Hypocalcemia and Recurrent Kidney Stones: A Diagnostic Challenge

Introduction: Autosomal dominant hypocalcemia type 1 (ADH1) is a rare genetic disorder caused by heterozygous activating mutations in the CASR gene, which encodes the calcium-sensing receptor (CaSR), a key regulator of calcium homeostasis. These mutations enhance CaSR activity, resulting in hypocalcemia, hypercalciuria, and low parathyroid hormone (PTH) levels. Case Description: A 47-year-old woman (BMI: 41.95) with a history of hypothyroidism, vitamin D and Factor V Leiden deficiency was referred to nephrology clinic for her unexplained hypocalcemia (7.3 mg/dL) and recurrent nephrolithiasis. She has no history of thyroidectomy or parathyroidectomy. Laboratory evaluation revealed suppressed PTH (4 pg/mL), hyperphosphatemia (5.5 mg/dL), hypokalemia (3.3 mEq/L), hypomagnesemia (1.6 mg/dL), and creatinine 0.7 mg/dL. 24h urine collection showed hypocitraturia. On review of her family history, father (deceased) had a known history of kidney stones. Among her 3 children, her 10-year-old daughter also had hypocalcemia and hyperphosphatemia. Imaging revealed bilateral kidney stones. Genetic testing reported a CASR gene mutation as a VUS (c.2519C>A, p.Ala840Asp). Her symptomatic daughter also underwent genetic testing, confirming the same CASR mutation. The patient was counseled on dietary modifications, including increased fluid intake, a low-sodium and plant-based protein diet. Pharmacologic management included chlorthalidone, calcitriol, and potassium citrate. Discussion: Here, we report a mother and daughter with hypocalcemia, low PTH, and hyperphosphatemia who have congruent mutations in CASR gene. Though reported as a VUS, we submit that this could be a disease-causing mutation for ADH1. ADH1 is a rare condition that should be considered in patients with recurrent kidney stones whose profile is not compatible with typical of stone former. Given her father’s history and confirmed mutation in patient and her daughter, the gene is autosomal dominant. Management of these patients should be based on symptoms. Calcium correction in asymptomatic patients is generally not recommended. In contrast, symptomatic patients should receive a minimal effective dose of calcium and activated vitamin D to minimize the risk of nephrocalcinosis. A low sodium and phosphorus diet is also advised in patients with hypoparathyroidism to reduce hypercalciuria and manage calcium-phosphate balance effectively.