Macronodular primary adrenal hyperplasia (Primary macronodular adrenal hyperplasia -PMAH-) - Genes ARMC5 and GNAS.

Primary adrenal hyperplasia macronodular (PMAH) is a disorder characterized by multiple nodes in the adrenal glands. These nodules, usually found in both adrenal glands and vary in size, leading to an enlargement of the adrenals and lead to the production of higher concentrations than normal cortisol. Cortisol is an important hormone that suppresses inflammation and protects the body from physical stress, such as infection or trauma, through various mechanisms, including raising the concentrations of blood glucose.

Generally, this disease becomes apparent around 40 or 50 years old. It is considered a form of Cushing 's syndrome, which is characterized by increased cortisol concentrations. This increase leads to increased volume in the face and upper body, fragile skin, bone loss, fatigue and other health problems. However, some people with PMAH do not show these signs and symptoms, which are said to have subclinical Cushing syndrome.

Macronodular primary adrenal hyperplasia is due to mutations in the gene ARMC5 and the GNAS gene. Mutations in the gene ARMC5 are responsible for about half of all cases of the disease. In addition, other mutations in other unknown genes, could lead to disease.

The ARMC5 gene, located on the short arm of chromosome 16 (16p11.2), encoding a protein of which little is known. This protein is mainly in the cytoplasm and their function depends on the interaction with other proteins. In addition, it is believed to act as a tumor suppressor. At least 24 mutations in the gene have been identified ARMC5 in people with primary macronodular (PMAH) adrenal hyperplasia. It is believed that these mutations altering tumor suppressor protein function, which allows the overgrowth of certain cells. It is unclear why this overgrowth is limited to the adrenal glands in those affected.

The GNAS gene, located on the long arm of chromosome 20 (20q13.3), encoding the protein subunit Gsa signaling Gs. G proteins are transducers that mediate binding of extracellular receptor ligands to intracellular messenger systems. Thus, the activity of adenylate cyclase (lyase which catalyzes the conversion of ATP to cAMP) is under control of Gs stimulation and inhibition of Gi. Adenylate cyclase enzyme, is involved in the production control of several hormones that help regulate the activity of the endocrine glands such as the thyroid, pituitary, ovaries, testes and adrenals. It is believed that the enzyme also plays a key role in osteogenesis. Thus, the enzyme helps the body to prevent the production of ectopic bone. They have identified at least two mutations in the GNAS gene in individuals with primary macronodular (PMAH) adrenal hyperplasia. It is believed that these mutations result in an overactive G protein may increase concentrations of adenylate cyclase, leading to overproduction of cyclic AMP (cAMP). An excess of cAMP can trigger the abnormal growth of cells and lead to adrenal nodules PMAH own.

People with PMAH due to mutations in the gene ARMC5 inherit a copy of the mutated gene in each cell. The autosomal dominant inheritance is considered because a copy of the mutated gene is sufficient to make an individual susceptible to PMAH. However, this disease develops only when affected individuals acquire another mutation in the other copy of the gene ARMC5 in certain cells of the adrenal glands. This second mutation is described as somatic. Instead of being transmitted from parents to children, somatic mutations are acquired during a person 's life and are present only in certain cells. Because somatic mutations are required to develop the disease, some people who have inherited the altered gene ARMC5 never develop the disease, a situation known as reduced penetrance. Meanwhile, when the disease is due to genetic mutations GNAS, not inherited. GNAS gene mutations that result PMAH are somatic mutations.

Tests in IVAMI: in IVAMI perform detection of mutations associated with primary adrenal hyperplasia macronodular (PMAH), by complete PCR amplification of the exons of ARMC5 and GNAS, respectively, genes and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).