CDC73 gene

Familial isolated hyperparathyroidism

Inherited mutations in the CDC73 gene have been found in some families with familial isolated hyperparathyroidism, a condition characterized by overactivity of the parathyroid glands (primary hyperparathyroidism). These glands release a hormone that helps control the normal balance of calcium in the blood. Primary hyperparathyroidism disrupts this balance, which can lead to high blood calcium levels (hypercalcemia), kidney stones, thinning of the bones (osteoporosis), nausea, vomiting, high blood pressure (hypertension), weakness, and fatigue. Primary hyperparathyroidism is a characteristic feature of hyperparathyroidism-jaw tumor syndrome (described below); however, familial isolated hyperparathyroidism is diagnosed in people with hyperparathyroidism but not the other features of hyperparathyroidism-jaw tumor syndrome.

CDC73 gene mutations that cause familial isolated hyperparathyroidism likely result in decreased activity of the parafibromin protein. Reduced parafibromin activity can cause increased cell proliferation, leading to the formation of tumors involving the parathyroid glands. Parathyroid tumors in people with familial isolated hyperparathyroidism are usually noncancerous (benign). The tumors cause the glands to be overactive, and this overactivity leads to the signs and symptoms of the condition. The mutations associated with familial isolated hyperparathyroidism are thought to have a less severe effect on protein function than those that cause hyperparathyroidism-jaw tumor syndrome. Occasionally, individuals with familial isolated hyperparathyroidism later develop features of hyperparathyroidism-jaw tumor syndrome, although some never do. Familial isolated hyperparathyroidism caused by CDC73 gene mutations may be an early or mild form of hyperparathyroidism-jaw tumor syndrome.

Hyperparathyroidism-jaw tumor syndrome

More than 45 inherited mutations in the CDC73 gene have been found to cause hyperparathyroidism-jaw tumor syndrome, which is a condition characterized by a type of benign tumor called a fibroma in the jaw and parathyroid tumors that cause hyperparathyroidism. Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, osteoporosis, nausea, vomiting, hypertension, weakness, and fatigue in people with hyperparathyroidism-jaw tumor syndrome.

Most of the CDC73 gene mutations that cause this condition result in a parafibromin protein that is abnormally short and nonfunctional. Without functional parafibromin, cell proliferation is not properly regulated. Uncontrolled cell division resulting from the loss of parafibromin function can lead to the formation of tumors in the parathyroid glands, jaw, and other tissues in people with hyperparathyroidism-jaw tumor syndrome. Parathyroid tumors, which can be cancerous or noncancerous, interfere with the gland's normal function and lead to primary hyperparathyroidism in people with hyperparathyroidism-jaw tumor syndrome.

Parathyroid cancer

Mutations in the CDC73 gene are found in up to 70 percent of cases of parathyroid cancer. In approximately one-third of affected individuals with changes in this gene, the mutation is inherited from a parent and is present in all of the body's cells (germline mutation). However, not everyone who inherits a mutation in the CDC73 gene will ultimately develop parathyroid cancer. Other genetic and non-genetic factors also contribute to a person's cancer risk.

In the remaining two-thirds of individuals with CDC73 gene mutations, the condition is associated with a mutation that occurs in parathyroid cells during their lifetime (somatic mutation). In individuals with either a germline or somatic CDC73 gene mutation, a second mutation in the other copy of the CDC73 gene must occur for parathyroid cancer to develop. Parathyroid cells with two altered copies of the CDC73 gene produce no functional parafibromin. As a result, cells grow and divide unchecked, which can lead to parathyroid cancer.

A significantly increased risk of parathyroid cancer is a feature of hyperparathyroidism-jaw tumor syndrome and familial isolated hyperparathyroidism (both described above). Parathyroid cancer occurs in 15 percent of individuals with hyperparathyroidism-jaw tumor syndrome and in 1 percent of individuals with familial isolated hyperparathyroidism. It is unclear why some CDC73 gene mutations cause isolated parathyroid cancer, others cause noncancerous tumors in the parathyroid glands and jaw, and still others cause only hyperparathyroidism.