Cowden Syndrome and the PTEN Hamartoma Tumor Syndrome: Systematic Review and Revised Diagnostic Criteria

“…Current data supports the hypothesis that both benign and malignant thyroid disease are a part of CS however again, due to the prevalence in the general population, this has a low predictive value for identifying those affected by mutations [ 2 ]. In particular however, follicular thyroid cancer appears overrepresented in PTEN mutation carriers compared with the general population [ 2 ]. Follicular thyroid cancer is thus included as a major criterion with papillary thyroid cancer and benign thyroid nodules considered as minor criteria [ 2 ] (Table 1 ).…”

“…Patients with TSC often grow lesions that disrupt the laminar organization of the cortex, nucleating epileptogenic foci; these patients may also have enlarged neurons and 'giant' astrocytes 193 . Similar phenotypes are found in patients with inactivating mutations in the negative PI3K regulator PTEN 194 , the AMPK activator STRADα 195 and the negative regulatory complexes GATOR1 and KICSTOR 196,197,198,199,200 , as well as those with activating mutations in Rheb or mTOR 201,202,203 . Given that mTORC1 has many roles in defining the morphology of the developing brain, the epilepsy that clinically distinguishes these disorders is likely seeded by prenatal neuronal mis-wiring 204 .…”

“…1 Although germline mutations in PIK3CA, AKT1, SDHB, and SDHD genes as well as KLLN epimutation have been reported in rare cases of CS and Cowden-like syndrome, 12,14,15 a germline inactivating mutation of the PTEN gene was confirmed in our case.…”

“…Current data supports the hypothesis that both benign and malignant thyroid disease are a part of CS however again, due to the prevalence in the general population, this has a low predictive value for identifying those affected by mutations [ 2 ]. In particular however, follicular thyroid cancer appears overrepresented in PTEN mutation carriers compared with the general population [ 2 ]. Follicular thyroid cancer is thus included as a major criterion with papillary thyroid cancer and benign thyroid nodules considered as minor criteria [ 2 ] (Table 1 ).…”

“…Patients with TSC often grow lesions that disrupt the laminar organization of the cortex, nucleating epileptogenic foci; these patients may also have enlarged neurons and 'giant' astrocytes 193 . Similar phenotypes are found in patients with inactivating mutations in the negative PI3K regulator PTEN 194 , the AMPK activator STRADα 195 and the negative regulatory complexes GATOR1 and KICSTOR 196,197,198,199,200 , as well as those with activating mutations in Rheb or mTOR 201,202,203 . Given that mTORC1 has many roles in defining the morphology of the developing brain, the epilepsy that clinically distinguishes these disorders is likely seeded by prenatal neuronal mis-wiring 204 .…”

“…1 Although germline mutations in PIK3CA, AKT1, SDHB, and SDHD genes as well as KLLN epimutation have been reported in rare cases of CS and Cowden-like syndrome, 12,14,15 a germline inactivating mutation of the PTEN gene was confirmed in our case.…”

“…Current data supports the hypothesis that both benign and malignant thyroid disease are a part of CS however again, due to the prevalence in the general population, this has a low predictive value for identifying those affected by mutations [ 2 ]. In particular however, follicular thyroid cancer appears overrepresented in PTEN mutation carriers compared with the general population [ 2 ]. Follicular thyroid cancer is thus included as a major criterion with papillary thyroid cancer and benign thyroid nodules considered as minor criteria [ 2 ] (Table 1 ).…”

“…Patients with TSC often grow lesions that disrupt the laminar organization of the cortex, nucleating epileptogenic foci; these patients may also have enlarged neurons and 'giant' astrocytes 193 . Similar phenotypes are found in patients with inactivating mutations in the negative PI3K regulator PTEN 194 , the AMPK activator STRADα 195 and the negative regulatory complexes GATOR1 and KICSTOR 196,197,198,199,200 , as well as those with activating mutations in Rheb or mTOR 201,202,203 . Given that mTORC1 has many roles in defining the morphology of the developing brain, the epilepsy that clinically distinguishes these disorders is likely seeded by prenatal neuronal mis-wiring 204 .…”

“…1 Although germline mutations in PIK3CA, AKT1, SDHB, and SDHD genes as well as KLLN epimutation have been reported in rare cases of CS and Cowden-like syndrome, 12,14,15 a germline inactivating mutation of the PTEN gene was confirmed in our case.…”