SNP Shot: Genomic Insights

Primary macronodular adrenal hyperplasia (PMAH) is a condition where multiple nodules, or lumps, develop in the adrenal glands. These glands sit atop each kidney and produce hormones. In PMAH, the nodules are usually present in both adrenal glands (bilateral) and vary in size. These nodules cause the adrenal glands to enlarge (hyperplasia) and overproduce cortisol. Cortisol is a vital hormone that reduces inflammation and helps the body cope with physical stress, such as infections or injuries. It achieves this, in part, by increasing blood glucose, also known as blood sugar.

PMAH is typically diagnosed in individuals in their 40s or 50s. It's a type of Cushing syndrome, which is defined by elevated cortisol levels due to various underlying causes. Excess cortisol can lead to weight gain concentrated in the face and upper body, thin and easily bruised skin, bone weakening, fatigue, and other health issues. However, some individuals with PMAH don't exhibit these typical symptoms and are classified as having subclinical Cushing syndrome.

Inheritance:

When PMAH is caused by mutations in the ARMC5 gene, individuals inherit one copy of the mutated gene in each cell. This is considered autosomal dominant inheritance, meaning that inheriting just one copy of the mutated gene increases the risk of developing PMAH. However, the disease only manifests if individuals acquire a second mutation in the other copy of the ARMC5 gene within specific adrenal gland cells. This second mutation is a somatic mutation, meaning it's not inherited from parents but acquired during a person's lifetime and only present in certain cells. Because both inherited and somatic mutations are necessary for PMAH, some individuals who inherit the altered ARMC5 gene never develop the condition, a phenomenon known as reduced penetrance.

In contrast, when PMAH is caused by mutations in the GNAS gene, it is not inherited. The GNAS gene mutations responsible for PMAH are somatic mutations. In these cases, the gene mutation is thought to occur early in embryonic development. Cells carrying the mutated GNAS gene are found in both adrenal glands.