This case highlights the importance of early screening for PTEN mutations in cases of hemimegalencephaly not otherwise explained by another disorder, even in the absence of signs of Proteus syndrome or the full manifestations of Bannayan-Riley Ruvalcaba syndrome.
Sequencing analysis confirmed the presence of PTEN splice-acceptor site mutation in intron 8 (c.1027-2A>G), a germline mutation which had not been previously reported in CS.
Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers.
Furthermore, we review the PTEN mutation positive BRRS cases, to further delineate the phenotype and to compare the cases with a genomic deletion with the cases with a point mutation.
We review the scanty literature data on the association of Cowden syndrome and autism and emphasize that the association of progressive macrocephaly and pervasive developmental disorder seems to be an indication for screening for PTEN mutations.
While germline mutations at this chromosome 10q22-23 locus have been observed in patients with Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR), both of which phenotypes are associated with hamartomata and neoplasia, somatic mutation of PTEN has been established in a wide variety of sporadically occurring neoplasia.
PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model.
This report provides clinical evidence that both BRR and CD are closely related and confirms the PTEN gene mutation in BRR and CD patients segregating in the same family, thus confirming the genetic linkage between the two genodermatoses.
We have trialled denaturing high-performance liquid chromatography (dHPLC) as a tool for rapid germline mutation scanning of genes implicated in three familial cancer syndromes -- Cowden syndrome (PTEN mutation), multiple endocrine neoplasia type 2 (RET mutation) and von Hippel-Lindau disease (VHL mutation).
To our knowledge, this is the first report that shows the presence of separate subjects with CS and with BZS in a single family associated with a single germline PTEN mutation.
Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR 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).
Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR 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).
Here we report that a missense mutation in PTEN, PTEN-G129E, which is observed in two Cowden disease kindreds, specifically ablates the ability of PTEN to recognize inositol phospholipids as a substrate, suggesting that loss of the lipid phosphatase activity is responsible for the etiology of the disease.
In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480).