Cushing’s syndrome is a complex condition and remains difficult to diagnose and treat. However, novel therapies and genetic discoveries may advance clinicians’ understanding of the disease.
For instance, new research suggests that some patients with Cushing’s syndrome may benefit from genetic screening for polymorphisms that cause certain forms of the disease.
An international team of researchers has identified genetic mutations that result in uncontrolled synthesis and secretion of cortisol.1
While performing genetic characterization of benign tumors of the adrenal gland, Felix Beuschlein, MD, and his colleagues found that a mutation in the gene for the enzyme phosphokinase A (PKA) was specifically associated with the continuous production of cortisol.
In addition, results indicated that this mutation occurs in the adrenal gland and is therefore restricted to the tumor cells. Lead study author Dr. Beuschlein, of the Ludwig Maximilian University of Munich, said the gene for PKA plays a key role in the regulation of adrenal gland function.
New data also suggest that screening family members of patients with bilateral adrenal Cushing’s syndrome may help identify affected silent carriers.
In another study, Guillaume Assié, MD, and colleagues found that 55% of patients with Cushing’s syndrome with bilaterally enlarged adrenal glands have mutations in a gene that predisposes them to developing adrenal tumors.2
In the New England Journal of Medicine, the researchers reported that some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic. The genetic alterations involve inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition might result in earlier identification and better management of the disease, the researchers suggested.
These latest findings also indicate that bilateral adrenal Cushing’s syndrome may have a much greater genetic component than previously recognized, and it may be possible to develop drugs that interrupt the genetic link.
This could pave the way for the development of personalized therapies for hypercortisolism, according to some experts.
“This is probably the hottest area of research right now,” said endocrinologist Henry Fein, MD, Assistant Professor of Medicine at Johns Hopkins University School of Medicine in Baltimore. “This work is in its infancy. Cushing’s syndrome is very complex, but we hope to better identify which patients will benefit from specific therapies based on genetics.”
A New Era
Because there are now more therapeutic options, clinicians have entered a new era in treatment of Cushing’s syndrome, Dr. Fein said.
For instance, he and his colleagues have been following a group of patients for almost 4 years and have found mifepristone (Korlym, Corcept Therapeutics), which was approved in 2012, produces long-term benefits for a significant number of patients.
Dr. Fein presented outcome data from a long-term extension study at the 2014 joint meeting of the International Society of Endocrinology and the Endocrine Society (ICE/ENDO 2014) in Chicago.3
In the study, Fein and colleagues found that 72% of patients lost 5% or more of their body weight at some point during the initial 6-month treatment period and a significant number of patients continued to experience treatment-related benefits after more than 3.5 years of treatment.
“I think this is an exciting time,” Dr. Fein told Endocrinology Advisor. “There are 100 different candidate drugs that are being worked on.”
Eventually, he envisions combination therapies that treat genetic components of the disease as well as metabolic risk factors such as diabetes.
Importance of Diagnosis
Despite advances in treatment, Dr. Fein noted that underdiagnosing Cushing’s syndrome remains an important clinical issue.
A review published in Trends in Endocrinology & Metabolism suggests that 36% of patients with overt Cushing’s syndrome and 22% of patients with subclinical Cushing’s syndrome had diabetes while another 17% to 23% have impaired glucose tolerance.4
“Undiagnosed Cushing’s syndrome is common in type 2 diabetics. There are a substantial number of patients with type 2 diabetes who have Cushing’s syndrome as a contributing factor to their diagnosis. You can substantially improve their diabetes and possibly eliminate it, if they are treated for their Cushing’s syndrome,” said Dr. Fein.