A Young Male with Parafibromin-Deficient Parathyroid Carcinoma Due to a Rare Germline HRPT2/CDC73 Mutation

Abstract

Hyperparathyroidism, commonly observed in asymptomatic middle-aged women, with mild hypercalcemia, is usually caused by a benign adenoma. Some cases present with more severe manifestation and greater hypercalcemia. Within this spectrum, several familial/genetic associations have been discovered. While the majority are caused by benign disease, adenomas, or hyperplasia, a small proportion (< 1%) are associated with malignant tumors and present with more severe symptoms. Although usually sporadic, recent reports document various gene mutations that strongly predispose to the development of parathyroid carcinoma. An increasing number of cases of hyperparathyroidism, benign or malignant, require and benefit from genetic analysis. We describe a 25-year-old male with hyperparathyroidism presenting with a pathological fracture, brown tumors, hypercalcemia, and markedly elevated parathyroid hormone levels. There was no family history of hyperparathyroidism or jaw tumors. Surgical removal revealed a single large tumor confirmed to be malignant. Immunohistochemical analysis revealed the absence of parafibromin and decreased APC (adenomatosis polyposis coli) expression. Genetic analysis revealed a rare germline nonsense mutation (R76X) in the parafibromin gene, HRPT2/CDC73. Parathyroid carcinoma should be suspected as a cause of hyperparathyroidism when clinical manifestations are severe, particularly in young individuals, < 59 years. Immunohistochemistry may lead to suspicion for a germline mutation as a significant contributor despite absence of a family history. The discovery of a germline mutation in parathyroid carcinoma alters the clinical management of the index case and that of family members. Long-term follow-up studies of such patients are necessary to develop evidence-based clinical guidelines.

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Acknowledgements

AK and NS contributed equally to this work and share first authorship. We thank the following physicians for providing clinical information relevant to this report: Dr. Catherine Kelly, Department of Medicine, Dr. Patrick Kennedy, Dr. Jagbir Khinda, and Dr. Robert Bleakney, Joint Department of Medical Imaging, and Dr. Christina MacMillan, Department of Laboratory Medicine and Pathobiology, University of Toronto.

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Correspondence to I. George Fantus.

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Kapur, A., Singh, N., Mete, O. et al. A Young Male with Parafibromin-Deficient Parathyroid Carcinoma Due to a Rare Germline HRPT2/CDC73 Mutation. Endocr Pathol 29, 374–379 (2018). https://doi.org/10.1007/s12022-018-9552-5

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Keywords

  • Parafibromin
  • Parathyroid carcinoma
  • HRPT2/CDC73