The Pathogenesis of Port Wine Stain and Sturge Weber Syndrome: Complex Interactions between Genetic Alterations and Aberrant MAPK and PI3K Activation

Abstract

Port wine stain (PWS) is a congenital vascular malformation involving human skin. Approximately 15-20% of children a facial PWS involving the ophthalmic (V1) trigeminal dermatome are at risk for Sturge Weber syndrome (SWS), a neurocutaneous disorder with vascular malformations in the cerebral cortex on the same side of the facial PWS lesions. Recently, evidence has surfaced that advanced our understanding of the pathogenesis of PWS/SWS, including discoveries of somatic genetic mutations (GNAQ, PI3K), MAPK and PI3K aberrant activations, and molecular phenotypes of PWS endothelial cells. In this review, we summarize current knowledge on the etiology and pathology of PWS/SWS based on evidence that the activation of MAPK and/or PI3K contributes to the malformations, as well as potential futuristic treatment approaches targeting these aberrantly dysregulated signaling pathways. Current data support that: (1) PWS is a multifactorial malformation involving the entire physiological structure of human skin; (2) PWS should be pathoanatomically re-defined as "a malformation resulting from differentiation-impaired endothelial cells with a progressive dilatation of immature venule-like vasculatures"; (3) dysregulation of vascular MAPK and/or PI3K signaling during human embryonic development plays a part in the pathogenesis and progression of PWS/SWS; and (4) sporadic low frequency somatic mutations, such as GNAQ, PI3K, work as team players but not as a lone wolf, contributing to the development of vascular phenotypes. We also address many crucial questions yet to be answered in the future research investigations.

Keywords: MAPK; Port wine stain; Sturge Weber syndrome; congenital vascular malformations; laser treatment; somatic mutation.

Figure 1

Role of EphB₁/EfnB₂ in differentiation of endothelial cell from primary capillary plexus (PCP). EphB₁ is a biomarker for venous ECs, while EfnB2 is a biomarker for arterial EC. In normal development, mutually exclusive expression of EphB1 or EfnB2 determines dermal arterial or venous differentiation from PCP [43]. In PWS model, both EphB₁ and EfnB₂ are co-expressed in ECs, leading to blood vessels with both venous and arterial characteristics.

Figure 2

The potential roles of aberrant activations of MAPK and PI3K signaling pathways in pathogenesis of PWS/SWS. Mutations in GNAQ, EphB4, RASA1, Tie2 and other genes, as well as co-expression of EphB1/EfnB2 lead to an activation of MAPK. Mutation in PIK3CA (G1049N) activates AKT/mTOR pathway. Overexpression of VEGF-A and VEGFR2 can activate in MAPK and AKT/mTOR. Altogether, these factors lead to aberrant activations of MAPK and PI3K signaling pathways, thus result in cell proliferation, migration, survival, cytoskeletal arrangement and vasopermeability, eventually causing development of PWS/SWS. Some anti-angiogenesis compounds or antibodies that are under development or have been approved by FDA are listed in the figure for potential treatments of vascular malformations.