title: Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3.
abstract: Hereditary lymphedema type I (HL-I), also known as Milroy disease, is an autosomal dominant disorder characterized by typical phenotype of infantile onset lower-limb lymphedema accompanied by variable expression of recurrent episodes of cellulites, toenail changes, and papillomatosis. Mutations in the vascular endothelial growth factor receptor 3 (VEGFR3), also known as FLT4 gene, which encodes a lymphatic endothelial-specific tyrosine kinase receptor, have been identified as a genetic cause of HL-I. We report a large Muslim Arab family residing in northern Israel with 14 individuals presenting clinical features of HL-I. Genetic analysis revealed novel missense mutation E1106K in the tyrosine kinase domain II of VEGFR3 that cosegregates with the disorder in the family. Most affected individuals presented with bilateral congenital lower-limb lymphedema. Wide intrafamilial phenotypic variability included two asymptomatic individuals, a case of prenatal hydrothorax evolving to hydrops fetalis, and a late-onset complication, yet unreported, of chronic degenerative joint disease of the knees. This report broadens the known "classic" phenotype of HL-I.
authors.affiliation: Genetic Institute, Ha'Emek Medical Center, Afula, 18101, Israel. spiegelr@zahav.net.il.|Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. spiegelr@zahav.net.il.
authors.forename: Ronen
authors.initials: R
authors.lastname: Spiegel
authors.affiliation: Laboratory of Human Molecular Genetics, Christian de Duve Institute and University of Louvain Medical School, Brussels, Belgium.
authors.forename: Arash
authors.initials: A
authors.lastname: Ghalamkarpour
authors.affiliation: Department of Obstetrics and Gynecology, Ha'Emek Medical Center, Afula, Israel.|Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Etty
authors.initials: E
authors.lastname: Daniel-Spiegel
authors.affiliation: Laboratory of Human Molecular Genetics, Christian de Duve Institute and University of Louvain Medical School, Brussels, Belgium.
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
authors.affiliation: Genetic Institute, Ha'Emek Medical Center, Afula, 18101, Israel.|Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Stavit
authors.initials: S
authors.lastname: A Shalev
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D005192:Family Health; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008209:Lymphedema / Q000151:congenital / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D053634:TYK2 Kinase / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics*
chemical_list: D040321:Vascular Endothelial Growth Factor Receptor-3; D053634:TYK2 Kinase; C070139:TYK2 protein, human