Spectrum of mucocutaneous, ocular and facial features and delineation of novel presentations in 62 classical Ehlers-Danlos syndrome patients

Clin Genet. 2017 Dec;92(6):624-631. doi: 10.1111/cge.13052. Epub 2017 Sep 4.


Classical Ehlers-Danlos syndrome (cEDS) is characterized by marked cutaneous involvement, according to the Villefranche nosology and its 2017 revision. However, the diagnostic flow-chart that prompts molecular testing is still based on experts' opinion rather than systematic published data. Here we report on 62 molecularly characterized cEDS patients with focus on skin, mucosal, facial, and articular manifestations. The major and minor Villefranche criteria, additional 11 mucocutaneous signs and 15 facial dysmorphic traits were ascertained and feature rates compared by sex and age. In our cohort, we did not observe any mandatory clinical sign. Skin hyperextensibility plus atrophic scars was the most frequent combination, whereas generalized joint hypermobility according to the Beighton score decreased with age. Skin was more commonly hyperextensible on elbows, neck, and knees. The sites more frequently affected by abnormal atrophic scarring were knees, face (especially forehead), pretibial area, and elbows. Facial dysmorphism commonly affected midface/orbital areas with epicanthal folds and infraorbital creases more commonly observed in young patients. Our findings suggest that the combination of ≥1 eye dysmorphism and facial/forehead scars may support the diagnosis in children. Minor acquired traits, such as molluscoid pseudotumors, subcutaneous spheroids, and signs of premature skin aging are equally useful in adults.

Keywords: COL5A1; COL5A2; atrophic scars; classical Ehlers-Danlos syndrome; diagnostic criteria; epicanthus; facial dysmorphism; skin hyperextensibility.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Cohort Studies
  • Collagen Type V / genetics*
  • Collagen Type V / metabolism
  • Ehlers-Danlos Syndrome / diagnosis
  • Ehlers-Danlos Syndrome / genetics*
  • Ehlers-Danlos Syndrome / metabolism
  • Ehlers-Danlos Syndrome / pathology
  • Eye Abnormalities / diagnosis
  • Eye Abnormalities / genetics*
  • Eye Abnormalities / metabolism
  • Eye Abnormalities / pathology
  • Face / abnormalities
  • Female
  • Gene Expression
  • Humans
  • Joint Instability / diagnosis
  • Joint Instability / genetics*
  • Joint Instability / metabolism
  • Joint Instability / pathology
  • Joints / abnormalities
  • Joints / metabolism
  • Male
  • Middle Aged
  • Mutation
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Skin Abnormalities / diagnosis
  • Skin Abnormalities / genetics*
  • Skin Abnormalities / metabolism
  • Skin Abnormalities / pathology


  • COL5A1 protein, human
  • Collagen Type V
  • Protein Isoforms