DOI: https://doi.org/10.14710/jbtr.v5i2.4531

Classification, nosology and diagnostics of Ehlers-Danlos syndrome

Department of Human Genetics, Radboud University Medical Center, Netherlands

Received: 23 Mar 2019; Revised: 10 Oct 2019; Accepted: 10 Oct 2019; Available online: 31 Dec 2019; Published: 31 Dec 2019.
Open Access Copyright (c) 2019 Journal of Biomedicine and Translational Research

Citation Format:
Abstract

Ehlers-Danlos syndrome (EDS) comprises a group of heritable connective tissue disorders which has as cardinal features varying degrees of skin hyperextensibility, joint hypermobility, easy bruising and skin fragility. The 2017 New York nosology distinguishes 13 types of EDS, which all, except hypermobile EDS, have a known molecular basis. Hypermobile EDS is recognized as a common and often disabling disorder, incorporating benign joint hypermobility syndrome. EDS needs to be differentiated from other connective tissue disorders, in particular Marfan syndrome, Loeys-Dietz syndrome and cutis laxa. The frequent types of EDS can be diagnosed after careful history taking and clinical examination, but for definite diagnosis molecular confirmation is needed in all types. Management for EDS patients preferably is provided by multidisciplinary teams in expertise centres. After diagnosing EDS genetic counselling is an essential part of the management of patients and their family.

Fulltext View|Download
Keywords: Ehlers-Danlos syndrome; classification; diagnosis
Funding: none

Article Metrics:

