Send to:

Choose Destination
See comment in PubMed Commons below
Endocrinol Metab Clin North Am. 2000 Sep;29(3):503-22.

Familial hypocalciuric hypercalcemia and other disorders with resistance to extracellular calcium.

Author information

  • 1Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.


Cloning of the CaR has increased understanding of the normal control of mineral ion homeostasis and has clarified the pathophysiology of PTH-dependent hypercalcemia. Cloning of the CaR has enabled identification of FHH and NSHPT as inherited conditions with generalized resistance to Ca2+o, which is caused in many cases by inactivating mutations in the CaR gene. In most kindreds with FHH, there is resetting of Ca2+o to a mildly elevated level that does not require an increase in the circulating level of PTH above the normal range to maintain it. FHH is not accompanied by the usual symptoms, signs, and complications of hypercalcemia. The kidney participates in the genesis of the hypercalcemia in FHH by avidly reabsorbing Ca2+; consequently, there is no increased risk of forming urinary calculi in most cases. Generally, there is no compelling rationale for attempting to lower the level of Ca2+o in these patients to a nominal normal level. In contrast, in primary hyperparathyroidism, the Ca2+o resistance is limited to the pathologic parathyroid glands, and the rest of the body suffers the consequences of high circulating levels of calcium, PTH, or both. In this condition, removal of the offending parathyroid glands is often the treatment of choice. Parathyroidectomy may also be appropriate in disorders with generalized resistance to Ca2+o owing to inactivating CaR mutations in the following special circumstances: in selected families with FHH in which there is unusually severe hypercalcemia, frankly elevated PTH levels, or atypical features such as hypercalciuria; in cases of NSHPT with severe hypercalcemia and hyperparathyroidism; and in the occasional mild case of homozygous FHH owing to CaR mutations that confer mild-to-moderate resistance to Ca2+o that escapes clinical detection in the neonatal period. As discussed elsewhere in this issue, selective calcimimetic CaR activators are being tested in clinical trials, which potentiate the activation of the CaR by Ca2+o, thereby resetting the elevated set point for Ca2+o-regulated PTH release in primary and secondary hyperparathyroidism toward normal. It is hoped that these agents may become an effective medical therapy for the acquired Ca2+o resistance in primary and secondary hyperparathyroidism and perhaps for that present in the unusual cases of FHH and NSHPT, resetting the "calciostat" downward and thereby reducing Ca2+o and PTH toward normal.

[PubMed - indexed for MEDLINE]
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Loading ...
    Write to the Help Desk