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Primary hyperparathyroidism (PHPT) results from the overproduction of parathyroid hormone (PTH) by one or more autonomously hyperfunctioning parathyroid glands that usually causes hypercalcemia. PHPT is usually caused by a single parathyroid adenoma (85%); the remaining cases (15%) are caused by multigland disease (MGD) in which more than one parathyroid gland is hyperfunctional.

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PHPT is the most common cause of hypercalcemia in the outpatient setting. Approximately 100,000 new cases per year of PHPT occur in the United States. Since the advent of routine laboratory testing, the prevalence of the disease has increased from 0.1% to 0.4%.1 PHPT may present at any age, with the majority occurring in patients older than age 45 years. Furthermore, women are affected twice as often as men; this is believed to be secondary to estrogen deficiency after menopause that unmasks underlying hyperparathyroidism.1

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Definite risk factors for PHPT can be identified in only a few patients. More specifically, PHPT may be associated with genetic abnormalities such as multiple endocrine neoplasia (MEN) syndromes or familial isolated hyperparathyroidism (FIHPT) and a history of radiation exposure. Some patients have a history of therapeutic neck radiation 30 to 40 years before developing PHPT. In one study of 2555 patients followed for 50 years, even low doses of radiation exposure during the teenage years was associated with a slight risk of developing PHPT 2.

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Several genetic anomalies, including tumor suppressor genes and proto-oncogenes, have been identified in the development of PHPT. A DNA mutation in a parathyroid cell may confer a proliferative advantage over normal neighboring cells, thus allowing for clonal growth. Large populations of these abnormal cells containing the same mutation within hyperfunctioning parathyroid tissue suggest that such glands are a result of clonal expansion.3

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MEN1 is a tumor suppressor gene that may play a role in the development of PHPT. The MEN1 gene, located on chromosome 11, encodes for the transcription factor menin. This gene has been found to be mutated in up to 16% of patients with sporadic PHPT.4PRAD1 proto-oncogene abnormalities have also been found in approximately 20% to 40% of patients with parathyroid adenomas. PRAD1, which is located on chromosome 11, encodes for cyclin D1, which is an important regulator of the cell cycle. Inversion of the PRAD1 gene allows for cyclin D1 overexpression, leading to adenoma formation.5 In families with hyperparathyroidism–jaw tumor syndrome (HPT-JT), inactivation of the HRPT2 gene that encodes the protein parafibromin has been established as a possible mechanism in the development of parathyroid tumors. HRPT2 mutations that inactivate parafibromin and its tumor suppressor function are found in patients with HPT-JT and parathyroid carcinoma and in a few cases of parathyroid adenomas with cystic features. There is evidence to suggest that whereas parafibromin expression remains intact in benign parathyroid adenomas, its loss of expression is indicative of HRPT2 mutations, which are highly associated with HPT-JT and parathyroid carcinoma.6

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