Cowden Syndrome

Abstract

Cowden syndrome (CS), due to germline mutations of the PTEN tumor-suppressor gene, is an often overlooked cancer predisposition syndrome associated with an increased risk of breast, thyroid, and endometrial cancers, as well as benign manifestations. Germline PTEN mutations also are associated with syndromes that have not been historically connected to an increase in risk for malignancy. These disorders include Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome (PSL). These syndromes can be described under the umbrella of PTEN hamartoma tumor syndrome (PHTS). As one would expect in allelic disorders, there is broad phenotypic overlap in the PHTS; however, the syndromes are clinically distinct. As additional information is discovered about new syndromes of cancer predisposition and their concordant genes, oncologists and allied healthcare providers must maintain vigilance to appropriately identify, and screen, individuals at an increased risk. Although CS is the only PHTS with a clearly documented predisposition to malignancies, pending further data, for precautionary reasons all individuals with a germline PTEN mutation are recommended to follow the cancer surveillance recommendations for CS.

PTEN signaling in brain: neuropathology and tumorigenesis

“…Other neurological manifestations of inherited PTEN mutation include decreased or delayed learning, such as mental retardation (IQ o75), which is a minor criterion for diagnosis of Cowden's syndrome (Gustafson et al, 2007). Macrocephaly is common and several studies have identified autism or autistic behaviors in PHTS patients with this feature (Goffin et al, 2001;Butler et al, 2005).…”

“…The diagnostic criteria for each of these disorders have overlapping features, such as the presence of hamartomas, although only Cowden's syndrome includes cancer predisposition (Gustafson et al, 2007). Comprehensive analysis of germline mutations in PTEN reveals missense, nonsense, frameshift and splice site mutations distributed throughout the gene, as well as small deletions or insertions and larger deletions encompassing whole exons, or in some cases whole gene deletions or translocation (Figure 2).…”

Breast cancer: Molecular basis and therapeutic strategies (Review)

“…Germline mutations of PTEN are associated with Cowden syndrome (CS), a multihamartomatous disorder and rare Mendelian syndrome that includes as part of its phenotype breast cancer (22), an increased risk of thyroid and endometrial cancers, and benign manifestations (23). CS patients with germline PTEN promoter mutations have aberrant PTEN protein expression and an increased frequency of breast cancer (21).…”

The Metabolic Basis of Kidney Cancer

“…(73)(74)(75) The protein product of the PTEN gene, PTEN, is a phosphatase that catalyzes the conversion of PIP3 (phosphatidylinositol 3,4,5 triphosphate) to PIP2 (phosphatidylinositol 4,5 biphosphate). In response to growth factor receptor stimulation, intracellular PIP3 rises, leading to activation of a number of effectors, including AKT/mTOR pathway, then PTEN lowers the levels of PIP3 to abrogate the response.…”