Endocrine Abstracts

JOINT1062

Introduction: Familial hypocalciuric hypercalcemia (FHH) is a typically benign condition marked by elevated serum calcium levels alongside relatively low urinary calcium excretion. In most cases, FHH arises from loss-of-function mutations in the CASR gene, which encodes the calcium-sensing receptor (CASR), a G-protein coupled receptor predominantly expressed in the parathyroid glands and kidneys. The condition is often asymptomatic and generally does not require treatment. Identifying CASR mutations through genetic testing is crucial to distinguish FHH from primary hyperparathyroidism and prevent unnecessary parathyroidectomy.

Case Report: An 18-year-old male undergoing medical assessment as part of a job application was incidentally found to have elevated serum calcium. Repeat measurements of corrected calcium ranged from 2.9 to 3.0 mmol/l. He was asymptomatic with no evidence of end-organ damage. His medical history was unremarkable, and he took no regular medications. His family history was notable for his mother, who was diagnosed 15 years earlier with PTH-mediated hypercalcemia, presumed primary hyperparathyroidism. Her imaging was negative, and she had not required surgery or treatment. There was no family history of nephrolithiasis, pheochromocytoma, or pituitary disorders. Further biochemical evaluation showed a PTH level of 5.0 pmol/l (RR: 1.6–6.9) and a vitamin D level of 62 mmol/l. Urinary calcium excretion was low, with a calcium-to-creatinine clearance ratio of 0.012. A sestamibi scan suggested a possible right parathyroid adenoma; however, ultrasound did not confirm this finding. Genetic analysis identified a novel pathogenic CASR gene mutation, c.1793G>C (p.Cys598Ser) (chromosome 3: 122002594), confirming familial hypocalciuric hypercalcemia type 1 (FHH1). The patient was counselled on the benign nature and inheritance of FHH and and this confirmation allowed him to proceed with his intended career path without unnecessary medical restrictions. Given the family history of hypercalcemia, genetic testing of his mother is planned to determine if she carries the same mutation.

Discussion: This case expands the spectrum of pathogenic CASR mutations linked to FHH. The identified missense variant disrupts an intramolecular disulfide bond essential for receptor function. Although this specific mutation has not been reported before, similar mutations affecting this bond have been classified as pathogenic, supporting its pathogenicity. Distinguishing FHH from primary hyperparathyroidism can be challenging, especially when imaging suggests a parathyroid adenoma, increasing the risk of unnecessary surgery. In this case, genetic testing was crucial in confirming the diagnosis and avoiding unnecessary intervention.