Carney complex and primary pigmented nodular adrenocortical diasease
The Carney complex (CNC) is a dominantly inherited syndrome characterized by spotty skin pigmentation, endocrine overactivity and myxomas. The most common endocrine gland manifestations are acromegaly, thyroid tumors, testicular tumors, and ACTH-independent Cushings syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). PPNAD, a rare cause of Cushings syndrome, is due to primary bilateral adrenal defect that can be also observed in some patients without other CNC manifestations nor familial history of the disease. Myxomas can be observed in the heart, skin and breast. Cardiac myxomas can develop in any cardiac chamber and may be multiple. One of the putative CNC genes located on 17q22-24, (PRKAR1A), has been identified to encode the regulatory subunit (R1A) of protein kinase A. Heterozygous inactivating mutations of PRKAR1A were reported initially in 45 to 65% of CNC index cases, and may be present in about 80% of the CNC families presenting mainly with Cushings syndrome. PRKAR1A is a key component of the cAMP signaling pathway that has been implicated in endocrine tumorigenesis and could, at least partly, function as a tumor suppressor gene. More recently, germline inactivating mutations of PDE11A4 have been identified in patients with isolated primary nodular adrenocortrical disease. This underlines the importance of the cAMP signalling pathway in the pathophysiology of secreting endocrine tumors. Somatic PRKAR1A mutations have been observed in adrenal adenomas responsible for Cushing syndrome. In vitro and transgenic models have been developped to study the consequences of PRKAR1A inactivation. In these models dysregulation of the cAMP pathway, but also others signalling pathways, have been observed. The new insights coming from the genetics of CNC and these experimental models in the pathophysiology of endocrine tumorigenesis will be discussed.