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Yulong Li and William F Simonds

Familial syndromes of hyperparathyroidism, including multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2A (MEN2A), and the hyperparathyroidism-jaw tumor (HPT-JT), comprise 2–5% of primary hyperparathyroidism cases. Familial syndromes of hyperparathyroidism are also associated with a range of endocrine and nonendocrine tumors, including potential malignancies. Complications of the associated neoplasms are the major causes of morbidities and mortalities in these familial syndromes, e.g., parathyroid carcinoma in HPT-JT syndrome; thymic, bronchial, and enteropancreatic neuroendocrine tumors in MEN1; and medullary thyroid cancer and pheochromocytoma in MEN2A. Because of the different underlying mechanisms of neoplasia, these familial tumors may have different characteristics compared with their sporadic counterparts. Large-scale clinical trials are frequently lacking due to the rarity of these diseases. With technological advances and the development of new medications, the natural history, diagnosis, and management of these syndromes are also evolving. In this article, we summarize the recent knowledge on endocrine neoplasms in three familial hyperparathyroidism syndromes, with an emphasis on disease characteristics, molecular pathogenesis, recent developments in biochemical and radiological evaluation, and expert opinions on surgical and medical therapies. Because these familial hyperparathyroidism syndromes are associated with a wide variety of tumors in different organs, this review is focused on those endocrine neoplasms with malignant potential.

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Yulong Li, Jianhua Zhang, Poorni R Adikaram, James Welch, Bin Guan, Lee S Weinstein, Haobin Chen and William F Simonds

Mutation of the CDC73 gene, which encodes parafibromin, has been linked with parathyroid cancer. However, no correlation between genotypes of germline CDC73 mutations and the risk of parathyroid cancer has been known. In this study, subjects with germline CDC73 mutations were identified from the participants of two clinical protocols at National Institutes of Health (Discovery Cohort) and from the literature (Validation Cohort). The relative risk of developing parathyroid cancer was analyzed as a function of CDC73 genotype, and the impact of representative mutations on structure of parafibromin was compared between genotype groups. A total of 419 subjects, 68 in Discovery Cohort and 351 in Validation Cohort, were included. In both cohorts, percentages of CDC73 germline mutations that predicted significant conformational disruption or loss of expression of parafibromin (referred as ‘high-impact mutations’) were significantly higher among the subjects with parathyroid cancers compared to all other subjects. The Kaplan–Meier analysis showed that high-impact mutations were associated with a 6.6-fold higher risk of parathyroid carcinoma compared to low-impact mutations, despite a similar risk of developing primary hyperparathyroidism between two groups. Disruption of the C-terminal domain (CTD) of parafibromin is directly involved in predisposition to parathyroid carcinoma, since only the mutations impacting this domain were associated with an increased risk of parathyroid carcinoma. Structural analysis revealed that a conserved surface structure in the CTD is universally disrupted by the mutations affecting this domain. In conclusion, high-impact germline CDC73 mutations were found to increase risk of parathyroid carcinoma by disrupting the CTD of parafibromin.