Members of the Lymphoedema Research Consortium.
Lymphatic Dysfunction, Not Aplasia, Underlies Milroy Disease
Article first published online: 8 APR 2010
© 2010 John Wiley & Sons Ltd
Volume 17, Issue 4, pages 281–296, May 2010
How to Cite
Mellor, R. H., Hubert, C. E., Stanton, A. W.B., Tate, N., Akhras, V., Smith, A., Burnand, K. G., Jeffery, S., Mäkinen, T., Levick, J. R. and Mortimer, P. S. (2010), Lymphatic Dysfunction, Not Aplasia, Underlies Milroy Disease. Microcirculation, 17: 281–296. doi: 10.1111/j.1549-8719.2010.00030.x
Sources of support: British Heart Foundation (grant no. PG/02/111), British Skin Foundation, Reece Spence Fund.
- Issue published online: 28 APR 2010
- Article first published online: 8 APR 2010
- Received 28 November 2009; accepted 24 February 2010.
- Milroy disease;
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.