PHENOTYPIC AND GENOTYPIC HETEROGENEITY IN FAMILIAL MILROY LYMPHEDEMA

Abstract

Familial Milroy lymphedema(ML) is classified as an autosomal dominant disordercharacterized by peripheral edema of the lower extremities at birth or in early childhood. Thevariety of phenotypes are not well described, and the genomic location and functional expressionof the gene or genes underlying this and related familial lymphedema syndromes remain largelyunknown. In this collaborative study between the University of Arizona and the University of SãoPaulo, we collected clinical pedigrees on 6 ML families, carried out clinical examination ofaffected and unaffected individuals, and, in representative affected members of two of thefamilies performed dynamic lymphangioscintigraphy (LAS) of the lower and upper limbs todelineate further the ML lymphangiodysplastic phenotype. To localize the gene for ML, weconducted a genome-wide search in 4 of the families using 387 polymorphic dinucleotide-repeatmarkers at approximate l0 cM spacing in 54 subjects (affected, unaffected bloodline relatives,and spouses). In all 6 families (86 subjects), we specifically examined the suggested linkage tothe vascular endothelial growth factor (VEGF)-C receptor (Flt4) gene localized to thechromosome region 5q34-q35. The findings provide evidence for a spectrum of ML clinical andLAS phenotypes and also suggest ML locus heterogeneity.