Lymphatic dysfunction, not aplasia, underlies Milroy disease.
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.


CONCLUSIONS
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.
Cardiac & Vascular Sciences (Dermatology), St George's Hospital Medical School, University of London, London, UK.
Russell H
RH
Mellor
Charlotte E
CE
Hubert
Anthony W B
AW
Stanton
Naomi
N
Tate
Victoria
V
Akhras
Alberto
A
Smith
Kevin G
KG
Burnand
Steve
S
Jeffery
Taija
T
Mäkinen
J Rodney
JR
Levick
Peter S
PS
Mortimer
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003911:Dextrans; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D005456:Fluorescent Dyes; D005528:Foot; D005542:Forearm; D006801:Humans; D007150:Immunohistochemistry; D008208:Lymphatic System / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D008209:Lymphedema / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008220:Lymphography / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018615:Ultrasonography, Doppler, Color; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000378:metabolism; D055815:Young Adult
D003911:Dextrans; D005456:Fluorescent Dyes; C119248:LYVE1 protein, human; D033921:Vesicular Transport Proteins; C015219:fluorescein isothiocyanate dextran; D040321:Vascular Endothelial Growth Factor Receptor-3; D016650:Fluorescein-5-isothiocyanate