A Genetic Approach to the Classification of Primary Lymphoedema and Lymphatic Malformations
Bernard Ho, Kristiana Gordon, Peter S. Mortimer. Eur J Vasc Endovasc Surg (2018)
Milroy lymphoedema is caused by mutations in vascular endothelial growth factor receptor 3 (VEGFR3), but clinically identical forms of congenital lymphoedema can be caused by mutations in vascular endothelial growth factor C (the ligand for VEGFR3); Kinesin family member 11 (KIF11), which causes microcephaly lymphoedema syndrome; and, of course, there is Turner syndrome, which is due to one of the two X chromosomes being missing or structurally altered. All these congenital forms of lymphoedema can look identical, but a genetic screen can provide an accurate diagnosis.
Mutations in FOXC2 cause lymphoedema distichiasis syndrome. Distichiasis is a double row of eyelashes and it is a pathognomonic feature of the syndrome. The mechanism for the lymphoedema is lymphatic valve reflux. There is also venous valve reflux, which affects 100% of superficial veins and approximately 30% of deep veins. FOXC2 is therefore the first gene known to be causal of venous disease.
Despite distichiasis being present from birth, lymphoedema never materialises before puberty and can emerge as late as the fifth decade of life.6 The same gene can therefore cause both lymphoedema praecox and lymphoedema tarda, indicating the futility of the traditional classification.