A Novel Variant in the Calcium-Sensing Receptor Associated with Familial Hypocalciuric Hypercalcemia and Low-to-Normal PTH

Abstract

Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by mild elevations in serum calcium and relatively low urinary calcium excretion. It results from an elevated set point in serum calcium arising from variants in the calcium-sensing receptor (CaSR) gene but also AP2S1 and GNA11 genes, which encode for adaptor-related protein complex 2 and G11 proteins, respectively. The manifestations of FHH can vary and sometimes overlap with primary hyperparathyroidism making the diagnosis challenging. Case Presentations. We report a mother and daughter with a novel heterozygous variant in the CaSR gene resulting in a serine to leucine substitution at position 147 (S147L) of the CaSR. Both patients had mild hypercalcemia, relatively low urinary calcium excretion, elevated calcitriol, and low-to-normal intact PTH. The proband (daughter) presented with symptoms associated with hypercalcemia and was incidentally found to have a bony lesion suspicious for osteitis fibrosa cystica, and she was also diagnosed with sarcoidosis. Subtotal parathyroidectomy revealed normal-weight parathyroid glands comprised of 50–80% parathyroid epithelial cells, which has been documented as within the spectrum of normal. Her mother had no symptoms, and no intervention was pursued. Conclusion. We report a novel variant in the CaSR associated with FHH in two patients with similar biochemical features yet differing clinical manifestations. While the relationship of the bony findings and parathyroid histology with this variant remains unclear, these cases enrich our knowledge of CaSR physiology and provide further examples of how varied the manifestations of FHH can be.

Calcium-Sensing Receptor (CaSR), Its Impact on Inflammation and the Consequences on Cardiovascular Health

“…Nonetheless, familial hypocalciuric hypercalcemia (FHH) patients are found to have a unique variant of the CaSR gene even though they do not have hyperparathyroidism. This novel variant highlighted that serine 147 is an important site on the gene that is essential for sensing calcium as substitution of this site results in a disturbance in the calcium homeostasis [ 41 ]. On the other hand, gain-of-function mutations of CaSR have been shown to result in hypocalcaemia as well as hypomagnesemia [ 42 ].…”