Genetic hypercalcemia

Joint Bone Spine. 2019 Jul;86(4):459-466. doi: 10.1016/j.jbspin.2018.10.001. Epub 2018 Oct 6.


A genetic disorder should be suspected in patients with hypercalcemia, notably those who are young; have family members with hypercalcemia; or have had a tumor of the endocrine pancreas, thyroid, pituitary, adrenal gland, or jaw bone. All forms of hypercalcemia should be interpreted according to the serum level of parathyroid hormone (PTH). Genetic forms are thus classified as related or unrelated to a parathyroid gland disorder. When the PTH level is elevated or is not depressed despite the hypercalcemia, findings that suggest family history of hypercalcemia due to a genetic cause include syndromic manifestations in the patient or family members, parathyroid cancer (either suspected before surgery or confirmed during parathyroidectomy), multiple or recurrent parathyroid tumors, a family history of primary hyperparathyroidism, and the onset of primary hyperthyroidism before 50 years of age. In patients with moderate hypercalcemia, a normal PTH level, and relative hypocalciuria, the first hypothesis is a mutation in the calcium-sensing receptor gene, which is often difficult to distinguish from primary hyperparathyroidism, particularly when there is no known family history of hyperparathyroidism, as is often the case. A low PTH level suggests non-parathyroid hypercalcemia due to a genetic defect in patients with no evidence of other conditions associated with hypercalcemia and low PTH levels and in those whose calcitriol levels are elevated or normal (instead of depressed as expected when PTH is elevated). Patients with hypercalciuria but no evidence of conditions such as granulomatous diseases should be evaluated for increased vitamin D sensitivity due to a CYP 4A1 mutation. Other very rare causes include hypophosphatasia due to ALPL mutations, which is characterized by a low alkaline phosphatase level; and renal phosphate wasting due to an NPT2A mutation, in which serum phosphate levels are low. A thorough analysis of the clinical and laboratory data can point toward a genetic disorder in patients with hypercalcemia. The diagnosis is then confirmed by obtaining genetic tests tailored to the clinical and laboratory test abnormalities. The current development of diagnostic genetic testing is shedding new light on the phenotypes, thereby improving their management.

Keywords: Familial hypercalcemia; Genetic hypercalcemia; Hypercalcemia in young patients; Syndromic hypercalcemia.

Publication types

  • Comparative Study
  • Review

MeSH terms

  • Cytochrome P-450 CYP4A / genetics*
  • Female
  • Gene Expression Regulation*
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Humans
  • Hypercalcemia / blood
  • Hypercalcemia / diagnosis
  • Hypercalcemia / epidemiology
  • Hypercalcemia / genetics*
  • Hyperparathyroidism / complications
  • Hyperparathyroidism / diagnosis
  • Incidence
  • Male
  • Mutation
  • Parathyroid Hormone / blood*
  • Prognosis
  • Receptors, Calcium-Sensing / genetics*
  • Risk Assessment


  • Parathyroid Hormone
  • Receptors, Calcium-Sensing
  • Cytochrome P-450 CYP4A