Inactivating Mutations of Calcium-Sensing Receptor Results in Parathyroid Lipohyperplasia

Abstract

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.

Identification and functional characterization of loss-of-function mutations of the calcium-sensing receptor in four Italian kindreds with familial hypocalciuric hypercalcemia

“…A mildly enlarged parathyroid gland was removed in the former and was histologically scored as a hyperplastic gland, possibly a parathyroid adenoma. The microscopic appearance was not consistent with the so-called 'lipohyperplasia', which has been reported in several parathyroid glands of FHH patients, where, at variance with what we found in our case, concurrent hyperplasia of fat and parathyroid chief cells have been observed in some cases (22,23). Thus, we believe that the resected parathyroid gland was pathological.…”

A novel mutation in the calcium-sensing receptor in a French family with familial hypocalciuric hypercalcaemia

“…Moreover, the resected glands showed principal cell hyperplasia without adipose cells. Interestingly, parathyroid hyperplasia has been previously described in patients with FHH, but this hyperplasia was in the form of simultaneous hyperplasia of fat and parathyroid principal cells called 'lipohyperplasia' (17). However, this was not the case in our patient or for those reported by Cetani et al (18).…”

The Calcium-Sensing Receptor: Physiology, Pathophysiology and Car-Based Therapeutics

“…Recent studies have described the presence of single and multiple parathyroid "adenomas" in several patients with FHH, although the parathyroid glands in FHH typically are of normal size and histology, or in some cases exhibit mild chief cell hyperplasia with one or more enlarged glands (Burski et al, 2002;Carling et al, 2000). A few cases of parathyroid lipohyperplasia have been described in FHH, and some authors have suggested that finding should prompt a search for inactivating mutations of CaR (Fukumoto et al, 2001).…”

“…She was asymptomatic, despite a serum calcium concentration of 3.75 to 4.25 mM (Aida et al, 1995). Another such patient, who was homozygous for a distinct inactivating CaR mutation was likewise not diagnosed until adulthood (Fukumoto et al, 2001). Both mutations produced relatively mild defects of their function when expressed heterologously, perhaps enabling a sufficient of control PTH release by calcium to be compatible with a relatively normal life, despite quite marked hypercalcemia.…”