Familial isolated hyperparathyroidism is an inherited condition that is characterized by overactive parathyroid glands (hyperparathyroidism). The four parathyroid glands are located in the neck. They release a hormone called parathyroid hormone that regulates the amount of calcium in the blood. 

In people with familial isolated hyperparathyroidism, too much parathyroid hormone is produced, and levels of calcium in the blood become elevated (hypercalcemia). Hypercalcemia causes many of the common signs and symptoms of familial isolated hyperparathyroidism, such as kidney stones, nausea, vomiting, high blood pressure (hypertension), thinning of the bones (osteoporosis), weakness, and fatigue.

Many people with familial isolated hyperparathyroidism have one or more noncancerous (benign) tumors called adenomas. Typically, only one of the four parathyroid glands is affected, but sometimes more than one gland has an adenoma. Rarely, the tumor can become cancerous; this is called parathyroid carcinoma.

In some cases, familial isolated hyperparathyroidism may not be diagnosed until adulthood. Often, the first indication of the condition is elevated calcium levels that are identified during a routine blood test, even though the affected individual may not yet have signs or symptoms of hyperparathyroidism or hypercalcemia.

The prevalence of familial isolated hyperparathyroidism is unknown. The condition accounts for 1 percent of all cases where the parathyroid glands produce too much parathyroid hormone (primary hyperparathyroidism).

Familial isolated hyperparathyroidism can be caused by variants (also called mutations) in the MEN1, CDC73, or CASR gene. Certain variants in the GCM2 gene may increase the risk of developing familial isolated hyperparathyroidism.

The MEN1 and CDC73 genes provide instructions for making proteins that act as tumor suppressors. Tumor suppressors keep cells from growing and dividing (proliferating) too fast or in an uncontrolled way. In people with familial isolated hyperparathyroidism, variants in either of these genes lead to the production of an altered protein that cannot effectively control cell growth and division. The resulting increase in cell proliferation can cause one or more of the parathyroid glands to become enlarged (hyperplasia) or to develop an adenoma.

The adenomas or enlarged parathyroid glands stimulate the overproduction of parathyroid hormone, which triggers the release of too much calcium into the blood. This excess calcium causes the characteristic features of familial isolated hyperparathyroidism. 

The CASR gene provides instructions for producing a protein called the calcium-sensing receptor (CaSR), which helps regulate the amount of calcium in the blood. In parathyroid gland cells, when calcium binds to the CaSR protein, the CaSR protein sends a signal that blocks the production and release of parathyroid hormone. Without parathyroid hormone, calcium is not released into the blood. The CASR gene variants that are associated with familial isolated hyperparathyroidism cause cells to produce a version of the CaSR protein that requires higher levels of calcium to trigger the signaling that blocks hormone production. As a result, parathyroid hormone is produced even when calcium levels are elevated, which leads to hyperparathyroidism, hypercalcemia, and the other features seen in people with familial isolated hyperparathyroidism.

The GCM2 gene provides instruction for making a protein that helps regulate the amount of parathyroid hormone that is produced. Certain variants in this gene cause cells to produce a version of the GCM2 protein that allows more parathyroid hormone to be produced. As a result, more calcium could be released into the blood, causing people to have an increased risk of developing the signs and symptoms of familial isolated hyperparathyroidism.

Many individuals with the signs and symptoms of familial isolated hyperparathyroidism do not have an identified variant in the associated genes, indicating that other genes may be involved in the development of this condition. The genetic cause in these cases is unknown.

Genetic Testing Information

• Genetic Testing Registry: Neonatal severe primary hyperparathyroidism
• Genetic Testing Registry: Hyperparathyroidism 1
• Genetic Testing Registry: Hyperparathyroidism 4

Genetic and Rare Diseases Information Center

• Familial isolated hyperparathyroidism

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• HYPERPARATHYROIDISM 1; HRPT1
• HYPERPARATHYROIDISM, NEONATAL SEVERE; NSHPT
• HYPERPARATHYROIDISM 4; HRPT4

Scientific Articles on PubMed

• PubMed

• Cetani F, Dinoi E, Pierotti L, Pardi E. Familial states of primary hyperparathyroidism: an update. J Endocrinol Invest. 2024 Sep;47(9):2157-2176. doi: 10.1007/s40618-024-02366-7. Epub 2024 Apr 18. Citation on PubMed
• Cetani F, Pardi E, Aretini P, Saponaro F, Borsari S, Mazoni L, Apicella M, Civita P, La Ferla M, Caligo MA, Lessi F, Mazzanti CM, Torregossa L, Oppo A, Marcocci C. Whole exome sequencing in familial isolated primary hyperparathyroidism. J Endocrinol Invest. 2020 Feb;43(2):231-245. doi: 10.1007/s40618-019-01107-5. Epub 2019 Sep 5. Citation on PubMed
• Cetani F, Saponaro F, Borsari S, Marcocci C. Familial and Hereditary Forms of Primary Hyperparathyroidism. Front Horm Res. 2019;51:40-51. doi: 10.1159/000491037. Epub 2018 Nov 19. Citation on PubMed
• English KA, Lines KE, Thakker RV. Genetics of hereditary forms of primary hyperparathyroidism. Hormones (Athens). 2024 Mar;23(1):3-14. doi: 10.1007/s42000-023-00508-9. Epub 2023 Dec 1. Citation on PubMed
• Guan B, Welch JM, Sapp JC, Ling H, Li Y, Johnston JJ, Kebebew E, Biesecker LG, Simonds WF, Marx SJ, Agarwal SK. GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism. Am J Hum Genet. 2016 Nov 3;99(5):1034-1044. doi: 10.1016/j.ajhg.2016.08.018. Epub 2016 Oct 13. Citation on PubMed
• Hannan FM, Nesbit MA, Christie PT, Fratter C, Dudley NE, Sadler GP, Thakker RV. Familial isolated primary hyperparathyroidism caused by mutations of the MEN1 gene. Nat Clin Pract Endocrinol Metab. 2008 Jan;4(1):53-8. doi: 10.1038/ncpendmet0718. Citation on PubMed
• Marini F, Giusti F, Brandi ML. Congenital primary hyperparathyroidism. Best Pract Res Clin Endocrinol Metab. 2025 Mar;39(2):101982. doi: 10.1016/j.beem.2025.101982. Epub 2025 Jan 31. Citation on PubMed
• Newey PJ. Hereditary Primary Hyperparathyroidism. Endocrinol Metab Clin North Am. 2021 Dec;50(4):663-681. doi: 10.1016/j.ecl.2021.08.003. Citation on PubMed
• Skefos CM, Waguespack SG, Perrier ND, Hu MI. CDC73-Related Disorders. 2008 Dec 31 [updated 2023 Sep 21]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK3789/ Citation on PubMed
• Vincze S, Peters NV, Kuo CL, Brown TC, Korah R, Murtha TD, Bellizzi J, Riccardi A, Parham K, Carling T, Costa-Guda J, Arnold A. GCM2 Variants in Familial and Multiglandular Primary Hyperparathyroidism. J Clin Endocrinol Metab. 2022 Apr 19;107(5):e2021-e2026. doi: 10.1210/clinem/dgab929. Citation on PubMed