Clinical and Molecular Characterization of Familial Hypocalciuric Hypercalcemia in an Endocrine Practice – A Case Series of 25 Patients

Abstract Familial hypocalciuric hypercalcemia (FHH) is a disorder caused by abnormal sensing of calcium by the parathyroids and renal tubules and may mimic primary hyperparathyroidism (PHPT). Patients with FHH should not be subjected to unnecessary and potentially harmful parathyroid surgery. We sought to evaluate the clinical and biochemical presentation of FHH in our endocrine practice. This was a retrospective chart review done after IRB approval. We describe 25 cases of likely FHH from our endocrine practice (20 FHH1, 1 FHH2, 4 FHH3). The 24-hour urinary calcium levels were often greater than 100 mg/24h and sometimes greater than 200 mg/24h. The calcium to creatinine clearance ratio (CCCR) was consistently < 0.01 in 10 of 22 (45%). We also describe several variants of CASR and 1 variant of GNA11 that are probably pathogenic. Some patients, particularly FHH3 patients, have hypercalcemia severe enough to warrant treatment with a calcimimetic medication (cinacalcet). Traditional methods of excluding FHH using 24-hour urinary calcium and CCCR are not adequate to distinguish FHH and PHPT. In addition to young age, family history of hypercalcemia and low CCCR, we believe molecular testing should be considered prior to surgery when hypercalcemia cannot be demonstrated to be acquired and in the case of persistent PHPT after surgery by an experienced parathyroid surgeon.