Primary macronodular adrenal hyperplasia (PMAH) is a disorder characterized by multiple lumps (nodules) in the adrenal glands, which are small hormone-producing glands located on top of each kidney. These nodules, which usually are found in both adrenal glands (bilateral) and vary in size, cause adrenal gland enlargement (hyperplasia) and result in the production of higher-than-normal levels of the hormone cortisol. Cortisol is an important hormone that suppresses inflammation and protects the body from physical stress such as infection or trauma through several mechanisms including raising levels of blood glucose, also called blood sugar.

PMAH typically becomes evident in a person's forties or fifties. It is considered a form of Cushing syndrome, which is characterized by increased levels of cortisol resulting from one of many possible causes. These increased cortisol levels lead to weight gain in the face and upper body, fragile skin, bone loss, fatigue, and other health problems. However, some people with PMAH do not experience these signs and symptoms and are said to have subclinical Cushing syndrome.

In about half of individuals with PMAH, the condition is caused by mutations in the ARMC5 gene. This gene provides instructions for making a protein that is thought to act as a tumor suppressor, which means that it helps to prevent cells from growing and dividing too rapidly or in an uncontrolled way. ARMC5 gene mutations are believed to impair the protein's tumor-suppressor function, which allows the overgrowth of certain cells. It is unclear why this overgrowth is limited to the formation of adrenal gland nodules in people with PMAH.

PMAH can also be caused by mutations in the GNAS gene. This gene provides instructions for making one component, the stimulatory alpha subunit, of a protein complex called a guanine nucleotide-binding protein (G protein). The G protein produced from the GNAS gene helps stimulate the activity of an enzyme called adenylate cyclase. This enzyme is involved in controlling the production of several hormones that help regulate the activity of certain endocrine glands, including the adrenal glands. The GNAS gene mutations that cause PMAH are believed to result in an overactive G protein. Research suggests that the overactive G protein may increase levels of adenylate cyclase and result in the overproduction of another compound called cyclic AMP (cAMP). An excess of cAMP may trigger abnormal cell growth and lead to the adrenal nodules characteristic of PMAH.

Mutations in other genes, some of which are unknown, can also cause PMAH.

Normal Function

The ARMC5 gene provides instructions for making a protein about which little is known. It is found mainly in the fluid surrounding the cell nucleus (cytoplasm), and studies suggest that its function depends on interacting with other proteins. It is thought to act as a tumor suppressor, which means that it helps to prevent cells from growing and dividing too rapidly or in an uncontrolled way.

Health Conditions Related to Genetic Changes

Primary macronodular adrenal hyperplasia

At least 24 mutations in the ARMC5 gene have been identified in people with primary macronodular adrenal hyperplasia (PMAH), a disorder that causes multiple lumps (nodules) to form in the adrenal glands, which are small hormone-producing glands located on top of each kidney. These nodules cause adrenal gland enlargement (hyperplasia) and result in production of higher-than-normal levels of the hormone cortisol. Cortisol normally helps maintain blood sugar (glucose) levels, protects the body from physical stress, and suppresses inflammation. Increased cortisol levels can lead to weight gain in the face and upper body, fragile skin, bone loss, fatigue, and other health problems, which often occur in people with PMAH.

People with PMAH caused by ARMC5 gene mutations inherit one copy of the mutated gene in each cell. However, the condition develops only when affected individuals acquire a second mutation in the other copy of the ARMC5 gene in certain cells of the adrenal glands. This second mutation is described as somatic. Instead of being passed from parent to child, somatic mutations are acquired during a person's lifetime and are present only in certain cells. Because somatic mutations are also required for PMAH to occur, some people who have inherited the altered ARMC5 gene never develop the condition, a situation known as reduced penetrance.

The ARMC5 gene mutations that cause PMAH are thought to impair the protein's tumor suppressor function, which allows the overgrowth of certain cells. It is unclear why this overgrowth is limited to the adrenal glands in people with PMAH.

Other Names for This Gene

• FLJ13063

Genomic Location

People with PMAH caused by ARMC5 gene mutations inherit one copy of the mutated gene in each cell. The inheritance is considered autosomal dominant because one copy of the mutated gene is sufficient to make an individual susceptible to PMAH. However, the condition develops only when affected individuals acquire another mutation in the other copy of the ARMC5 gene in certain cells of the adrenal glands. This second mutation is described as somatic. Instead of being passed from parent to child, somatic mutations are acquired during a person's lifetime and are present only in certain cells. Because somatic mutations are also required for PMAH to occur, some people who have inherited the altered ARMC5 gene never develop the condition, a situation known as reduced penetrance.

When PMAH is caused by GNAS gene mutations, the condition is not inherited. The GNAS gene mutations that cause PMAH are somatic mutations. In PMAH, the gene mutation is believed to occur early in embryonic development. Cells with the mutated GNAS gene can be found in both adrenal glands.

PMAH is a rare disorder. It is present in less than 1 percent of cases of endogenous Cushing syndrome, which describes forms of Cushing syndrome caused by factors internal to the body rather than by external factors such as long-term use of certain medicines called corticosteroids. The prevalence of endogenous Cushing syndrome is about 1 in 26,000 people.