FOXC2 and primary lymphedema: We previously presented arguments for why connexin-deficient mice31 and other mice with more severe lymphatic system defects, e.g., Foxc2- or Rasa1-deficiency, which produce lymphatic valve incompetency,57,58,61 do not develop detectable peripheral lymphedema in the absence of a chronic gravitational load,31 whereas the homologous mutations cause primary lymphedema in a high percentage of human subjects.62–68