Article Info
Section: Review Articles
Language : EN
Recent articles
Antioxidant Herbs Supplementation Inhibits Endometriosis Extension in Mice Effect of Superoxide Dismutase (SOD) Supplementation on Plasma Levels of Malondialdehyde (MDA), Total Cholesterol and LDL Cholesterol in the Elderly Nested PCR methods for detection Toxoplasma gondii B1 gene in Cerebrospinal Fluid of HIV patients Classification, nosology and diagnostics of Ehlers-Danlos syndrome Focal areas of a high rate of fragile X in Indonesia: a long term follow up More recent articles
  1. Beighton P. The Ehlers-Danlos syndrome. London, England: William Heinemann Medical Books, 1970
  2. Beighton P, De Paepe A, Danks D, et al. International nosology of heritable disorders of connective tissue, Berlin 1986. Am J Med Genet 1988;29:581-594
  3. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Am J Med Genet 1998;77:31-37
  4. Malfait F, Francomano C, Byers P, et al. The 2017 International classification of the Ehlers-Danlos syndromes. Am J Med Genet Part C Semin Med Genet 2017;175C:8-26
  5. Steinmann B, Royce PM, Superi-Furga A. The Ehlers-Danlos syndrome. In: Royce Pm, Steinmann B, eds. Connective tissue and its heritable disorders. 2nd ed. New York, USA: Wiley-Liss, 2002:431-525
  6. Berk DR, Bentley DD, Bayliss SJ, Lind A, Urban Z. Cutis laxa: a review. J Am Acad Dermatol 2012;66:842.e1-17
  7. Firth H, Hurst J. Oxford Desk reference: Clinical Genetics. 1st ed Oxford, England: Oxford University Press, 2005:138-139
  8. Rikken-Bultman DG, Wellink L, van Dongen PW. Hypermobility in two Dutch school populations. Eur J Obstet Gynecol Reprod Biol 1997;73:189-192
  9. Hakim AJ, Grahame R, Norris P, Hopper C. Local anaesthetic failure in joint hypermobility syndrome. J R Soc Med 2005;98:84-85
  10. Bowen JM, Sobey GJ, Burrows NP, et al. Ehlers-Danlos syndrome, classical type. Am J Med Genet Part C Semin Med Genet 2017;175C:27-39
  11. Colombi M, Dordoni C, Venturini M, et al. Spectrum of mucocutaneous, ocular and facial features and delineation of novel presentations in 62 classical Ehlers-Danlos syndrome patients. Clin Genet 2017;92:624-631
  12. Gaines R, Tinkle BT, Halandras PM, Al-Nouri O, Crisostomo P, Cho JS. Spontaneous Ruptured Dissection of the Right Common Iliac Artery in a Patient with Classic Ehlers-Danlos Syndrome Phenotype. Ann Vasc Surg 2015;29:595.e11-4
  13. Brady AF, Demirdas S, Fournel-Gigleux S, et al. The Ehlers-Danlos syndromes, rare types. Am J Med Genet Part C Semin Med Genet 2017;175C:70-115
  14. Demirdas S, Dulfer E, Robert L, et al. Recognizing the tenascin-X deficient type of Ehlers-Danlos syndrome: a cross-sectional study in 17 patients. Clin Genet 2017; 91:411-425
  15. Schwarze U, Hata R, McKusick VA, et al. Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. Am J Hum Genet 2004;74:917-930
  16. Byers PH, Belmont J, Black J, et al. Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome. Am J Med Genet Part C Semin Med Genet 2017;175C:40-47
  17. Frank M, Albuisson J, Ranque B, et al. The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome. Eur J Hum Genet 2015;23:1657-64
  18. Legrand A, Devriese M, Dupuis-Girod S, et al. Frequency of de novo variants and parental mosaicism in vascular Ehlers-Danlos syndrome. Genet Med 2018 Nov 26. [Epub ahead of print]
  19. Murray ML, Pepin M, Peterson S, Byers PH. Pregnancy-related deaths and complications in women with vascular Ehlers-Danlos syndrome. Genet Med 2014;16:874-880
  20. Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-β receptor. N Engl J Med 2006;355:788-798
  21. Pyeritz RE. Heritable thoracic aortic disorders. Curr Opin Cardiol 2014;29:97-102
  22. 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 Part C Semin Med Genet 2017;175C:48-69
  23. Syx D, Symoens S, Steyaert W, De Paepe A, Coucke PJ, Malfait F. Ehlers-Danlos syndrome, hypermobility type, is linked to chromosome 8p22-8p21.1 in an extended Belgian family. Dis Markers 2015;2015:828970
  24. Grahame R, Bird HA, Child A. The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome. J Rheumatol 2000;27:1777-1779
  25. Zweers MC, Bristow J, Steijlen PM, et al. Haplo-insufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos syndrome. Am J Hum Genet 2003;73:214-217
  26. Castori M, Morlino S, Grammatico P. Towards a re-thinking of the clinical significance of generalized joint hypermobility, joint hypermobility syndrome, and Ehlers-Danlos syndrome, hypermobility type. Am J Med Genet A 2014;164A:588-590
  27. Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A. A framework for the classification of joint hypermobility and related conditions. Am J Med Genet Part C Semin Med Genet 2017;175C:148-157
  28. Van Damme T, Colige A, Syx D, et al. Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis type. Genet Med 2016;18:882-91
