Genetic defects associated with familial and sporadic hyperparathyroidism

Front Horm Res. 2013;41:149-65. doi: 10.1159/000345675. Epub 2013 Mar 19.


Primary hyperparathyroidism (PHPT) occurs sporadically, but occasionally it may be a feature of a familial condition, such as multiple endocrine neoplasia type 1 (MEN1), MEN2A, or the HPT-jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia/neonatal severe hyperparathyroidism (FHH/NSHPT). PHPT may also occur as familial isolated hyperparathyroidism (FIHP), and has been observed as a consequence of mutations in the CDKN1B gene (MEN4). Tumorigenesis in these conditions may be the result of protooncogene activation (e.g. RET in MEN2) or two-hit losses of a tumor suppressor (e.g. MEN1, HPT-JT). In patients with MEN1, HPT-JT or FHH/NSHPT, the hyperparathyroidism manifests at a younger age and affects both sexes equally. In MEN1, mutations of the MEN1 gene also cause enteropancreatic and anterior pituitary tumors. In MEN2, activating mutations in the RET protooncogene also cause medullary thyroid carcinoma and pheochromocytoma. In HPT-JT, mutations of CDC73/HRPT2 are associated with parathyroid carcinoma, but tumors of the kidneys and uterus are additional features. In some FIHP families, a CASR mutation may be identified. In parathyroid carcinoma, even if sporadic, molecular diagnostics for CDC73/HRPT2 should be considered, as it should be for younger patients. Further exploration of these hereditary syndromes may shed light on the molecular mechanisms giving rise to nonhereditary PHPT.

MeSH terms

  • Cyclin D1 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Female
  • Humans
  • Hypercalcemia / congenital
  • Hyperparathyroidism, Primary / genetics*
  • Infant, Newborn
  • Infant, Newborn, Diseases / genetics
  • Jaw Neoplasms / genetics
  • Loss of Heterozygosity
  • Male
  • Multiple Endocrine Neoplasia Type 1 / complications
  • Multiple Endocrine Neoplasia Type 1 / genetics
  • Multiple Endocrine Neoplasia Type 2a / complications
  • Multiple Endocrine Neoplasia Type 2a / genetics
  • Parathyroid Neoplasms / genetics*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-ret / genetics
  • Receptors, Calcium-Sensing / genetics
  • Tumor Suppressor Proteins / genetics


  • CCND1 protein, human
  • CDC73 protein, human
  • CDKN1B protein, human
  • MEN1 protein, human
  • Proto-Oncogene Proteins
  • Receptors, Calcium-Sensing
  • Tumor Suppressor Proteins
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • Proto-Oncogene Proteins c-ret
  • RET protein, human

Supplementary concepts

  • Hypocalciuric hypercalcemia, familial, type 1