PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome

Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndr ome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 an d encodes a dual specificity phosphatase, a substrate of which is phosphati dylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increas ed risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documen ted in ERR. The partial clinical overlap in these two syndromes is exemplif ied by the hallmark features of ERR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional fea tures observed in ERR, which may also occur in a minority of CS patients, i nclude Hashimoto's thyroiditis, vascular malformations and mental retardati on. Pigmented macules of the glans penis, delayed motor development and neo natal or infant onset are noted only in ERR. In this study, constitutive DN A samples from 43 ERR individuals comprising 16 sporadic and 27 familial ca ses, 11 of which were families with both CS and ERR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) ERR cases. Genotype -phenotype analyses within the ERR group suggested a number of correlations , including the association of PTEN mutation and cancer or breast fibroaden oma in any given CS, ERR or BRR/CS overlap family (P = 0.014), and, in part icular, truncating mutations were associated with the presence of cancer an d breast fibroadenoma in a given family (P = 0.024). Additionally, the pres ence of lipomas was correlated with the presence of PTEN mutation in ERR pa tients (P = 0.028). In contrast to a prior report, no significant differenc e in mutation status was found in familial versus sporadic cases of ERR (P = 0.113). Comparisons between ERR and a previously studied group of 37 CS f amilies suggested an increased likelihood of identifying a germline PTEN mu tation in families with either CS alone or both CS and ERR when compared wi th ERR alone (P = 0.002). Among CS, ERR and BRR/CS overlap families that ar e PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN m utation-positive CS and ERR may be different presentations of a single synd rome and, hence, both should receive equal attention with respect to cancer surveillance.