Proteus syndrome (PS, OMIM 176920) is a hamartoma-tous disorder characterised by overgrowth of multiple tissues, connective tissue and epidermal naevi, and vascular malformations. 1 These presentations are usually apparent at birth or soon after and continue to develop as the patient ages. It is named after the Greek god Proteus who, legend has it, could change his shape at will to avoid capture. It is probably the disease suffered by the Elephant Man. 2 Tumours, mostly benign but some malignant, have also been reported in PS, generally presenting by the age of 20 years and including papillary adenocarcinoma of the testis, meningioma, and cystadenoma of the ovaries. 3 Given the predominantly sporadic nature of this syndrome and the mosaic distribution of lesions, it has been suggested that PS may be caused by somatic mosaicism for a genetic change that is lethal in the non-mosaic state. 4

Clinical overlap, in the form of tissue overgrowth, macrocephaly, and the presence of lipomas, exists between PS and another hamartoma syndrome, Bannayan-Riley-Ruvalcaba syndrome (BRR, OMIM 153480), 5 in which up to 60% of affected subjects are known to carry a germline mutation of the tumour suppressor gene PTEN. 6 BRR also shows partial clinical overlap with Cowden syndrome (CS, OMIM 158350), in which affected subjects are at risk of developing hamartomas in multiple organs including the breast, thyroid, central nervous system, skin, and gastrointestinal tract, as well as malignant tumours of the breast, thyroid, and endometrium. PTEN is mutated in the germline in up to 80% of patients with CS. 6 Two recent reports have shown germline, and probably germline mosaic, PTEN mutations in a subset of patients with PS or a PS-like disorder, 7 8 although other studies of patients with PS have been unable to confirm these findings. 9 10 PTEN is a dual specificity phosphatase, shown in vitro to dephosphorylate protein substrates on threonine, serine, and tyrosine residues as well as lipid substrates. 6 In the phosphatidylinositol 3-kinase (PI3-kinase) pathway, PTEN functions as a 3 phosphatase, dephosphorylating phosphatidylinositol (3, 4, 5) triphosphate [PtdIns (3, 4, 5) P3] to PtdIns (4, 5) P2. When PTEN is mutant, PtdIns (3, 4, 5) P3 accumulates, activating the serine threonine kinase AKT, a known anti-apoptotic factor, leading to cell survival. In addition to being mutated in the germline in CS and BRR, somatic loss of function PTEN mutations are seen in a wide range of sporadic human tumours, including endometrial cancer, glioblastoma, and prostate cancer. Given the clinical overlap between PTEN associated syndromes and PS, as well as the conflicting studies of PTEN and PS recently published, we sought to determine whether a patient presenting with classical PS harboured a germline