A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease

Milroy and Milroy-like disease are rare disorders characterised by congenital lymphoedema caused by dysfunctional lymphatic vessel formation. Loss of extracellular response mediated by vascular endothelial growth factor receptor 3 (VEGFR-3) is associated with Milroy disease, and VEGFR-3 gene is mutated in around 70% of the cases diagnosed. The only genetic alteration known to be associated with Milroy-like disease was recently identified in a family with a frameshift mutation in vascular endothelial growth factor C (VEGFC) gene, which encodes a VEGFR3 ligand.

We report a newborn patient with an external phenotype consistent with Milroy disease and a truncating mutation (p.R210X) in the VEGFC gene detected by exome sequence analysis. Subsequent analysis, by lymphoscintigraphic scan, performed for research purposes, allowed us to correct the diagnosis, confirming patient's disease as Milroy-like. The mutation segregates with the phenotype in the family according to a dominant model with full penetrance.

The clinical presentation, similar to Milroy disease, indicates an overlapping of the external phenotype of both diseases, suggesting that genetic analysis of VEGFC would be useful in diagnosing patients that present with Milroy features but have no mutation in VEGFR-3. Establishing a well-defined genetic pattern would help with differential diagnosis.