Inactivating mutations of calcium-sensing receptor results in parathyroid lipohyperplasia.

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disease characterized by mild hypercalcemia, an inappropriately high parathyroid hormone level, and absence of hypercalciuria. Heterozygous inactivating mutations of calcium-sensing receptor (CaSR) are found in about two thirds of patients with FHH. Histologic examination of parathyroid glands in FHH is reported to show normal histology or chief cell hyperplasia. Thus, histologic features of the parathyroid glands in FHH vary, and there is no clear histologic criterion that indicates FHH. The authors have encountered three hypercalcemic patients with characteristic histologic features of enlarged parathyroid glands. Clusters of parenchymal cells were mixed with fat cells, and the area of fat cells was 33% to 49% of the total area. These features are similar to those described as parathyroid lipohyperplasia. Postoperative evaluation showed that fractional excretion of calcium was low in these patients. Direct sequencing of the polymerase chain reaction product showed that the first patient was heterozygous for an already reported inactivating mutation of CaSR (P55L). The second patient was also heterozygous for a novel inactivating mutation (R220W). The third was homozygous for an inactivating mutation (Q27R). These results indicate that histologic features of parathyroid lipohyperplasia suggest the presence of inactivating mutations of CaSR.