Hyperparathyroidism-jaw tumor syndrome is a condition characterized by overactivity of the parathyroid glands (hyperparathyroidism). The four parathyroid glands are located in the neck and secrete a hormone that regulates the body's use of calcium. Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of the bones (osteoporosis), nausea, vomiting, high blood pressure (hypertension), weakness, and fatigue.

In people with hyperthyroidism-jaw tumor syndrome, hyperparathyroidism is caused by tumors that form in the parathyroid glands. Typically only one of the four parathyroid glands is affected, but in some people, tumors are found in more than one gland. The tumors are usually noncancerous (benign), in which case they are called adenomas. Approximately 15 percent of people with hyperparathyroidism-jaw tumor syndrome develop a cancerous tumor called parathyroid carcinoma. People with hyperparathyroidism-jaw tumor syndrome may also have a type of benign tumor called a fibroma in the jaw. Even though jaw tumors are specified in the name of this condition, it is estimated that only 25 to 50 percent of affected individuals have this symptom.

Other tumors, both benign and cancerous, are often seen in hyperparathyroidism-jaw tumor syndrome. For example, tumors of the uterus occur in about 75 percent of women with this condition. The kidneys are affected in about 20 percent of people with hyperparathyroidism-jaw tumor syndrome. Benign kidney cysts are the most common kidney feature, but a rare tumor called Wilms tumor and other types of kidney tumor have also been found.

Mutations in the CDC73 gene (also known as the HRPT2 gene) cause hyperparathyroidism-jaw tumor syndrome. The CDC73 gene provides instructions for making a protein called parafibromin. This protein is found throughout the body and is likely involved in gene transcription, which is the first step in protein production. Parafibromin is also thought to play a role in cell growth and division (proliferation), either promoting or inhibiting cell proliferation depending on signals within the cell.

CDC73 gene mutations cause hyperparathyroidism-jaw tumor syndrome by reducing the amount of functional parafibromin that is produced. Most of these mutations result in a parafibromin protein that is abnormally short and nonfunctional. Without functional parafibromin, cell proliferation is not properly regulated. Uncontrolled cell division can lead to the formation of tumors. It is unknown why only certain tissues seem to be affected by changes in parafibromin.

Some people with hyperparathyroidism-jaw tumor syndrome do not have identified mutations in the CDC73 gene. The cause of the condition in these individuals is unknown.

Normal Function

The CDC73 gene (also known as HRPT2) provides instructions for making a protein called parafibromin. This protein is found primarily in the nucleus of cells and is likely involved in regulating gene transcription, which is the first step in protein production. Parafibromin functions as a tumor suppressor, which means it keeps cells from growing and dividing (proliferating) too rapidly or in an uncontrolled way. When parafibromin is found outside the nucleus, it appears to be involved in the organization of the cell's structural framework (the cytoskeleton).

Health Conditions Related to Genetic Changes

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.

Other Names for This Gene

• C1orf28
• CDC73_HUMAN
• cell division cycle 73, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae)
• cell division cycle protein 73 homolog
• HRPT2
• hyperparathyroidism 2 protein
• hyrax
• HYX
• parafibromin

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

The exact prevalence of hyperparathyroidism-jaw tumor syndrome is unknown. Approximately 200 cases have been reported in the medical literature.