Familial hypocalciuric hypercalcemia and related disorders

Best Pract Res Clin Endocrinol Metab. 2018 Oct;32(5):609-619. doi: 10.1016/j.beem.2018.05.004. Epub 2018 May 26.


Familial hypocalciuric hypercalcemia (FHH) causes hypercalcemia by three genetic mechanisms: inactivating mutations in the calcium-sensing receptor, the G-protein subunit α11, or adaptor-related protein complex 2, sigma 1 subunit. While hypercalcemia in other conditions causes significant morbidity and mortality, FHH generally follows a benign course. Failure to diagnose FHH can result in unwarranted treatment or surgery for the mistaken diagnosis of primary hyperparathyroidism (PHPT), given the significant overlap of biochemical features. Determinations of urinary calcium excretion greatly aid in distinguishing PHPT from FHH, but overlap still exists in certain cases. It is important that 24-h urine calcium and creatinine be included in the initial workup of hypercalcemia. FHH should be considered if low or even low normal urinary calcium levels are found in what is typically an asymptomatic hypercalcemic patient. The calcimimetic cinacalcet has been used to treat hypercalcemia in certain symptomatic causes of FHH.

Keywords: Ca-sensing receptor; familial hypocalciuric hypercalcemia; hyperparathyroidism.

Publication types

  • Review

MeSH terms

  • Adaptor Protein Complex 2 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • Humans
  • Hypercalcemia / complications
  • Hypercalcemia / congenital*
  • Hypercalcemia / diagnosis
  • Hypercalcemia / epidemiology
  • Hypercalcemia / genetics
  • Hypercalcemia / therapy
  • Hyperparathyroidism, Primary / complications
  • Hyperparathyroidism, Primary / diagnosis
  • Hyperparathyroidism, Primary / epidemiology
  • Hyperparathyroidism, Primary / therapy
  • Kidney Diseases / diagnosis
  • Kidney Diseases / epidemiology
  • Kidney Diseases / genetics
  • Kidney Diseases / therapy
  • Mutation
  • Receptors, Calcium-Sensing / genetics


  • Adaptor Protein Complex 2
  • Receptors, Calcium-Sensing
  • GTP-Binding Protein alpha Subunits, Gq-G11

Supplementary concepts

  • Hypocalciuric hypercalcemia, familial, type 1