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 syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in ERR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of ERR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in ERR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in ERR. In this study, constitutive DNA samples from 43 ERR individuals comprising 16 sporadic and 27 familial cases, 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 fibroadenoma in any given CS, ERR or BRR/CS overlap family (P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family (P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in ERR patients (P = 0.028). In contrast to a prior report, no significant difference 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 families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and ERR when compared with ERR alone (P = 0.002). Among CS, ERR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and ERR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.