Genetics of micronodular hyperplasias (associated with Cushing syndrome)
The overwhelming majority of benign lesions of the adrenal cortex (AC) leading to Cushing syndrome (CS) are linked to one or another abnormality of the cAMP signaling pathway. Benign adrenocortical causes of CS include the common and sporadic cortisol-producing adenoma (CPA) and a spectrum of corticotropin (ACTH)-independent, and almost always bilateral, hyperplasias. Macro-hyperplasias are more common among older patients, whereas micro-hyperplasias are frequent among children and young adults. Massive macronodular adrenocortical disease (MMAD) or ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) describes a heterogeneous group of disorders that are associated with aberrant G-protein-coupled receptor (GPCR) expression (E). Abnormal GPCR-E has been found in CPAs; a small number of both MMADs and CPAs harbor somatic GNAS (Gsa) mutations. AIMAH can also be found in the context of McCune-Albright syndrome. Micro-hyperplasias are either pigmented (the classic form being that of primary pigmented nodular adrenocortical disease or PPNAD) or non-pigmented (NP-MAH) and isolated (i) or in the context of other syndromes (Carney complex CNC). CNC and iPPNAD are caused by germline PRKAR1A mutations; somatic mutations of this gene that regulates cAMP-dependent protein kinase (PKA) are also found in 1020% of all CPAs and abnormalities of PKA are present in MMADs. NP-MAH forms of adrenal hyperplasia and some CPAs are associated with phopshodiesterase (PDE)-11A and PDE-8B defects. Mouse models of PRKAR1A deficiency also show that increased cAMP signaling leads to tumors in AC and other tissues. Micro-RNA studies identified the Wnt-signaling pathway as a possible culprit. We also investigated Prkar1a (±) mice when bred within the Rb1 (±) or Trp53 (±) backgrounds. These studies identified Wnt signaling as the main pathway activated by abnormal cAMP signaling. Prkar1a haploinsufficiency is a relatively weak tumorigenic signal that can act synergistically with other defects to induce tumors, mostly through Wnt-signaling activation and cell cycle dysregulation.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.