Familial hypocalciuric hypercalcemia

Familial hypocalciuric hypercalcemia (FHH), also known as familial benign hypercalcemia, is a genetic disorder characterized by lifelong mild to moderate elevation of calcium levels in the blood (hypercalcemia) accompanied by inappropriately low calcium excretion in the urine (hypocalciuria). The condition is caused by mutations that affect the calcium-sensing receptor (CaSR) or its signaling pathway, which plays a critical role in how the body regulates calcium levels. The parathyroid glands, kidneys, and bones are the primary systems affected. There are three recognized subtypes: FHH type 1 (most common, caused by loss-of-function mutations in the CASR gene), FHH type 2 (caused by mutations in GNA11), and FHH type 3 (caused by mutations in AP2S1). Because the calcium-sensing receptor is less sensitive to calcium, the parathyroid glands do not appropriately suppress parathyroid hormone (PTH) secretion, and the kidneys reabsorb more calcium than normal. Most individuals with FHH are asymptomatic and the condition is often discovered incidentally on routine blood tests showing elevated serum calcium. When symptoms do occur, they may include fatigue, weakness, excessive thirst, and mild cognitive difficulties, though these are uncommon. Serum magnesium may also be mildly elevated, and PTH levels are typically normal or mildly elevated despite the hypercalcemia. Importantly, FHH must be distinguished from primary hyperparathyroidism, as the two conditions share biochemical similarities but require very different management. The calcium-to-creatinine clearance ratio (typically below 0.01 in FHH) is a key diagnostic tool. FHH type 3 (AP2S1 mutations) may present with more pronounced hypercalcemia and can be associated with cognitive and behavioral difficulties. In the vast majority of cases, FHH is a benign condition that does not require treatment. Parathyroidectomy, which is the standard treatment for primary hyperparathyroidism, is generally ineffective and not recommended for FHH because the fundamental defect lies in calcium sensing rather than parathyroid gland overactivity. Calcimimetic drugs such as cinacalcet, which enhance the sensitivity of the calcium-sensing receptor, have been explored in some cases, particularly in FHH type 1, but their routine use is not established. Regular monitoring of calcium levels is generally advised, and genetic testing can confirm the diagnosis and help guide family counseling.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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