Human Molecular Genetics, 2000, Vol. 9, No. 5 765-768
© 2000 Oxford University Press
Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis
1Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA, 2Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA, 3Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA and 4CRC Human Cancer Genetics Research Group, University of Cambridge, Cambridge CB2 2QQ, UK
Germline PTEN mutations cause Cowden syndrome (CS) and Bannayan–Riley–Ruvalcaba syndrome (BRR), two harmatoma-tumour syndromes, and somatic PTEN alterations 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-specificity phosphatase which affects apoptosis via its lipid phosphatase activity in the phosphoinositol-3-kinase and AKT pathway as well as inhibiting cell spreading via the focal adhesion kinase pathway. CS and BRR share some features, such as hamartomas and lipomatosis. To determine whether other syndromes characterized by overgrowth and lipomas are part of the PTEN syndrome spectrum, we ascertained six individuals with overgrowth and lipomas but who did not meet the diagnostic criteria for CS or BRR. 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, only the Proteus-like patient was found to harbour a germline R335X mutation. Interestingly, a lipomatous mass, an epidermoid naevus and arteriovenous malformation tissue, all of which were sampled from physically distinct sites, were all found to carry a second hit R130X mutation on the allele opposite the germline R335X. Both mutations have been described in CS and BRR. We postulate that the second hit, R130X, occurred early in embryonic development and may even represent germline mosaicism. Thus, PTEN may be involved in Proteus-like syndrome with its implications for cancer development in the future.
+ To whom correspondence should be addressed at: Human Cancer Genetics Program, Ohio State University, 420 West 12th Avenue, Room 690C MRF, Columbus, OH 43210, USA. Tel: +1 614 688 4508; Fax: +1 614 688 3582 or 4245; Email: eng-1@medctr.osu.edu
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