  29. Giunta C, Baumann M, Fauth C, et al. A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history. Genet Med 2018;20:42-54
  30. Burkitt Wright EM, Porter LF, Spencer HL, et al. Brittle cornea syndrome: recognition, molecular diagnosis and management. Orphanet J Rare Dis 2013;8:68
  31. Okajima T, Fukumoto S, Furukawa K, Urano T, Furukawa K. Molecular basis for the progeroid variant of Ehlers-Danlos syndrome: identification and characterization of two mutations in galactosyltransferase I gene. J Biol Chem 1999;274:28841-28844
  32. Nakajima M, Mizumoto S, Miyake N, et al. Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders. Am J Hum Genet 2013;92:927-934
  33. 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;82:1290-1305
  34. Van Damme T, Pang X, Guillemyn B, et al. Biallelic B3GALT6 mutations cause spondylodysplastic Ehlers-Danlos syndrome. Hum Mol Genet 2018;27:3475-3487
  35. Janecke AR, Li B, Boehm M, et al. The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations. Am J Med Genet A 2016;170:103-15
  36. Uehara M, Kosho T, Yamamoto N, et al. Spinal manifestations in 12 patients with musculocontractural Ehlers-Danlos syndrome caused by CHST14/D4ST1 deficiency (mcEDS-CHST14). Am J Med Genet A 2018;176:2331-2341
  37. Zou Y, Zwolanek D, Izu Y, et al. Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice. Hum Mol Genet 2014;23:2339-2352
  38. Kapferer-Seebacher I, Pepin M, Werner R, et al. Periodontal Ehlers-Danlos syndrome is caused by mutations in C1R and C1S, which encode subcomponents C1r and C1s of complement. Am J Hum Genet 2016;99:1005-1014
  39. Kapferer-Seebacher I, Waisfisz Q, Boesch S, et al. Periodontal Ehlers-Danlos syndrome is associated with leukoencephalopathy. Neurogenetics 2019;20:1-8
  40. Rinner A, Zschocke J, Schossig A, Gröbner R, Strobl H, Kapferer-Seebacher I. High risk of peri-implant disease in periodontal Ehlers-Danlos Syndrome. A case series. Clin Oral Implants Res 2018 Sep 25. [Epub ahead of print]
  41. Alazami AM, Al-Qattan SM, Faqeih E, et al. Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue. Hum Genet 2016;135:525-40
  42. Blackburn PR, Xu Z, Tumelty KE, et al. Bi-allelic alterations in AEBP1 lead to defective collagen assembly and connective tissue structure resulting in a variant of Ehlers-Danlos syndrome. Am J Hum Genet 2018;102:696-705
  43. Hebebrand M, Vasileiou G, Krumbiegel M, et al. A biallelic truncating AEBP1 variant causes connective tissue disorder in two siblings. Am J Med Genet A 2019;179:50-56
  44. Syx D, De Wandele I, Symoens S, et al. Bi-allelic AEBP1 mutations in two patients with Ehlers-Danlos syndrome. Hum Mol Genet 2019 Jan 22. [Epub ahead of print]
  45. Byers PH, Murray ML. Ehlers–Danlos syndrome: A showcase of conditions that lead to understanding matrix biology. Matrix Biol 2014;33:10-15
  46. Sulli A, Talarico R, Scirè CA, et al. Ehlers-Danlos syndromes: state of the art on clinical practice guidelines. RMD Open. 2018;4 (Suppl 1):e000790
  47. Ericson W, Wolman R. Orthopaedic management of the Ehlers-Danlos syndromes. Am J Med Genet Part C Semin Med Genet 2017;175C:188-194
  48. Engelbert RH, Juul-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. Am J Med Genet Part C Semin Med Genet 2017;175C:158-167
  49. Chopra P, Tinkle B, Hamonet C, et al. Pain management in the Ehlers-Danlos syndromes. Am J Med Genet Part C Semin Med Genet 2017;175C:212-219
  50. Mitakides J, Tinkle B. Oral and mandibular manifestations in the Ehlers-Danlos syndromes. Am J Med Genet Part C Semin Med Genet 2017;175C:220-225
  51. Hakim A, de Wandele I, O’Callaghan C, Pocinki A, Rowe P. Chronic fatigue in Ehlers-Danlos syndrome, hypermobile type. Am J Med Genet Part C Semin Med Genet 2017;175C:175-180
  52. Hakim A, O’Callaghan C, de Wandele I, Stiles L, Pocinki A, Rowe P. Cardiovascular autonomic dysfunction in Ehlers-Danlos syndrome, hypermobile type. Am J Med Genet Part C Semin Med Genet 2017;175C:168-174
  53. Fikree A, Chelimsky G, Collins H, Kovacic K, Aziz Q. Gastrointestinal involvement in the Ehlers-Danlos syndromes. Am J Med Genet Part C Semin Med Genet 2017;175C:181-187
  54. Bulbena A, Baeza-Velasco C, Bulbena-Cabré A, et al. Psychiatric and psychological aspects in the Ehlers-Danlos syndromes. Am J Med Genet Part C Semin Med Genet 2017;175C:237-245
  55. Voermans NC, van Alfen N, Pillen S et al. Neuromuscular involvement in various types of Ehlers-Danlos syndrome. Ann Neurol 2009;65:687-697
  56. Henderson FC, Austin C, Benzel E, et al. Neurological and spinal manifestations of the Ehlers-Danlos syndromes. Am J Med Genet Part C Semin Med Genet 2017;175C:195-211

Last update:

No citation recorded.

Last update:

No citation recorded.