SUN-722 A Rare CaSR Gene Variant Causing Autosomal Dominant Hypocalcemia Type 1

Abstract Disclosure: M. Malik: None. S. Minhas: None. R. Mimms: None. Introduction: Autosomal dominant hypocalcemia type 1 (ADH1) is caused by a gain-of-function mutation of the calcium sensing receptor (CaSR). ADH1 can cause symptomatic hypocalcemia and risk of adverse renal and systemic complications, which can be exacerbated by standard therapy. Although ADH1 is considered a rare condition, its prevalence is likely underreported. Herein we describe a case of ADH1 involving a novel CaSR sequence variant in a young woman. Case: A 35-year-old female presented to the emergency department with a 1-month history of worsening nausea and vomiting. Labs showed a corrected calcium level of 13.2 mg/dL. Patient had been diagnosed with nonsurgical hypoparathyroidism months prior to admission despite a history of chronic symptomatic hypocalcemia. Her outpatient treatment regimen included calcium citrate 600 mg twice daily (BID), calcitriol 0.75 mcg BID, magnesium oxide 400 mg BID, and cholecalciferol 50,000 IU monthly. Hypercalcemia was corrected and she was discharged to see Endocrinology. Historical outpatient labs were notable for a corrected calcium 7.8 mg/dL, PTH 19.4, magnesium 1.8 mg/dL, 25-OH vitamin D 48.4 ng/mL, 24-hour urine calcium of 323 mg and negative anti-PTH antibodies. Family history of hypocalcemia was noted in her mother, later confirmed as non-surgical hypoparathyroidism. Our patient underwent genetic testing which revealed an autosomal dominant CaSR mutation at codon 964. She was enrolled in an investigational clinical trial for an oral calcilytic and is no longer requiring vitamin or mineral supplementation. Discussion: Patients with ADH1 present with symptoms of hypocalcemia and lab work demonstrating low or low-normal PTH, hypocalcemia, hypomagnesemia, hyperphosphatemia, and elevated urinary calcium levels. Complications include nephrocalcinosis, nephrolithiasis, cerebral calcifications, and renal impairment due to increased urinary calcium excretion. Treatment includes cautious calcium and activated vitamin D supplementation to target a serum calcium at low-normal range. Worsening of hypercalciuria and its undesired complications is common with therapy. Thiazides can be used to reduce urinary calcium excretion. A novel selective antagonist of CaSR, Encaleret, is currently being studied in qualifying patients with ADH1 in a Phase 3 clinical trial. This patient was heterozygous in the CaSR gene for a sequence variant defined as c.964CG, which is predicted to result in the amino acid substitution p.Leu322Val. To our knowledge, this variant has not been reported in literature or in a large population database indicating this variant is rare. This case highlights some of the complexities in the diagnosis and management of non-surgical hypoparathyroidism, while also contributing to the body of knowledge regarding genotype-phenotype expression of CaSR and raising awareness of novel therapeutic options for this condition. Presentation: Sunday, July 13, 2025