Ex vivo nonlinear microscopy imaging of Ehlers-Danlos syndrome-affected skin

Arch Dermatol Res. 2018 Jul;310(5):463-473. doi: 10.1007/s00403-018-1835-7. Epub 2018 May 3.


Ehlers-Danlos syndrome (EDS) is the name for a heterogenous group of rare genetic connective tissue disorders with an overall incidence of 1 in 5000. The histological characteristics of EDS have been previously described in detail in the late 1970s and early 1980s. Since that time, the classification of EDS has undergone significant changes, yet the description of the histological features of collagen morphology in different EDS subtypes has endured the test of time. Nonlinear microscopy techniques can be utilized for non-invasive in vivo label-free imaging of the skin. Among these techniques, two-photon absorption fluorescence (TPF) microscopy can visualize endogenous fluorophores, such as elastin, while the morphology of collagen fibers can be assessed by second-harmonic generation (SHG) microscopy. In our present work, we performed TPF and SHG microscopy imaging on ex vivo skin samples of one patient with classical EDS and two patients with vascular EDS and two healthy controls. We detected irregular, loosely dispersed collagen fibers in a non-parallel arrangement in the dermis of the EDS patients, while as expected, there was no noticeable impairment in the elastin content. Based on further studies on a larger number of patients, in vivo nonlinear microscopic imaging could be utilized for the assessment of the skin status of EDS patients in the future.

Keywords: Collagen structure; Ehlers–Danlos syndrome; Nonlinear microscopy; Second-harmonic generation.

Publication types

  • Case Reports

MeSH terms

  • Collagen Type III / genetics
  • Collagen Type V / genetics
  • Connective Tissue / diagnostic imaging*
  • Connective Tissue / pathology*
  • Ehlers-Danlos Syndrome / diagnostic imaging*
  • Ehlers-Danlos Syndrome / genetics
  • Elastin / metabolism
  • Female
  • Humans
  • Middle Aged
  • Nonlinear Optical Microscopy / methods*
  • Pedigree
  • Protein Conformation
  • Skin / diagnostic imaging*
  • Skin / pathology


  • COL3A1 protein, human
  • COL5A1 protein, human
  • Collagen Type III
  • Collagen Type V
  • Elastin