Mutations in the GNAS gene might indicate patients with subclinical Cushing’s syndrome — mild cortisol elevation without physical signs of Cushing’s — whose disease is caused by distinct mechanisms of other Cushing’s syndrome patients.
Screening for GNAS gene mutations may help diagnose patients with this type of Cushing’s syndrome and improve their outcomes, researchers say.
The report, “A case of autonomous cortisol secretion in a patient with subclinical Cushing’s syndrome, GNAS mutation, and paradoxical cortisol response to dexamethasone,” was published in the journal BMC Endocrine Disorders.
The production of cortisol and other adrenal hormones is mainly regulated by the cAMP-dependent protein kinase A (PKA) signaling pathway. Mutations in this pathway are known to cause adrenal tumors, excess adrenal hormones, and in some cases, Cushing’s syndrome.
Some patients develop a condition called primary pigmented nodular adrenocortical disease (PPNAD), a rare disease where multiple small masses in the adrenal glands cause abnormally high levels of cortisol. In these patients, responses to dexamethasone are paradoxical, with levels of cortisol increasing even further.
PPNAD patients have mutations in the cAMP-dependent protein kinase type 1α regulatory subunit (PRKAR1A) — a key player in the cAMP-dependent PKA pathway — but researchers now described the case of a 65-year-old woman who had similar responses to dexamethasone without any such mutations.
The woman had been diagnosed with subclinical Cushing’s syndrome. Despite failing to show the typical signs of Cushing’s syndrome — round face, acne, weight gain and poor muscle tone — the patient had mildly elevated cortisol levels that increased in urine after dexamethasone administration.
She had functioning adrenal adenomas — benign tumors in both adrenal glands that secreted both cortisol and androgen — as well as tumors in several other organs, including the heart, brain, thyroid gland, colon, and pancreas.
The patient underwent a non-invasive surgery, called laparoscopy, to remove the right adrenal gland tumor. Genetic analysis of the resected tumor revealed the presence of a mutation in the GNAS gene as the driving mechanism of the subclinical Cushing’s syndrome.
These mutations have been described as McCune-Albright syndrome — a disorder that affects the skin, bones, and several hormone-producing organs — and in some adrenal tumors producing too much cortisol, but a paradoxical response to dexamethasone had not been described in such patients.
After the laparoscopy, cortisol levels in the blood and urine decreased. However, the paradoxical response to dexamethasone administration persisted.
Overall, “this is the first reported case of [subclinical Cushing’s syndrome] due to an autonomous cortisol secreting adrenal adenoma, harboring a GNAS mutation, which exhibited a paradoxical increase in urinary free cortisol levels in response to the oral administration of dexamethasone,” researchers said.
This case highlights how evaluating adrenal adenomas for GNAS mutations could help diagnose different types of Cushing’s syndrome, and detect tumors outside of the adrenal glands in these patients, which “may contribute to an improved prognosis for patients with this type of Cushing’s syndrome.”