Lack of Genetic Mutation May Still Indicate Glucocorticoid Resistance Syndrome, Case Study Suggests

Patients with high levels of cortisol but no clinical symptoms of Cushing’s syndrome can instead have a disease known as glucocorticoid resistance syndrome, according to a case report that documented a woman who had glucocorticoid resistance syndrome but without its associated genetic mutation.

The study, “Cushing’s syndrome with no clinical stigmata – a variant of glucocorticoid resistance syndrome,” was published in the journal Clinical Diabetes and Endocrinology.

Cushing’s syndrome is a condition characterized by hypercortisolism, which refers to high levels of cortisol in the body. It is a well-characterized disease, with easily identifiable clinical features.

However, a subset of patients with hypercortisolism do not show any clinical features that would suggest Cushing’s syndrome. In these cases, researchers have to consider other possibilities, such as pseudo-Cushing’s, cyclic Cushing’s syndrome, or glucocorticoid resistance syndrome.

The case study describes a 41-year-old woman who was referred to the Michigan State University endocrinology clinic in 2008 to undergo a cortisol test as she suffered from hirsutism (excessive body hair) and irregular menstrual cycles, which are symptoms of Cushing’s syndrome.

A physical examination showed her blood pressure and body mass index to be normal. She had mildly increased hair on her chin and a thyroid nodule (mass), but no other clinical features of Cushing’s syndrome. The patient also had high cortisol levels, which was caused by high levels of the adrenocorticotropic hormone (ACTH) — a hormone that provides the instructions for the adrenal glands to produce cortisol. However, she continued to show no clinical signs of Cushing’s syndrome.

The patient was started on metformin, which led to some improvement in hirsutism. She also met another endocrinologist for a second opinion, and was told no further workup was needed until she started to show clinical signs of Cushing’s.

Over the next 10 years, the patient did not develop any further signs of Cushing’s syndrome or pseudo-Cushing’s. Furthermore, the clinicians excluded the possibility of cyclic Cushing’s syndrome as the patient had persistently elevated cortisol levels during this time.

This led physicians to suspect she had glucocorticoid resistance syndrome, a disease characterized by high cortisol levels with no clinical signs of Cushing’s syndrome. Generally, patients with glucocorticoid resistance syndrome have mutations in the human glucocorticoid receptor (hGR) gene. Therefore, clinicians had the patient undergo genetic testing of the hGR gene, which revealed she had no mutations.

The “majority of patients, but not all, have a genetic mutation in the hGR NR3C1 gene,” the investigators said. “Although we were not able to identify any new mutations, we believe that our patient has a variant of the glucocorticoid resistance syndrome.”

Typically, high doses of medicines such as dexamethasone can be used to suppress cortisol levels in patients with glucocorticoid resistance syndrome. However, the treatment should be individualized to the patient’s condition, the researchers wrote.

“Mild asymptomatic patients, such as ours, may not require suppression by dexamethasone,” they said.