Familial hypocalciuric hypercalcemia (FHH) is a benign, autosomal dominant condition caused chiefly by inactivating mutations in the calcium-sensing receptor gene (CASR, causing FHH1), with rarer forms from GNA11 (FHH2) and AP2S1 (FHH3) mutations. Because it is benign, management is usually watchful monitoring without intervention — and the most important clinical point is distinguishing FHH from primary hyperparathyroidism to prevent unnecessary parathyroid surgery, using the urinary calcium-to-creatinine clearance ratio and genetic testing. For the uncommon patient with significant or symptomatic hypercalcemia, the calcimimetic cinacalcet can lower serum calcium, and an emerging precision-medicine theme is that the response to calcimimetics is mutation-specific — certain CASR variants have their signaling "rescued" by cinacalcet or evocalcet, while others respond poorly — pointing toward genotype-guided use of these agents.
Further reading: disorders of the calcium-sensing pathway (Höppner et al., 2022); personalized medicine for familial hypercalcemia (Josephs et al., 2022); genetic testing for heritable hyperparathyroidism (De Sousa et al., 2022).