Phenotypic and genotypic heterogeneity in familial Milroy lymphedema

Familial Milroy lymphedema (ML) is classified as an autosomal dominant diso rder characterized by peripheral edema of the lower extremities at birth or in early childhood. The variety of phenotypes are not well described, and the genomic location and functional expression of the gene or genes underly ing this and related familial lymphedema syndromes remain largely unknown. In this collaborative study between the University of Arizona and the Unive rsity of Sao Paulo, we collected clinical pedigrees on 6 ML families, carri ed out clinical examination of affected and unaffected individuals, and in representative affected members of two of the families performed dynamic ly mphangioscintigraphy (LAS) of the lower and upper limbs to delineate furthe r the ML lymphangiodysplastic phenotype. To localize the gene for ML, we co nducted a genome-wide search in 4 of the families using 387 polymorphic din ucleotide-repeat markers at approximate 10 cM spacing in 54 subjects (affec ted, unaffected bloodline relatives, and spouses). In all 6 families (86 su bjects), we specifically examined the suggested linkage to the vascular end othelial growth factor (VEGF)-C receptor (Flt4) gene localized to the chrom osome region 5q34-q35, The findings provide evidence for a spectrum of ML c linical and LAS phenotypes and also suggest ML locus heterogeneity.