Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations.

Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations.

October 2006

Ghalamkarpour A,
Morlot S,
Raas-Rothschild A,
Utkus A,
Mulliken JB,
Boon LM,
Vikkula M.

Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology, Universite catholique de Louvain, Brussels, Belgium.

Mutations in the vascular endothelial growth factor receptor 3 gene, VEGFR3/FLT4, have been identified in a subset of families with hereditary lymphedema type I or Milroy disease (MIM 153100). Individuals carrying a VEGFR3 mutation exhibit congenital edema of the lower limbs, usually bilaterally and below the knees, sometimes associated with cellulitis, prominent veins, papillomatosis, upturned toenails, and hydrocele.

In this study, we report the first de novo VEGFR3 mutation in a patient with sporadic congenital lymphedema. We also describe three other families with a VEGFR3 mutation. In each family, one individual had an atypical clinical presentation of hereditary lymphedema type I, whereas the others had the classical VEGFR3 mutation-caused phenotype. The atypical presentations included pre-natal pleural effusion, spontaneous resorption of lymphedema and elephantiasis. Three of the four identified mutations were novel. These data show that de novo VEGFR3 mutations may be present in patients without family history of congenital lymphedema. This has implications for follow-up care, as such individuals have nearly a 50% risk for occurrence of lymphedema in their children.

Our findings also indicate that although most patients with a VEGFR3 mutation have the well-defined phenotype for hereditary lymphedema type I, there are exceptions that should be considered in genetic counseling. Because VEGFR3 mutation can cause generalized lymphatic dysfunction and can thus result in hydrops fetalis, VEGFR3 screening should be added to the investigation of cases of hydrops fetalis of an unknown etiology.

PMID: 16965327 [PubMed - in process]

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Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3.

August 2006

Spiegel R,
Ghalamkarpour A,
Daniel-Spiegel E,
Vikkula M,
A Shalev S.
Genetic Institute, Ha'Emek Medical Center, Afula, 18101, Israel.
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.

PMID: 16924388 [PubMed - as supplied by publisher]