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The Ehlers–Danlos syndromes

Nature Reviews Disease Primers volume 6, Article number: 64 (2020) Cite this article

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Abstract

The Ehlers–Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue, with common features including joint hypermobility, soft and hyperextensible skin, abnormal wound healing and easy bruising. Fourteen different types of EDS are recognized, of which the molecular cause is known for 13 types. These types are caused by variants in 20 different genes, the majority of which encode the fibrillar collagen types I, III and V, modifying or processing enzymes for those proteins, and enzymes that can modify glycosaminoglycan chains of proteoglycans. For the hypermobile type of EDS, the molecular underpinnings remain unknown. As connective tissue is ubiquitously distributed throughout the body, manifestations of the different types of EDS are present, to varying degrees, in virtually every organ system. This can make these disorders particularly challenging to diagnose and manage. Management consists of a care team responsible for surveillance of major and organ-specific complications (for example, arterial aneurysm and dissection), integrated physical medicine and rehabilitation. No specific medical or genetic therapies are available for any type of EDS.

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Fig. 1: General structure of fibrillar type I collagen.
Fig. 2: Collagen fibrillogenesis in the context of Ehlers–Danlos syndromes.
Fig. 3: Biosynthetic pathway of CS/DS and HS/heparin proteoglycans.
Fig. 4: Clinical presentations of Ehlers–Danlos syndromes.
Fig. 5: Clinical skin features associated with Ehlers–Danlos syndromes.
Fig. 6: The Beighton scale.

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Acknowledgements

F.M. is partly supported by the Research Foundation, Flanders, Belgium. M.C. is partly supported by the Ricerca Corrente program 2020. C.A.F. is partly supported by the Ehlers–Danlos Society as the Director of the Center for Ehlers–Danlos Syndromes at Indiana University Health. T.K. is supported by the Japan Society for the Promotion of Science (grant-in-aid for scientific research), the Ministry of Health, Labour and Welfare, Japan (Research on Rare and Intractable Diseases), and the Japan Agency for Medical Research Development (AMED) (the Practical Research Project for Rare/Intractable Diseases, Initiative on Rare and Intractable Diseases, and Program for an Integrated Database of Clinical and Genomic Information).

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Authors and Affiliations

  1. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

    Fransiska Malfait

  2. Division of Medical Genetics, Fondazione IRCCS–Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy

    Marco Castori

  3. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    Clair A. Francomano

  4. Connective Tissue Unit, Division of Metabolism and Children’s Research Centre, University Children’s Hospital, Zurich, Switzerland

    Cecilia Giunta

  5. Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan

    Tomoki Kosho

  6. Department of Pathology and Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA

    Peter H. Byers

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  1. Fransiska Malfait
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  2. Marco Castori
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  4. Cecilia Giunta
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Contributions

Introduction (F.M. and P.H.B.); Epidemiology (F.M., M.C. and P.H.B.); Mechanisms/pathophysiology (F.M., C.G., T.K. and P.H.B.); Diagnosis, screening and prevention (F.M., M.C. and P.H.B.); Management (F.M., M.C., C.A.F. and P.H.B.); Quality of life (F.M., C.A.F. and P.H.B.); Outlook (F.M. and P.H.B.); Overview of the Primer (F.M.).

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Correspondence to Fransiska Malfait.

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Related links

Ehlers–Danlos Society: https://www.Ehlers–Danlos.com

European Reference Networks for Rare Diseases: https://vascern.eu and https://reconnet.ern-net.eu

The International EDS Consortium: https://www.ehlers-danlos.com/international-consortium

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Malfait, F., Castori, M., Francomano, C.A. et al. The Ehlers–Danlos syndromes. Nat Rev Dis Primers 6, 64 (2020). https://doi.org/10.1038/s41572-020-0194-9

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