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 h ormone level, and absence of hypercalciuria. Heterozygous inactivating muta tions of calcium-sensing receptor (CaSR) are found in about two thirds of p atients with FHH. Histologic examination of parathyroid glands in FHH is re ported to show normal histology or chief cell hyperplasia. Thus. histologic features of the parathyroid glands in FHH vary, and there is no clear hist ologic criterion that indicates FHH. The authors have encountered three hyp ercalcemic patients with characteristic histologic features of enlarged par athyroid glands. Clusters of parenchymal cells were mixed with fat cells, a nd the area of fat cells was 33% to 49% of the total area. These features a re similar to those described as parathyroid lipohyperplasia. Postoperative evaluation showed that fractional excretion of calcium was low in these pa tients. Direct sequencing of the polymerase chain reaction product showed t hat the first patient was heterozygous for an already reported inactivating mutation of CaSR (P55L). The second patient was also heterozygous for a no vel inactivating mutation (R220W). The third was homozygous for an inactiva ting mutation (Q27R). These results indicate that histologic features of pa rathyroid lipohyperplasia suggest the presence of inactivating mutations of CaSR.