DF, Miles JH, Silver D. Spontaneous arterial perforation: the Ehlers—Danlos specter. J Vasc Surg. 1987;5:248–55PubMedGoogle Scholar
  12. De Paepe A, Malfait F. Bleeding and bruising in patients with Ehlers— Danlos syndrome and other collagen vascular disorders. Br J Haematol. 2004;127:491–500PubMedCrossRefGoogle Scholar
  13. Dolan AL, Mishra MB, Chambers JB, et al Clinical and echocardio-graphic survey of the Ehlers—Danlos syndrome. Br J Rheumatol. 1997;36:459–62PubMedCrossRefGoogle Scholar
  14. Ferrell WR, Tennant N, Sturrock RD, et al Amelioration of symptoms by enhancement of proprioception in patients with joint hypermo-bility syndrome. Arthritis Rheum. 2004;50:3323–8PubMedCrossRefGoogle Scholar
  15. Freeman RK, Swegle J, Sise MJ. The surgical complications of Ehlers— Danlos syndrome. Am Surg. 1996;62:869–73PubMedGoogle Scholar
  16. Gazit Y, Nahir AM, Grahame R, et al Dysautonomia in the joint hyper-mobility syndrome. Am J Med. 2003;115:33–40PubMedCrossRefGoogle Scholar
  17. Giunta C, Elcioglu NH, Albrecht B, et al Spondylocheiro dysplastic form of the Ehlers—Danlos syndrome — an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet. 2008;82:1290–305PubMedCrossRefGoogle Scholar
  18. Grahame R. Joint hypermobility and genetic collagen disorders: are they related? Arch Dis Child. 1999;80:188–91PubMedCrossRefGoogle Scholar
  19. Grahame R, Bird HA, Child A. The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). J Rheumatol. 2000;27:1777–9PubMedGoogle Scholar
  20. Hakim A, Grahame R. Joint hypermobility. Best Pract Res Clin Rheumatol. 2003;17:989–1004PubMedCrossRefGoogle Scholar
  21. Hakim AJ, Grahame R. Non-musculoskeletal symptoms in joint hyper-mobility syndrome. Indirect evidence for autonomic dysfunction. Rheumatology (Oxford) 2004;43:1194–5CrossRefGoogle Scholar
  22. Hall MG, Ferrell WR, Sturrock RD, et al The effect of the hypermobil-ity syndrome on knee joint proprioception. Br J Rheumatol. 1995; 34:121–5PubMedCrossRefGoogle Scholar
  23. Kirk JA, Ansell BM, Bywaters EG. The hypermobility syndrome. Musculoskeletal complaints associated with generalized joint hypermobility. Ann Rheum Dis. 1967;26:419–25PubMedCrossRefGoogle Scholar
  24. Levy HP. Ehlers—Danlos syndrome, hypermobility type. Accessed September 16, 2008
  25. Malfait F, Coucke P, Symoens S, et al The molecular basis of classic Ehlers—Danlos syndrome: a comprehensive study of biochemical and molecular findings in 48 unrelated patients. Hum Mutat. 2005;25: 28–37PubMedCrossRefGoogle Scholar
  26. Malfait F, De Coster P, Hausser I, et al The natural history, including orofacial features of three patients with Ehlers—Danlos syndrome, dermatosparaxis type (EDS type VIIC). Am J Med Genet A. 2004;131:18–28PubMedCrossRefGoogle Scholar
  27. Malfait F, Hakim AJ, De Paepe A, et al The genetic basis of the joint hypermobility syndromes. Rheumatology (Oxford). 2006a;45: 502–7CrossRefGoogle Scholar
  28. Malfait F, Symoens S, Coucke P, et al Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers—Danlos syndrome with hypermobility and propensity to cardiac valvular problems. J Med Genet. 2006b;43:e36CrossRefGoogle Scholar
  29. Malfait F, Symoens S, De Backer J, et al Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers– Danlos syndrome with a propensity to arterial rupture in early adulthood. Hum Mutat. 2007;28:396–405CrossRefGoogle Scholar
  30. Mao JR, Taylor G, Dean WB, et al Tenascin-X deficiency mimics Ehlers—Danlos syndrome in mice through alteration of collagen deposition. Nat Genet. 2002;30:421–5PubMedCrossRefGoogle Scholar
  31. Martin-Santos R, Bulbena A, Porta M, et al Association between joint hypermobility syndrome and panic disorder. Am J Psychiatry. 1998;155:1578–83PubMedGoogle Scholar
  32. McDonnell NB, Gorman BL, Mandel KW, et al Echocardiographic findings in classical and hypermobile Ehlers–Danlos syndromes. Am J Med Genet A. 2006;140:129–36PubMedGoogle Scholar
  33. McKusick VA In: McKusick VA, editor. Heritable disorders of connective tissue. 1st ed. Saint Louis: Mosby; 1972. p. 292–371Google Scholar
  34. Oderich GS, Panneton JM, Bower TC, et al The spectrum, management and clinical outcome of Ehlers—Danlos syndrome type IV: a 30-year experience. J Vasc Surg. 2005;42:98–106PubMedCrossRefGoogle Scholar
  35. Pepin M, Byers PH. Ehlers—Danlos syndrome, vascular type.. Accessed September 16, 2008
  36. Pepin M, Schwarze U, Superti-Furga A, et al Clinical and genetic features of Ehlers—Danlos syndrome type IV, the vascular type. N Engl J Med. 2000;342:673–80PubMedCrossRefGoogle Scholar
  37. Pierard GE, Lapiere M. Skin in dermatosparaxis. Dermal microarchitecture and biomechanical properties. J Invest Dermatol. 1976;66: 2–7PubMedCrossRefGoogle Scholar
  38. Rowe PC, Barron DF, Calkins H, et al Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers–Danlos syndrome. J Pediatr. 1999;135:494–9PubMedCrossRefGoogle Scholar
  39. Sacheti A, Szemere J, Bernstein B, et al Chronic pain is a manifestation of the Ehlers—Danlos syndrome. J Pain Symptom Manage. 1997;14: 88–93PubMedCrossRefGoogle Scholar
  40. Steinmann B, Royce P, Superti-Furga A. The Ehlers—Danlos syndrome. In: Royce P and Steinmann B, editors. Connective tissue and its heritable disorders. 2nd ed. New York: Wiley-Liss; 2002. p. 431–523CrossRefGoogle Scholar
  41. Stine KC, Becton DL. DDAVP therapy controls bleeding in Ehlers— Danlos syndrome. J Pediatr Hematol Oncol. 1997;19:156–8PubMedCrossRefGoogle Scholar
  42. Zweers MC, Bristow J, Steijlen PM, et al Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers—Danlos syndrome. Am J Hum Genet. 2003;73:214–7PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Fransiska Malfait
    • 1
  • Anne De Paepe
    • 1
  1. 1.Medical Genetics DepartmentGhent University HospitalDe PintelaanBelgium

Personalised recommendations