PTEN and the Cowden and Bannayan–Riley–Ruvalcaba Syndromes
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abstract
AbstractThe PTEN Hamartoma Tumor Syndrome (PHTS) includes not only the entities Cowden Syndrome (CS; MIM 158350) and Bannayan–Riley–Ruvalcaba syndrome (BRRS; MIM 153480), which are the focus of this chapter, but also Proteus syndrome (PS; MIM 176920), and Proteus-like syndrome (PSL), and perhaps other developmental disorders. These heterogeneous groups of disorders are all, to varying degrees, associated with germline mutations of the PTEN [for phosphatase and tensin homolog, deleted on chromosome 10 (ten)] tumor suppressor gene. PTEN, localized to 10q23.3 is a dual specicity phosphatase. Its lipid phosphatase is crucial in down-regulating the Akt pathway through dephosphorylation of phosphoinositol-3,4,5triphosphate (PIP3) thus facilitating G1 cell cycle arrest and/or apoptosis. It’s protein phosphatase down-regulates cyclin D1 and prevents the phosphorylation of mitogen-activated protein kinase (MAPK), playing important roles in inhibition of cell growth and spreading, in addition to mediating, cell cycle arrest. The importance of PTEN localization to different subcellular compartments is increasingly recognized and will undoubtedly offer insight into novel mechanisms of PTEN dysfunction. CS is an underrecognized and underdiagnosed autosomal dominant disorder. Patients with CS are at increased risk of developing breast, thyroid, and endometrial cancers, in addition to benign neoplasias of these same organs, and have characteristic cutaneous manifestations including papillomatous papules and trichilemmomas. BRRS is characterized by macrocephaly, lipomas, hemangiomas, and speckled penis.
