New Studies Shed Light on Cushing's Syndrome

Marlene Busko

November 29, 2013

A study has identified, for the first time, a gene mutation that appears to be implicated in patients with Cushing's syndrome, and a second study has shed light on abnormal receptors in the adrenal gland in patients with this disease.

This early research suggests that in the future, family members of patients with Cushing's syndrome could be offered genetic screening to look for "silent carriers" and novel drugs could be developed to target abnormal receptors and possibly halt the progression of this disease.

The 2 studies were published in the November 28 issue of the New England Journal of Medicine.

These "surprising" findings advance researchers' knowledge about a disease that affects a fair number of people and for which the current gold standard treatment is adrenalectomy, said André Lacroix, MD, from Centre Hospitalier de l'Université de Montréal, who is the author of an accompanying editorial.

Adrenal Nodules Detected Incidentally

About 4% of the population develop nodules in and/or an increase in size in one or both adrenal glands when they are middle-aged, which are usually incidentally detected — for example, when a patient has an X-ray to investigate abdominal pain, Dr. Lacroix told Medscape Medical News. About 10% of incidentally detected adrenal lesions are bilateral.

"Bilateral macronodular hyperplasia just means that both adrenal glands get progressively larger in the portion that produces cortisol and sometimes other hormones," he noted. This was first described about 50 years ago, but why it happens remains a mystery.

Cushing's syndrome can develop secondary to bilateral nodular adrenal hyperplasia. In patients with the syndrome, the adrenal glands progressively produce 2 to 10 times the normal 20 to 30 mg of cortisol a day and cause symptoms of severe weight gain, high blood pressure, diabetes, muscle weakness, osteoporosis, and a tendency to develop infections. If it is not cured, the mortality rate is 50% within 5 years.

Only a small percentage of patients with bilateral nodular adrenal hyperplasia have adrenal glands that are large enough to produce enough cortisol to have Cushing's syndrome, however. Normally, each adrenal gland is no more than 1 cm wide and weighs 4 to 6 g; with bilateral nodular hyperplasia, each can be 10 to 20 times larger and weigh as much as 200 g.

Identification of a Gene Mutation

In the first study, senior author Jérôme Bertherat, MD, from INSERM in Paris, France, and colleagues "identify for the first time, a [mutation in a] gene that is found in individuals who carry this growth of both adrenal glands," Dr. Lacroix explained.

The researchers analyzed adrenal tumor tissue samples from 33 patients with bilateral macronodular adrenal hyperplasia and Cushing's syndrome who had undergone adrenalectomy. Using whole-exome sequencing, they identified the mutation in 55% of these 33 patients.

Importantly, "the study also indicates that bilateral macronodular adrenal hyperplasia is genetically determined more frequently than previously believed — approximately 50% of first-degree relatives of patients with apparently sporadic cases of Cushing's syndrome carried the same mutation and had unsuspected subclinical adrenal nodular hyperplasia," said Dr. Lacroix.

His research laboratory has just completed a study in a family of 200 individuals where 35 members have this gene mutation. And other genes are likely to be identified in the future.

Although this is still very much a research tool, understanding this and future mutations that remain to be discovered could one day allow clinicians to screen family members who have this disease to detect "silent carriers," Dr. Lacroix predicted.

Discovery of Abnormal Cortisol Receptors

In the second study, senior author Hervé Lefebvre, MD, from INSERM in Rouen, France, and colleagues demonstrate, "very surprisingly, that the hormone that is normally produced in the pituitary, adrenocorticotropic hormone [ACTH, also called corticotropin], which regulates cortisol production, is produced within the adrenal gland itself," said Dr. Lacroix.

The researchers analyzed adrenal tissue samples from 30 patients with subclinical Cushing's syndrome. Using a blocker for the ACTH receptor, they were able to show that the production of cortisol was decreased by about 50%.

The next step will be to see if these in vitro results can be repeated in patients.

N Engl J Med. 2013;369:2105-2114, 2115-2125, 2147-2149. Bertherat abstract, Lefebvre abstract, Editorial

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