Cushing Syndrome results from the prolonged exposure of the body’s tissues to excessive levels of the hormone cortisol. Cortisol, produced by the adrenal glands, helps regulate metabolism and the body’s response to stress, but too much of it creates a cascade of physical changes. While the vast majority of cases are acquired and not passed down through families, a small fraction of Cushing Syndrome diagnoses are directly linked to inherited genetic mutations. Understanding the cause is paramount, as the treatment strategy relies entirely on identifying the source of the cortisol overproduction.
Exogenous vs. Endogenous The Typical Causes of Cushing Syndrome
Most people acquire Cushing Syndrome through external or sporadic internal factors, meaning it is not inherited. The most common cause is exogenous hypercortisolism, which occurs from taking high doses of glucocorticoid medications over an extended period. These synthetic drugs, such as prednisone or dexamethasone, are chemically similar to natural cortisol and are prescribed to treat inflammatory conditions. This is known as iatrogenic Cushing Syndrome, and it stops once the medication is safely discontinued.
When the cause originates inside the body, the condition is termed endogenous Cushing Syndrome. These cases are sporadic, arising from spontaneous tumor formation that is not inherited. The most frequent form is Cushing Disease, accounting for approximately 70% of internal cases. It is caused by a benign pituitary tumor (adenoma) that secretes excess adrenocorticotropic hormone (ACTH), which then overstimulates the adrenal glands to produce cortisol.
Other sporadic endogenous causes include tumors located directly on the adrenal glands, which produce cortisol independently of ACTH stimulation. These adrenal adenomas are typically non-cancerous and arise spontaneously. Rarely, a tumor outside the pituitary or adrenal glands, such as in the lung, can secrete ACTH, leading to ectopic ACTH production. In these sporadic scenarios, the tumor develops due to somatic mutations, which are gene changes that occur only in the tumor cells and cannot be passed to children.
The Rare Inherited Syndromes Linked to Cushing Syndrome
A small percentage of endogenous Cushing Syndrome cases are linked to a germline mutation, meaning the genetic change is present in every cell and was inherited from a parent. These inherited cases often manifest as part of multiple endocrine neoplasia syndromes, which predispose individuals to developing tumors in several hormone-producing glands. For example, Carney Complex (CNC) is an autosomal dominant disorder caused by a mutation in the PRKAR1A gene. This mutation leads to uncontrolled cell growth and frequently causes bilateral adrenal hyperplasia that results in hypercortisolism.
Multiple Endocrine Neoplasia Type 1 (MEN1) is another inherited condition featuring Cushing Syndrome, caused by a mutation in the MEN1 tumor suppressor gene. While pituitary tumors in MEN1 are often prolactin-secreting, they can occasionally be corticotroph adenomas that lead to Cushing Disease. Familial isolated pituitary adenomas (FIPA) can also be a cause, sometimes linked to mutations in the AIP gene, though Cushing Disease development in these families is uncommon.
A different genetic pathway involves the ARMC5 gene, where mutations have been identified in patients with primary bilateral macronodular adrenal hyperplasia (BMAH). BMAH is an adrenal-based cause of Cushing Syndrome. These inherited genetic disorders provide a direct mechanism by which a faulty gene can predispose an individual to developing the tumors or hyperplasia that results in cortisol overproduction.
Determining the Etiology of Cushing Syndrome
Once biochemical tests confirm hypercortisolism, the diagnostic process determines the source of the excess cortisol production. The first step involves a detailed history to rule out the long-term use of glucocorticoid medications. If exogenous use is excluded, professionals measure ACTH levels in the blood to differentiate between pituitary-dependent (high ACTH) and adrenal-dependent (low ACTH) causes.
Imaging studies, such as MRI of the pituitary gland or CT scan of the adrenal glands, are used to locate the tumor. Imaging alone cannot distinguish between a sporadic tumor and one that is part of an inherited syndrome. The patient’s family history is important, as a history of endocrine tumors, skin lesions, or features associated with syndromes like Carney Complex or MEN1 raises suspicion for an inherited cause.
When an inherited cause is suspected, genetic sequencing is performed to look for specific germline mutations, such as in the PRKAR1A or MEN1 genes. Identifying these mutations is particularly important because it influences the treatment approach and allows for genetic counseling and screening of other family members who may be at risk.