Clinical and genetic study of 46 Italian patients with primary lymphedema

Primary lymphedema is characterizedby altered morphological development oflymphatic vessels causing fluid accumulationin interstitial spaces. In familial forms, it isprimarily transmitted as a dominantMendelian trait with heterozygous mutationsin genes involved in lymphangiogenesis. Weused PCR and direct sequencing to analyzethe region of the fms-related tyrosine kinase4 (FLT4) gene encoding the “tyrosine-kinasedomain” and the single exon of the forkheadbox C2 (FOXC2) gene in 46 Italian probandswith primary lymphedema, 42 of whom hadfamilial forms. We identified 12 mutations in12 patients (12/46, 26%), six in the FLT4 geneand six in the FOXC2 gene. Most of themutations (9/12, 75%) were new, and nonewere identified in 100 healthy subjects orlisted in the NCBI dbSNP. A clear relationemerged between genotype and phenotypebecause 4/5 (80%) probands with onset atbirth showed FLT4 mutations and 4/5 (80%)probands without distichiasis and withFOXC2 mutations had an amino-acidsubstitution outside the forkhead domain.Besides the allelic heterogeneity shown byunique mutations in each proband, the absence of mutations in almost 75% offamilial cases of primary lymphedema alsosuggests genetic heterogeneity.