ORF16-01 - Defying Expectations: Low Urinary Calcium in Autosomal Dominant Hypocalcemia Type 1

Background:
Autosomal dominant hypocalcemia type 1 (ADH-1) is a rare disorder caused by gain-of-function mutations in the calcium-sensing receptor (CaSR), resulting in hypocalcemia with inappropriately normal or suppressed parathyroid hormone (PTH) and typically hypercalciuria. Recognition is critical, as conventional hypoparathyroidism therapy may worsen renal complications. We report an atypical ADH-1 presentation with hypocalciuria.

Case Presentation:
A 57-year-old woman with hypothyroidism and prior sleeve gastrectomy was noted to have intermittent hypocalcemia during thyroid evaluation. She reported fatigue, anxiety, sleep disturbance, musculoskeletal pain, and distal paresthesias. Family history included nephrolithiasis and renal failure in a maternal aunt. Initial labs showed corrected calcium 8.1 mg/dL (8.4–10.2), PTH 32.6 pg/mL (12–88), 25-hydroxyvitamin D 44 ng/mL (30–100), phosphorus 3.0 mg/dL (2.7–4.5), vitamin B12 158 pg/mL (180–914), ferritin 13 ng/mL (11–307), suppressed TSH, and normal free T4. Iron and vitamin B12 were started. Repeat testing revealed ionized calcium 0.99 mmol/L (1.12–1.32), PTH 21.3 pg/mL, magnesium 1.9 mg/dL (1.9–2.7), 1,25-dihydroxyvitamin D 71.3 pg/mL (5–200), and 24-hour urinary calcium 78.3 mg/24h. Parathyroid antibodies were negative. Genetic testing identified a rare c.1990C>T variant in CASR, consistent with ADH-1.

Discussion:
ADH-1 classically presents with hypocalcemia, suppressed PTH, hypercalciuria, normal-to-high phosphorus, and low-normal magnesium. Gain-of-function CaSR mutations inhibit PTH and increase renal calcium excretion, predisposing to nephrolithiasis, nephrocalcinosis, and ectopic calcifications. This patient exhibited hypocalciuria, likely due to impaired intestinal calcium absorption after bariatric surgery, as evidenced by iron and vitamin B12 deficiencies. Vitamin D levels were normal with supplementation. Accurate diagnosis is essential, as calcium and active vitamin D may worsen renal complications, and PTH analogs may not sufficiently correct electrolyte abnormalities. Encaleret, a CaSR antagonist, is an emerging therapy currently in phase 3 trials.

Conclusion:
This case highlights the importance of determining the cause of hypoparathyroidism and pursuing genetic testing in patients with atypical features, as management of ADH-1 differs from other forms of hypoparathyroidism.