Mutations in Internal Clock Regulators May Be Root Cause of Cyclic Cushing’s, Case Report Suggests

Development of cyclic Cushing’s disease — a form of Cushing’s in which cortisol levels are intermittently high — may be a result of mutations in genes controlling both pituitary tumor growth and the body’s internal clock system, a case report suggests.

The study, “A putative role for the aryl hydrocarbon receptor (AHR) gene in a patient with cyclical Cushing’s disease,” was published in BMC Endocrine Disorders.

While cortisol excess is a hallmark of Cushing’s syndrome, only about 80% of patients experience consistently high cortisol levels as a result of their condition. The remaining 20% have the cyclic form of the disease, in which intervals of excess cortisol production are interspersed with periods of normal levels.

Cycles vary greatly among patients, lasting from days to years, but are fairly consistent in individuals. This has led researchers to believe that the condition might be caused by defects in the genes controlling circadian rhythms.

Circadian rhythms, found in most living beings, are natural, internal biological processes that follow a daily cycle. Cortisol production is one such process, peaking in the morning and dropping at night.

The genetic and molecular bases of cyclic Cushing’s disease have not been thoroughly investigated.

In their case study, the researchers described a 47-year old man with cyclic Cushing’s disease who had a mutation in the aryl hydrocarbon receptor (AHR) gene, which is thought to play a role both in tumor suppression in the pituitary gland and in the circadian control of cortisol production.

The patient had swelling in his optic disc, the area at the back of the eye where the optic nerve connects to the retina. MRI and biopsy revealed a pituitary adenoma (benign tumor in the pituitary gland) producing too much adrenocorticotrophic hormone (ACTH) and measuring 7.1 centimeters.

The man had a history of obesity, high blood pressure, and kidney stones. His cortisol levels fluctuated, ranging from normal to 35 times the upper normal limit. Clinicians saw no signs of cyclical symptoms, however.

The exact duration of his cycles could not be determined, as part of the tumor was removed one week after his diagnosis with cyclic Cushing’s disease.

After surgery, the man’s cortisol and ACTH went back to normal levels. Later, he noticed his blood pressure was better controlled, his appetite had decreased and he felt full sooner, with “early but transient weight loss,” the researchers said.

Aiming to “investigate the possibility that [cyclic Cushing’s syndrome] may be due to perturbation in the clock genes responsible for circadian rhythms,” including the signaling axis involved in cortisol production, the researchers examined the entire protein-coding regions (exons) of the genome through a technique called whole exome sequencing.

The researchers found 14 rare, possibly disease-causing mutations in circadian rhythm/pituitary-associated genes. However, only one of these genes – the AHR gene – was relevant to both circadian rhythm and development of pituitary tumors.

While AHR mutations have not been reported in patients with pituitary adenomas, there is evidence supporting their role in suppressing tumor growth in the pituitary. In fact, research suggests that AHR interacts with the pituitary tumor-promoting gene AIP, and that loss of AHR function may lead to AIP-related tumor development in the gland.

AHR also has a role in the regulation of the clock system, potentially affecting the circadian rhythm of cortisol.

The researchers speculated that the mutation in AHR contributed to the man’s cyclic Cushing’s disease “via a loss of tumor suppressor function in the pituitary and disruption of circadian/infradian rhythms.”

A new mutation in the RXRG gene, which is also a tumor-suppressing gene in the pituitary, may have added to the AHR mutation-related disease causing effects, they said.

“Preliminary data from this case study suggest that the highly conserved AHR gene may represent a link between pituitary tumorigenesis, the HPA axis, and the clock system, implicating it in the development of CCD [cyclic Cushing’s disease],” the researchers said.

“Given the rarity of Cushing’s syndrome in general and CCD in particular, collaborative research is required to further examine the potential relationship between AHR and CCD raised by this case study,” they said.