Kidney Week

Abstract: TH-PO178

Familial Hypercalcemia and Hypercalciuria with a Novel Calcium-Sensing Receptor Mutation

Session Information

• CKD-MBD: Clinical
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 502 Bone and Mineral Metabolism: Clinical

Authors

• Brand, Kenneth, Baystate Medical Center, Springfield, Massachusetts, United States

Kenneth Brand, MD

• Greco, Barbara A., Baystate Medical Center, Springfield, Massachusetts, United States

Barbara A. Greco, MD

Introduction

The most common cause of hereditary hypercalcemia is Familial Hypocalciuric Hypercalcemia (FHH). Over 200 loss-of-function CaSR mutations have been associated with FHH. We report a family with hypercalcemia due to a novel mutation in the CaSR with associated hypercalciuria.

Case Description

An 80-year-old white man initially presented at age 67 with longstanding hypercalcemia, no history of renal stones or osteoporosis, and on no supplemental calcium. Over the years, his serum calcium ranged from 10 to 11.6 mg/dl, phosphorus 1.9-2.9 with PTH levels between 29-50 pg/ml. Vit D and magnesium levels were normal. Several 24-hour urine collections confirmed hypercalciuria and hyperphosphaturia. Two 24-hour renal calcium to creatinine clearance ratios (CCCR) were 0.013 and 0.017. NM sestamibi scan showed no parathyroid adenoma. Genetic testing (Invitae) identified a cytosine to thymine substitution at position 1880 of the CaSR gene with threonine replacing isoleucine at position 627 in the intramembranous portion, a variant of unknown significance (VUS). Cinacalcet 30 mg daily had no effect whereas 60 mg daily normalized serum calcium. His daughter was found to be hypercalcemic and hypercalciuric (210 mg) at age 40 and her 16-year-old son had hypercalcemia, 10.6 mg/dl.

Discussion

The finding of a CaSR VUS in a family with hypercalcemia supports the diagnosis of FHH. This patient’s CCCRs were nondiagnostic for differentiating primary hyperparathyroidism from FHH. Our patient had hypercalciuria and hyperphosphaturia. The mechanism is unclear but raises the question as to whether this mutation affects the function of the CaSR in the parathyroid gland and renal tubules differently- reducing the activity of the CaSR in the parathyroid and proximal tubule to a greater extent than in the thick ascending limb. Response to moderate but not low dose cinacalcet is consistent with an inactivating CaSR mutation.

Laboratory Investigations