Is Cushing Syndrome Genetic? The Role of Heredity and Causes
Gain a clearer understanding of the causes behind Cushing syndrome and the limited, specific role that genetic inheritance plays in its development.
Cushing syndrome is a condition caused by prolonged exposure to high levels of the hormone cortisol, leading to symptoms like weight gain, fragile skin, and fatigue. While most cases of Cushing syndrome are not inherited, some rare forms are connected to genetic factors that increase the risk of developing the underlying causes. The potential role of genetics depends on the specific origin of the excess cortisol, which explains why some families may see a pattern of the syndrome.
Differentiating the Causes of Cushing Syndrome
The origins of Cushing syndrome are divided into two categories. The most frequent cause is exogenous Cushing syndrome, which develops from factors outside the body, specifically the long-term use of corticosteroid medications. Because it is a result of medication, this type is not inherited.
A much rarer form is endogenous Cushing syndrome, which occurs when the body itself produces too much cortisol. This internal overproduction is caused by tumors on the adrenal glands or the pituitary gland at the base of the brain. The pituitary gland produces a hormone called ACTH that signals the adrenal glands to release cortisol. It is within this endogenous category that a hereditary link can sometimes be found.
The Role of Genetics in Endogenous Cushing Syndrome
Most cases of endogenous Cushing syndrome are considered “sporadic,” meaning they happen randomly in individuals with no family history of the disorder. These sporadic cases are often due to somatic mutations, which are genetic changes that occur in a single cell during a person’s lifetime and are not passed down. For example, somatic mutations in the USP8 gene are a common finding in the pituitary tumors that cause many cases of Cushing’s disease.
Only a small fraction of cases are “familial,” meaning they are linked to an inherited gene mutation. In these instances, an individual inherits a genetic variant that increases their risk of developing tumors in the endocrine glands. These tumors are what ultimately lead to the overproduction of cortisol.
Inherited Conditions Associated with Cushing Syndrome
Several rare, inherited syndromes are known to increase the risk of developing tumors that cause Cushing syndrome.
- Multiple Endocrine Neoplasia, type 1 (MEN1) is an autosomal dominant disorder caused by mutations in the MEN1 gene. It predisposes individuals to tumors in various endocrine glands, including the pituitary and adrenal glands, though only a fraction of these secrete the ACTH hormone that leads to Cushing syndrome.
- Carney complex (CNC) results from mutations in the PRKAR1A gene and is characterized by spotty skin pigmentation and various endocrine tumors. Approximately 25% of individuals with Carney complex develop primary pigmented nodular adrenocortical disease (PPNAD), which directly causes cortisol overproduction.
- Familial Isolated Pituitary Adenoma (FIPA) is a condition linked to an inherited predisposition for developing pituitary tumors. Mutations in the AIP gene are found in some FIPA families, and although Cushing’s disease is rare within this group, it can occur.
- Primary Pigmented Nodular Adrenocortical Disease (PPNAD) can also be a familial condition on its own, sometimes occurring outside of Carney complex, and is also associated with Cushing syndrome.
Genetic Testing and Family Risk
A doctor might recommend genetic testing if Cushing syndrome onsets at a very young age, there is a personal or family history of endocrine tumors, or if other physical signs suggest a specific genetic syndrome. The decision to test is made to identify an underlying hereditary cause, which has implications for long-term health monitoring.
If a hereditary link is suspected, genetic counseling is an important step. A genetic counselor helps individuals understand the testing process, the meaning of the results, and the potential implications for themselves and their relatives, providing context on inheritance patterns and risk.
When an inherited mutation is identified, first-degree relatives, such as siblings and children, may also be at risk. Most of these syndromes are inherited in an autosomal dominant pattern, meaning a child of an affected parent has a 50% chance of inheriting the gene mutation. This does not guarantee they will develop Cushing syndrome, but it does mean they have an increased risk and may benefit from regular screening.