*1.4. Thyroid Cancer as Part of Genetic Syndromes*

Thyroid malignancies are also associated with at least two syndromes with inherited tumor predisposition, Cowden syndrome (CS, OMIM# 158350) and Carney Complex (CNC, OMIM #160980). CS is a multiple hamartoma syndrome, including FTC, brain and breast cancer. It is caused by inactivating mutations in the *PTEN* gene, a dual-specificity phosphatase that negatively regulates PI3 Kinase/AKT pathway; mutations in this gene have been detected in 5% of FTCs [22]; however, a mouse harboring a deletion of *Pten* in the thyroid developed thyroid hyperplasia and not FTC [23].

In this review, we will focus on CNC, which is a multiple neoplasia syndrome that presents as the complex of myxomas, spotty skin pigmentation and endocrine tumors (Table 1) [24]. CNC is caused by inactivating mutations in the *PRKAR1A* gene (mapped in 17q22–24) [25]; somatic mutations in this gene have been reported in sporadic cases of thyroid cancer [26]. In tumors associated with CNC as well as in thyroid and adrenal tumors with downregulation of *PRKAR1A*, allelic losses of the 17q22–24 *PRKAR1A* chromosomal locus are frequently identified and are associated with changes in PKA activity [26–29].


#### **Main Diagnostic Criteria**


#### **Supplementary Criteria**


<sup>a</sup> with histologic confirmation; *LCCSCT* large cell calcifying Sertoli cell tumor, *PPNAD* primary pigmented nodular adrenocortical disease; To make a diagnosis of CNC, a patient must either: (1) exhibit two of the manifestations of the disease listed, or (2) exhibit one of these manifestations and meet one of the supplemental criteria.
