A Novel Missense CASR Gene Sequence Variation Resulting in Familial Hypocalciuric Hypercalcemia

Familial hypocalciuric hypercalcemia (FHH) is an uncommon cause of hypercalcemia; however, it is important to consider and rule out in patients with suspected primary hyperparathyroidism (PHPT), ideally, before proceeding with surgery. Herein, we present a patient where this process identified a calcium-sensing receptor gene (CASR) sequence variant currently labeled as a variant of unknown significance (VUS), yet the patient's family pedigree suggests that it is in fact a pathogenic CASR sequence variant.

A 35-year-old woman was referred to the Endocrine Surgery clinic for evaluation of "recurrent PHPT" and need for reoperative parathyroidectomy. Before referral, she was treated with subtotal parathyroidectomy for the presumed diagnosis of PHPT-related symptomatic hypercalcemia. Postoperatively, she had persistent symptoms. Upon referral, additional relevant information was elicited that suspected FHH instead of PHPT, including a family history of hypercalcemia with CASR VUS in multiple family members and hypocalciuria in the patient. She underwent genetic testing revealing a missense CASR VUS in exon 3 c.392C>A (p.Ala110Asp), the same as in her mother. Medical management instead of reoperation was advised for the diagnosis of FHH.

To our knowledge, this CASR sequence variation has not been previously reported in the literature. Reporting newly discovered sequence variations with the context of a family's medical history is important because it allows for the recognition of new pathogenic variants. This expands the registry of already known sequence variations and their associated clinical pathology for future patients undergoing genetic testing.

This CASR variant represents a novel pathogenic sequence variation causing FHH.