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

Panagiotis Bletsis; Rosemarie Metzger; J Alex Nelson; Justin Gasparini; Mahmoud Alsayed; Mira Milas

doi:10.1016/j.aace.2022.05.002

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

AACE Clin Case Rep. 2022 May 17;8(5):194-198. doi: 10.1016/j.aace.2022.05.002. eCollection 2022 Sep-Oct.

Authors

Panagiotis Bletsis¹, Rosemarie Metzger¹, J Alex Nelson¹, Justin Gasparini², Mahmoud Alsayed³, Mira Milas¹

Affiliations

¹ Division of Endocrine Surgery, Department of Surgery, Banner University Medical Center Phoenix/University of Arizona College of Medicine Phoenix.
² Department of Clinical Cancer Genetics, Banner MD Anderson Cancer Center Phoenix.
³ Division of Endocrinology, Department of Internal Medicine, Banner University Medical Center Phoenix/University of Arizona College of Medicine Phoenix.

Abstract

Background/objective: 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.

Case report: 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.

Discussion: 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.

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

Keywords: CCCR, calcium creatinine clearance ratio; CaSR, calcium-sensing receptor; FHH, familial hypocalciuric hypercalcemia; PHPT, primary hyperparathyroidism; PTH, parathyroid hormone; RR, reference range; Sherloc classification system; VUS, variant of unknown significance; familial hypocalciuric hypercalcemia (FHH); genetic testing; primary hyperparathyroidism (PHPT).

Publication types

Case Reports