Lymphatic dysfunction, not aplasia, underlies Milroy disease

Microcirculation. 2010 May;17(4):281-96. doi: 10.1111/j.1549-8719.2010.00030.x.


Objective: Milroy disease is an inherited autosomal dominant lymphoedema caused by mutations in the gene for vascular endothelial growth factor receptor-3 (VEGFR-3, also known as FLT4). The phenotype has to date been ascribed to lymphatic aplasia. We further investigated the structural and functional defects underlying the phenotype in humans.

Methods: The skin of the swollen foot and the non-swollen forearm was examined by (i) fluorescence microlymphangiography, to quantify functional initial lymphatic density in vivo; and (ii) podoplanin and LYVE-1 immunohistochemistry of biopsies, to quantify structural lymphatic density. Leg vein function was assessed by colour Doppler duplex ultrasound.

Results: Milroy patients exhibited profound (86-91%) functional failure of the initial lymphatics in the foot; the forearm was unimpaired. Dermal lymphatics were present in biopsies but density was reduced by 51-61% (foot) and 26-33% (forearm). Saphenous venous reflux was present in 9/10 individuals with VEGFR3 mutations, including two carriers.

Conclusion: We propose that VEGFR3 mutations in humans cause lymphoedema through a failure of tissue protein and fluid absorption. This is due to a profound functional failure of initial lymphatics and is not explained by microlymphatic hypoplasia alone. The superficial venous valve reflux indicates the dual role of VEGFR-3 in lymphatic and venous development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Case-Control Studies
  • Dextrans
  • Female
  • Fluorescein-5-isothiocyanate / analogs & derivatives
  • Fluorescent Dyes
  • Foot
  • Forearm
  • Humans
  • Immunohistochemistry
  • Lymphatic System / diagnostic imaging
  • Lymphatic System / pathology
  • Lymphatic System / physiopathology*
  • Lymphedema / etiology*
  • Lymphedema / genetics
  • Lymphedema / pathology
  • Lymphedema / physiopathology
  • Lymphography / methods
  • Male
  • Middle Aged
  • Mutation
  • Ultrasonography, Doppler, Color
  • Vascular Endothelial Growth Factor Receptor-3 / genetics
  • Vesicular Transport Proteins / metabolism
  • Young Adult


  • Dextrans
  • Fluorescent Dyes
  • LYVE1 protein, human
  • Vesicular Transport Proteins
  • fluorescein isothiocyanate dextran
  • Vascular Endothelial Growth Factor Receptor-3
  • Fluorescein-5-isothiocyanate