Ehlers-Danlos syndrome

Ehlers-Danlos syndrome encompasses thirteen officially classified subtypes within the , sharing the cardinal triad of skin hyperextensibility, generalised joint hypermobility, and tissue fragility while differing markedly in organ involvement and severity.

Classic Ehlers-Danlos syndrome (cEDS) presents with soft, hyperextensible skin, atrophic scarring, abnormal wound healing, and generalised joint hypermobility with recurrent dislocations.

Vascular Ehlers-Danlos syndrome (vEDS) is characterised by arterial, intestinal, and uterine fragility; spontaneous pneumothorax, gastrointestinal perforation, and arterial dissection or rupture may be seen in childhood but generally come to clinical attention in the third decade of life.

Kyphoscoliotic (kEDS), arthrochalasia (aEDS), dermatosparaxis (dEDS), and cardiac‑valvular subtypes (cvEDS) add congenital muscular hypotonia, severe progressive scoliosis, ocular fragility, congenital hip dislocation, extreme skin fragility, or progressive cardiac valvular disease to the spectrum.

Hypermobility EDS (hEDS), the most common subtype, is defined by generalised joint hypermobility with chronic musculoskeletal pain and proprioceptive impairment, typically without marked skin fragility, while classical‑like EDS (clEDS) presents with skin hyperextensibility and joint hypermobility in the absence of atrophic scarring.

Myopathic EDS (mEDS) features congenital or early-onset muscle hypotonia and proximal muscle weakness, whereas musculocontractural EDS (mcEDS) is characterised by multiple congenital contractures, distinctive craniofacial features, and marked soft-tissue fragility.

Spondylodysplastic EDS (spEDS) presents with short stature, muscle hypotonia, and skeletal dysplasia; brittle cornea syndrome (BCS) with extreme corneal fragility and a high risk of ocular rupture; and periodontal EDS (pEDS) with severe early‑onset periodontitis and gingival fragility.

Inter‑ and intra‑familial variability is substantial, even within a single subtype.

Current epidemiological evidence suggests that hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are relatively common in the general population, with estimated prevalences of approximately 1 in 500 to 1 in 1,000 individuals. In contrast, the remaining genetically defined EDS subtypes are rare disorders, typically occurring in fewer than 1 in 20,000 individuals.

Pathogenic germline variants in at least 19 genes have been associated with the Ehlers-Danlos syndromes. The most frequently implicated genes include COL5A1 (approximately 81% of classic EDS cases), COL5A2 (approximately 16% of classic EDS cases), and COL3A1, which accounts for the vast majority of vascular EDS cases. In classic Ehlers-Danlos syndrome, the predominant pathogenic mechanisms are haploinsufficiency or dominant-negative effect affecting type V collagen heterotrimers. In vascular Ehlers-Danlos syndrome, pathogenic variants disrupt the structure or function of type III collagen.

Other EDS subtypes are associated with pathogenic variants in genes including TNXB, COL1A1, COL1A2, PLOD1, FKBP14, ADAMTS2, COL12A1, CHST14, DSE, B4GALT7, B3GALT6, SLC39A13, ZNF469, PRDM5, C1R and C1S.

Several Ehlers-Danlos syndrome (EDS) subtypes, including classic EDS (cEDS) and vascular EDS (vEDS), are inherited in an autosomal dominant manner, with a 50% recurrence risk for the offspring of an affected individual. Approximately 50% of individuals with cEDS carry a de novo pathogenic variant. Classical-like EDS (clEDS) and multiple other rare subtypes are inherited in an autosomal recessive manner.

Subtype‑specific clinical diagnosis is established according to the of the Ehlers–Danlos Syndromes, which defines major and minor clinical criteria for each of the thirteen recognised subtypes. Meeting the specified clinical criteria supports the diagnosis of a given subtype; however, for most genetically defined EDS subtypes, diagnostic confirmation requires identification of a pathogenic variant in the corresponding causative gene through molecular genetic testing. In contrast, hypermobile Ehlers–Danlos syndrome (hEDS) remains a clinical diagnosis, as no causative gene has yet been identified.

Clinical evaluation includes assessment of skin extensibility, atrophic scarring, the Beighton score for generalised joint hypermobility, family history, and subtype‑specific features such as arterial imaging in suspected vascular Ehlers–Danlos syndrome or ophthalmological and skeletal assessment in suspected kyphoscoliotic subtypes.

Main differential diagnoses include:

• Hypermobility spectrum disorder: generalised joint hypermobility with systemic musculoskeletal features but failing the 2017 hypermobile Ehlers-Danlos syndrome diagnostic criteria; no identified causal gene
• : aggressive arterial aneurysms and dissections with craniofacial anomalies and skeletal manifestations and a high incidence of pregnancy-related complications
• : dolichostenomelia and arachnodactyly with ectopia lentis and dilatation or aneurysm typically restricted to the aorta

• Establishing the molecular genetic diagnosis confirms the clinical suspicion, defines the specific subtype, and clarifies the underlying mechanism.
• A confirmed molecular diagnosis enables specific and individualised surveillance and clinical management – including arterial imaging in vascular Ehlers-Danlos syndrome – and is a prerequisite for targeted medical care, which remains the responsibility of the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is identified, predictive testing of at-risk relatives becomes possible and supports informed family planning and surveillance decisions.

• Malfait F, Symoens S, Syx D. Classic Ehlers-Danlos syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026 [updated 2024 Feb 1; cited 2026 Jun]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1244/. PMID: .
• Byers PH. Vascular Ehlers-Danlos syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026 [updated 2025 Apr 10; cited 2026 Jun]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1494/. PMID: .
• Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8-26. doi:10.1002/ajmg.c.31552. PMID: . PMCID: PMC5537067.
• Demmler JC, Atkinson MD, Reinhold EJ, Choy E, Lyons RA, Brophy ST. 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. doi:10.1136/bmjopen-2019-031365. PMID: . PMCID: PMC6858200