Lymphatic Dysfunction, Not Aplasia, Underlies Milroy Disease


  • Sources of support: British Heart Foundation (grant no. PG/02/111), British Skin Foundation, Reece Spence Fund.

Professor P.S. Mortimer, Cardiac & Vascular Sciences (Dermatology), St George’s Hospital Medical School, University of London, Cranmer Terrace, London SW17 0RE, UK. E-mail:


Microcirculation (2010) 17, 281–296. 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.