Many cases of a rare disorder of the adrenal glands appear to result from two copies of a mutant gene, according to a research team made up of scientists in France and at the US National Institutes of Health.

The adrenal disorder, corticotropin-independent macronodular adrenal hyperplasia, results in the formation of numerous tumours in the adrenal glands located on top of the kidneys, and which produce hormones that help the body respond to stress. The condition is one of many causes of Cushing’s syndrome, a group of symptoms resulting from an excess of cortisol, a stress hormone. Untreated, Cushing syndrome can result in high blood pressure, heart disease, bone loss, diabetes, and other health problems.

The researchers found that about a third of a group of patients with corticotropin-independent macronodular adrenal hyperplasia had mutations in both copies of a gene, designated ARMC5. This gene is thought to play a role in preventing tumors from forming. One copy of the gene occurred in all the patients’ cells, and the second copy was found only in the cells of the patients’ adrenal tumours.

Single copies of the mutant AMRC5 gene were also found in some of the family members of patients who took part in the study. Most of the family members with only one copy of the mutant gene had not developed corticotropin-independent macronodular adrenal hyperplasia and did not have Cushing’s syndrome.

Based on these observations, the researchers believe that it’s necessary to have two copies of the mutant gene to develop corticotropin-independent macronodular adrenal hyperplasia. The first mutation likely arises before birth, and occurs in all the cells of the body. Presumably, the second mutation arises sometime later in life, in the cells of the adrenal gland. The tumours then develop in the adrenal glands after the second mutation has occurred. The researchers are unsure why the second mutation develops, and why the tumors appear in the adrenal glands and not in some other part of the body.

“Because they often don’t cause any obvious symptoms, adrenal tumours may go undiagnosed for many years,” explained study co-author Constantine A Stratakis, MD, of the Division of Intramural Research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). “If we could screen family members for the ARMC5gene, we could monitor their cortisol levels and treat them after the first sign of Cushing’s syndrome, and avoid the long-term consequences of the disorder.”

The study’s first author was Guillaume Assie, MD, Ph.D. Along with NICHD’s Stratakis, the study also included senior author Jerome Bertherat, MD, of the Cochin Institute, in Paris, and scientists at other French research institutions.

The study findings appear in the New England Journal of Medicine.

“Apparently, quite a few individuals with the single mutation do not go on to develop tumours,” Dr Bertherat said. “Now that we have discovered this connection with ARMC5, we would like to investigate what happens to allow the secondary mutations in adrenal tissue that precede the development of tumours.”

The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation.

NIH, the nation's medical research agency, and is a component of the US Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.