Primary Hyperparathyroidism Focused on Molecular Pathogenesis

Primary hyperparathyroidism (PHPT) is a common cause of hypercalcaemia. The most common lesion found in patients is the solitary benign parathyroid adenoma. Multiple parathyroid adenomas have also been reported. Parathyroid carcinomas are an uncommon cause of PHPT. In 15% of patients, all four parathyroid glands are involved and it may be associated with a familial hereditary syndrome, such as multiple endocrine neoplasia, types 1, 2A and 4. PHPT jaw tumour syndrome is associated with fibromas in the mandible and tumours can also be present in the kidneys and the uterus. No predisposing germline DNA variants in parathyroid adenomas have been demonstrated and only a few clonally altered genes that drive parathyroid tumorigenesis have been identified. Frequently parathyroid adenomas have HRPT2 gene mutations that are likely to be of pathogenetic importance. Mutations in the MEN1 gene (localised to 11q13) are responsible for multiple endocrine neoplasia 1. Multiple endocrine neoplasia 2A, which can be associated with medullary thyroid cancer, is due to a germline mutation of the RET proto-oncogene located on chromosome 10. In MEN1-like negative patients some of the germline mutations in this new susceptibility gene were due to gene CDKN1B (12p13). This new syndrome was classified as multiple endocrine neoplasia 4. In PHPT jaw tumour syndrome, HRPT2, the gene on the long arm of chromosome 1, is responsible for the syndrome. It is suggested to perform genetic testing in patients with PHPT below the age of 30 years, but at any age in patients presenting with multigland parathyroid disease.