PTEN hamartoma tumour syndrome: variability of an entity.

C owden syndrome (CS; OMIM 158350) is an autosomal dominant disorder with age related penetrance characterised by mucocutaneous lesions, macrocephaly and an increased risk of cancer, especially of the breast, thyroid and endometrium. 2 The phenotype in CS has proven to be highly variable, which became especially evident after identification of the susceptibility gene PTEN. 4 This is also shown in the change in incidence figures, which were found to be at least five times higher after PTEN was identified (estimated incidence before PTEN identification 1:1 000 000, and after .1:200 000. ). Bannayan-Riley-Ruvalcaba syndrome (BRRS; OMIM 153480) is allelic to CS and is characterised by the triad of macrocephaly, lipomas, and pigmented macules of the glans penis. Proteus syndrome (PS; OMIM 176920) is a disorder characterised by overgrowth of hands and/or feet, asymmetry of limbs, connective tissue, and epidermal naevi, vascular and lymphatic malformations, and cranial hyperostosis. Proteus-like syndrome (PLS) is another closely related disorder, where individuals are characterised by the presence of macrocephaly, lipomas and overgrowth not meeting the criteria for CS, BRRS, or PS. Germline PTEN mutations have been found in 80% of individuals with CS, 60% of individuals with BRRS, up to 20% with PS, and 50% with PLS. 10 Here, we present a family (a mother and three sons) in which phenotype was extremely variable, one member having macrocephaly, normal intelligence, and minimal pigmentation abnormalities; another member with macrocephaly with developmental delay; another with macrocephaly, delay and lipoma; and the last member having hemimegalencephaly (HME), Jadassohn naevus sebaceous, and neonatal demise. All were found to have the same germline mutation in PTEN.