Distribution of serum calcium values in patients with familial benign hypercalcemia (hypocalciuric hypercalcemia): evidence for a discrete genetic defect.

One group has reported hypocalcemic individuals in families affected with familial benign hypercalcemia (FBH), suggesting either that FBH is merely an extreme of normality or that hypocalcemia is independently inherited in that kindred. To test these hypotheses, we examined the distributions of serum total calcium (Ca) values in 260 normal adults and 171 adult individuals in 21 FBH kindreds. We excluded from analysis the 21 adult probands, leaving 85 apparently affected persons (Ca, greater than 10.1 mg/dL or greater than 2.52 mmol/L) and 65 apparently unaffected individuals (Ca, less than or equal to 10.1 mg/dL or less than or equal to 2.52 mmol/L). Five FBH family members were hypocalcemic (less than 8.9 mg/dL or less than 2.22 mmol/L); of these, 3 had hypoproteinemia or hypoalbuminemia, 1 had surgical hypoparathyroidism, and 1 was pregnant (and thus excluded from further analysis). Histogram analysis suggested a bimodal distribution of Ca in the FBH families, and familial serum Ca levels were significantly elevated (P less than 0.001, rank sum). When only apparently unaffected family members were compared with normal individuals with serum Ca of 10.1 mg/dL or 2.52 mmol/L or less, the distributions were virtually identical. Our results indicate that hypocalcemia in members of families with FBH is of sporadic nongenetic origin. Furthermore, FBH is not an extreme of the normal distribution, but, instead, a clear disturbance with its own distribution about a supranormal mean serum calcium value.