People who are obese and have type 2 diabetes, as well as those with high blood pressure, have an increased risk of developing Cushing's syndrome, a relatively rare hormonal disorder. Now, researchers have discovered how mutations in the PRKACA gene, which contains part of the information needed to make an enzyme that provides energy for governing basic cell functions, may contribute to a particularly severe form of Cushing’s syndrome. Their work appears in the New England Journal of Medicine.

Cushing's syndrome is sometimes called hypercortisolism because it is a hormonal disorder caused by high levels of the stress hormone cortisol. Commonly, it affects adults between 20 and 50, though children may develop it as well. Outward signs include upper body obesity, a rounded face, a fatty hump between the shoulders, and relatively slender arms and legs. Women with Cushing's syndrome often have excess hair growth on their face, neck, chest, abdomen, and thighs. Symptoms also may include high blood pressure, severe fatigue, muscle weakness, and osteoporosis.

Sometimes the body itself will produce excess cortisol, causing Cushing’s syndrome. In other cases, people may develop the disorder because they are taking synthetic glucocorticoids, a class of steroid hormones that are chemically similar to cortisol. Prednisone, dexamethasone, and hydrocortisone are among the available glucocorticoids, which are commonly used to treat asthma, rheumatoid arthritis, lupus, and other inflammatory diseases. Glucocorticoids are also prescribed to suppress the immune system after transplantation to keep the body from rejecting the new organ or tissue.

Summary of the Research

For their study on Cushing’s syndrome, an international team of researchers examined tissue from patients who have a severe form of the disorder. In this form, it is a noncancerous tumor in just one of the adrenal glands that is producing the excess cortisol and causing symptoms. After examining samples from nearly 200 such adrenal gland tumors, they discovered 37 percent contained a mutation in the gene known as PRKACA. The PRKACA gene contains the information needed to make a subunit of the PKA (protein kinase A) enzyme, which is involved in numerous chemical reactions in the cell.

“The mutation we identified appears to give rise to one of the most common kinds of adrenal tumors seen in Cushing’s syndrome,” said Dr. Constantine Stratakis, director of the Division of Intramural Research and head of the Program on Developmental Endocrinology and Genetics at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. “The discovery suggests a clear path forward for investigating medications that might block the production of excess cortisol.”

The researchers discovered that the mutant PRKACA gene was found only in the tumor cells, and not in other cells of the body. Because the gene was not found in other cells of the body, the mutation likely arose spontaneously in the adrenal tissue, where it increased the activity of the PKA enzyme. “The mutation appears to spur the activity of this enzyme,” Dr. Stratakis stated in a press release. “The result appears to be an increase in cell growth and division in adrenal tissue, and an overproduction of cortisol.”

Source: Stratakis CA, Beuschlein F, Fassnacht M, et al. Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome. New England Journal of Medicine. 2014.