Familial isolated hyperparathyroidism

Other Names: Hyperparathyroidism 1; HRPT1; Hyperparathyroidism, familial isolated primary; FIHP; Familial primary hyperparathyroidism

Familial isolated hyperparathyroidism is an inherited condition characterized by overactivity of the parathyroid glands (hyperparathyroidism). The four parathyroid glands are located in the neck, and they release a hormone called parathyroid hormone that regulates the amount of calcium in the blood. In familial isolated hyperparathyroidism, one or more overactive parathyroid glands release excess parathyroid hormone, which causes the levels of calcium in the blood to rise (hypercalcemia).

Parathyroid hormone stimulates the removal of calcium from bone and the absorption of calcium from the diet, and the mineral is then released into the bloodstream.

The tumors are usually noncancerous (benign), in which case they are called adenomas. Rarely, people with familial isolated hyperparathyroidism develop a cancerous tumor called parathyroid carcinoma. Because the production of excess parathyroid hormone is caused by abnormalities of the parathyroid glands, familial isolated hyperparathyroidism is considered a form of primary hyperparathyroidism.

Cause

FIHP may be caused by mutations in the MEN1, CDC73 (also known as the HRPT2 gene), or CASR genes . In some cases, the cause is unknown.

The MEN1 gene provides instructions for producing a protein called menin. Menin acts as a tumor suppressor, which means it normally keeps cells from growing and dividing (proliferating) too rapidly or in an uncontrolled way. In familial isolated hyperparathyroidism, MEN1 gene mutations result in an altered menin protein that is no longer able to control cell growth and division.

The CDC73 gene provides instructions for making the parafibromin protein, which is also thought to act as a tumor suppressor. Parafibromin is likely involved in regulating the activity of other genes (gene transcription) and in cell proliferation. CDC73 gene mutations that cause familial isolated hyperparathyroidism likely result in decreased activity of the parafibromin protein.

The CASR gene provides instructions for producing a protein called the calcium-sensing receptor (CaSR), which helps regulate the amount of calcium in the body, in part by controlling the production of parathyroid hormone.

CASR gene mutations associated with familial isolated hyperparathyroidism lead to the production of a less sensitive CaSR that requires an abnormally high concentration of calcium to trigger signaling. As a result, parathyroid hormone is produced even when the concentration of calcium in the blood is elevated, allowing the calcium levels to continue to rise.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

Familial isolated hyperparathyroidism (FIHP) is typically inherited in an autosomal dominant manner.

This means that having only one changed (mutated) copy of the responsible gene in each cell is enough to cause signs or symptoms of the condition. When a person with an autosomal dominant condition has children, each child has a 50% (1 in 2) chance to inherit the mutated copy of the gene from the affected parent.

Mutations in the MEN1 and CDC73 genes cause other conditions in which hyperparathyroidism is one of many features, but some people with mutations in these genes have only isolated hyperparathyroidism. FIHP can also represent an early stage of other syndromes.

Signs and symptoms

Disruption of the normal calcium balance resulting from overactive parathyroid glands causes many of the common signs and symptoms of familial isolated hyperparathyroidism, such as kidney stones, nausea, vomiting, high blood pressure (hypertension), weakness, and fatigue. Because calcium is removed from bones to be released into the bloodstream, hyperparathyroidism often causes thinning of the bones (osteoporosis).

Diagnosis

The diagnosis of familial isolated hyperparathyroidism (FIHP) is primarily a diagnosis of exclusion. This means that it is diagnosed when no symptoms or genetic features of other forms of familial hyperparathyroidism are present. FIHP may be the only feature of another condition that is not manifesting completely, or it may be a distinct condition due to mutations in genes that have not yet been identified. Clinical exams, laboratory tests, and histological (microscopic) findings are needed before making a diagnosis of FIHP. A diagnosis of FIHP may include the findings of:

• hypercalcemia (defined as a serum calcium level greater than 10.5 mg/dL)
• inappropriately high parathyroid hormone (PTH) concentrations
• parathyroid adenomas
• exclusion of multiple endocrine neoplasia type 1 (MEN 1) and hyperparathyroidism-jaw tumor syndrome (HPT-JT)
• In the majority of people with FIHP, genetic mutations are not found. However, in some people, mutations in
• the MEN1, CASR, and CDC73 (HRPT2) genes have been reported. At this time, no gene has been associated exclusively with FIHP.

Treatment

Treatment for FIHP often includes surgical removal of the affected gland(s) The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Cinacalcet(Brand name: Sensipar®) Treatment of hypercalcemia in adult patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy.

NIH genetic and rare disease info

• NIH info on Familial isolated hyperparathyroidism

Familial isolated hyperparathyroidism is a rare disease.

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