The overwhelming majority of benign lesions of the adrenal cortex leading to
Cushing syndrome are linked to one or another abnormality of the cAMP signaling pathway. A small number of both massive macronodular adrenocortical disease and
cortisol-producing
adenomas harbor somatic GNAS mutations. Micronodular adrenocortical
hyperplasias are either pigmented (the classic form being that of primary pigmented nodular adrenocortical disease) or non-pigmented; micronodular adrenocortical
hyperplasias can be seen in the context of other conditions or isolated; for example, primary pigmented nodular adrenocortical disease usually occurs in the context of
Carney complex, but isolated primary pigmented nodular adrenocortical disease has also been described. Both
Carney complex and isolated primary pigmented nodular adrenocortical disease are caused by germline PRKAR1A mutations; somatic mutations of this gene that regulates
cAMP-dependent protein kinase are also found in
cortisol-producing
adenomas, and abnormalities of PKA are present in most cases of massive macronodular adrenocortical disease. Micronodular adrenocortical
hyperplasias and some
cortisol-producing
adenomas are associated with
phosphodiesterase 11A and 8B defects, coded, respectively, by the PDE11A and PDE8B genes. Mouse models of Prkar1a deficiency also show that increased cAMP signaling leads to
tumors in adrenal cortex and other tissues. In this review, we summarize all recent data from ours and other laboratories, supporting the view that Wnt-signaling acts as an important mediator of tumorigenicity induced by abnormal PRKAR1A function and aberrant cAMP signaling.