Germline and germline mosaic PTEN mutations associated with a Proteus-likesyndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis

Germline PTEN mutations cause Cowden syndrome (CS) and Bannayan-Riley-Ruval caba syndrome (BRR), two harmatoma-tumour syndromes, and somatic PTEN alter ations have been shown to participate, to a greater or lesser extent, in a wide variety of sporadic neoplasia. PTEN is a tumour suppressor and dual-sp ecificity phosphatase which affects apoptosis via its lipid phosphatase act ivity in the phosphoinositol-3-kinase and AKT pathway as well as inhibiting cell spreading via the focal adhesion kinase pathway. CS and ERR share som e features, such as hamartomas and lipomatosis, To determine whether other syndromes characterized by overgrowth and lipomas are part of the PTEN synd rome spectrum, we ascertained six individuals with overgrowth and lipomas b ut who did not meet the diagnostic criteria for CS or ERR. Five had Proteus syndrome and one, a Proteus-like syndrome. When germline DNA and DNA from at least one involved tissue per case were examined for PTEN mutations, onl y the Proteus-like patient was found to harbour a germline R335X mutation. Interestingly, a lipomatous mass, an epidermoid naevus and arteriovenous ma lformation tissue, all of which were sampled from physically distinct sites , were all found to carry a second hit R130X mutation on the allele opposit e the germline R335X, Both mutations have been described in CS and ERR. We postulate that the second hit. R130X, occurred early in embryonic developme nt ana may even represent germline mosaicism. Thus, PTEN may be involved in Proteus-like syndrome with its implications for cancer development in the future.