An adrenal adenoma is a common, non-cancerous growth that forms in the cortex, or outer layer, of the adrenal glands. These small, triangular organs sit atop the kidneys and produce hormones like cortisol and aldosterone, which help regulate metabolism, blood pressure, and the body’s response to stress. Adenomas are the most frequent type of adrenal mass. They are often discovered incidentally when a person undergoes an imaging test like a CT scan or MRI for an unrelated health concern, leading to the term adrenal incidentalomas. The vast majority of these growths do not cause symptoms or require treatment. The underlying cause of an adenoma is directly linked to whether the tumor is silently present or actively producing excess hormones.
Classification: Functional Versus Non-Functional Tumors
Physicians classify adrenal adenomas based on their hormonal activity. Non-functional adenomas are the most common type, making up about 80% of all incidentalomas. They do not produce hormones in amounts large enough to disrupt the body’s normal functions and are usually monitored over time.
Functional adenomas cause serious hormonal disorders because the tumor cells produce hormones autonomously. This hormone overproduction is not regulated by the body’s normal feedback mechanisms, leading to a state of chronic excess. The two most commonly encountered types are cortisol-producing and aldosterone-producing adenomas.
Cortisol-producing adenomas cause Cushing syndrome, or more frequently, mild autonomous cortisol excess (MACE). Aldosterone-producing adenomas lead to primary hyperaldosteronism, historically known as Conn syndrome, which is characterized by high blood pressure and sometimes low potassium levels.
The Mechanisms of Sporadic Genetic Mutations
The formation of most adrenal adenomas is due to sporadic, or somatic, genetic mutations. These are DNA changes that occur in a single cell during a person’s lifetime and are not inherited. These acquired mutations grant the cell an advantage, leading to uncontrolled growth and, in functional tumors, perpetual hormone synthesis.
A significant proportion of aldosterone-producing adenomas are caused by a mutation in the KCNJ5 gene, which codes for the GIRK4 potassium channel protein. When mutated, the channel malfunctions, allowing an abnormal flow of positive ions into the cell. This causes membrane depolarization, which subsequently activates voltage-gated calcium channels, leading to a sustained increase in intracellular calcium.
Elevated intracellular calcium drives the excessive activity of the enzyme aldosterone synthase, resulting in the continuous and autonomous production of aldosterone. Other genes, such as CACNA1D, ATP1A1, and ATP2B3, are also found mutated in these adenomas, all disrupting ion balance to trigger hormone overproduction.
In cortisol-producing adenomas, two major sporadic genetic pathways are frequently involved. One involves mutations in the PRKACA gene, which codes for a component of Protein Kinase A (PKA). The mutation causes PKA to be constantly active, acting like an “on” switch for the cell to produce cortisol regardless of the body’s need.
The other mechanism involves a mutation in the CTNNB1 gene, a core component of the Wnt/beta-catenin signaling pathway. A change in this gene stabilizes the beta-catenin protein, preventing its normal breakdown. This accumulation enters the cell nucleus, where it activates genes that promote cell division and tumor growth, contributing to both cortisol-producing and non-functional adenomas.
Inherited Syndromes and Predisposition
While the majority of adrenal adenomas are sporadic, a small percentage result from inherited, or germline, mutations. These genetic changes are present in all cells from birth and predispose an individual to developing adenomas, often at a younger age or affecting both adrenal glands. These inherited conditions typically involve genetic defects that cause tumors in multiple endocrine glands, not just the adrenal glands.
One such condition is Multiple Endocrine Neoplasia Type 1 (MEN1), caused by a mutation in the MEN1 gene. Individuals with MEN1 have a heightened risk for adenomas, which may be non-functioning or produce excess cortisol or aldosterone. The adrenal involvement in MEN1 is part of a broader risk for tumors in the parathyroid glands and the pancreas.
Carney Complex is another inherited disorder that causes Primary Pigmented Nodular Adrenocortical Disease (PPNAD). This condition is due to a mutation in the PRKAR1A gene, resulting in multiple small, pigmented nodules that overproduce cortisol, leading to Cushing syndrome. The same genetic defect also predisposes individuals to tumors in the heart and skin.
Familial Primary Aldosteronism (FAPA) represents a group of rare, inherited conditions where the genetic defect specifically causes the adrenal glands to overproduce aldosterone. For instance, Familial Hyperaldosteronism Type III is caused by a germline mutation in the KCNJ5 gene, the same gene frequently mutated in sporadic aldosterone-producing tumors.