Persistent Hypercalcemia: Diagnostic Complexity With Multiglandular Hyperparathyroidism, Renal Cell Carcinoma, and Hereditary Tumor Features

Persistent hypercalcemia after parathyroidectomy is a diagnostic challenge that requires careful evaluation beyond the parathyroid glands. We describe the case of a 76-year-old man with chronic kidney disease, resistant hypertension, and vestibular schwannoma who presented with weakness, constipation, and new, dark, raised lesions across his back. He reported undergoing parathyroidectomy one year earlier for presumed primary hyperparathyroidism, after which his hypercalcemia persisted. On admission, serum calcium was 13.1 mg/dL (reference = 8.5-10.5 mg/dL), and examination revealed numerous seborrheic keratoses across his posterior thoracolumbar region, consistent with the Leser-Trélat sign. A Tc-99m sestamibi scan localized a left inferior parathyroid adenoma. MRI of the abdomen revealed a 4.1 × 3.6 × 3.1 cm enhancing posterior right renal mass consistent with renal cell carcinoma (RCC). Further history revealed long-term thiazide diuretic use and consumption of one gallon of milk every other day. He was treated with intravenous fluids, zoledronic acid, and calcitonin with symptomatic improvement and was referred to a tertiary center for surgical evaluation. Persistent hypercalcemia after parathyroidectomy is most often due to multiglandular disease, but it may coexist with other etiologies. This patient's concurrent parathyroid adenoma, RCC, thiazide use, and high calcium intake illustrate multifactorial hypercalcemia. Additionally, vestibular schwannoma, cutaneous lesions, and resistant hypertension suggest a possible hereditary tumor syndrome such as multiple endocrine neoplasia type 2A, neurofibromatosis type 2, or von Hippel-Lindau disease. This case highlights the risk of cognitive anchoring when hypercalcemia is attributed to a single pathology. Instead, a broad differential should be maintained, including concurrent malignancy or inherited syndromes. Early recognition of overlapping etiologies is essential to prevent delayed diagnosis or missed malignancy in patients with persistent hypercalcemia.