Endocrine Abstracts (2017) 50 PL1 | DOI: 10.1530/endoabs.50.PL1

Primary hyperparathyroidism: molecular genetic insights and clinical implications

Andrew Arnold


University of Connecticut School of Medicine, Farmington, Connecticut, USA.


Primary hyperparathyroidism, a common endocrine disorder manifested by hypercalcemia and excessive parathyroid hormone levels, is most often due to a benign parathyroid adenoma but can also result from multigland involvement or, rarely, from malignant parathyroid neoplasia. Further, while most cases of primary hyperparathyroidism have a nonfamilial/sporadic presentation, an important minority occurs in the setting of strong familial predispositions. In recent years much has been learned about the heritable genetic mutations responsible for, or contributing to, the major familial hyperparathyroid syndromes, including multiple endocrine neoplasia types 1 and 2A, the hyperparathyroidism-jaw tumor syndrome (HPT-JT), familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and familial isolated hyperparathyroidism; important insights into the acquired driver mutations underlying sporadic parathyroid tumors have also accrued. The direct role of the oncogene cyclin D1 in human neoplasia was first established in parathyroid adenomas, followed by recognition of its importance in other tumors such as breast and squamous cell cancers, mantle cell lymphoma, and multiple myeloma. Recent insights into the landscape of somatic driver mutations in parathyroid carcinoma, including the discovery of recurrent alterations in the PI3K/MTOR pathway, carry immediate therapeutic implications in the setting of metastatic disease where effective treatment has been lacking. Recognition of predisposing germline mutations can have significant implications in patient management, for example in preventing parathyroid carcinoma in HPT-JT, and in optimizing the approach to parathyroidectomy in MEN1. Finally, the existence of lower penetrance germline variants in common sporadic hyperparathyroidism is an emerging area of interest.

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