Hypercalcemia in Pheochromocytoma: From MEN to VHL

Background: Co-occurrence of phaeochromocytoma and primary hyperparathyroidism is usually seen in patients of Multiple Endocrine neoplasia 2A(MEN2A) and is rare in Von Hippel Lindau disease (VHL). Parathyroid adenoma with pheochromocytoma in a genetically confirmed VHL has been reported only once till date (1). Clinical Case: A 30-year male was admitted for evaluation of hypertension and incidentally diagnosed adrenal mass on ultrasound. 9-years back, he was diagnosed as a case of VHL (right renal clear cell carcinoma, pancreatic cystadenoma, spinal hemangioblastoma and epididymal cysts). Right nephrectomy and pancreatic cyst excision had been done and past work-up for pheochromocytoma was normal. He also had been operated twice for recurrent renal calculi. Family history revealed surgery in mother for pancreatic mass. Current imaging revealed right adrenal mass (4.7*4.6 cm) with left renal cysts and calculi, pancreatic cysts and spinal- medullary hemangioblastoma and epididymal cysts. Fundus examination was normal. 24-hours urinary fractionated normetanephrines were elevated (2062 mcg/24 hours) and I131MIBG scan showed 4.7*4.6cm concentrating lesion in right renal fossa suggestive of right adrenal pheochromocytoma. However his biochemical evaluation revealed hypercalcemia (12.1 mg/dl), low phosphorus (3.2 mg/dl), low 25(OH) D (24.84 nmol/l), and raised PTH (121pg/ml). Ultrasound neck and Tc99m-Sestamibi localized left inferior parathyroid adenoma. DEXA scan showed severe osteoporosis. Genetic analysis confirmed VHL mutation in exon-1. Calcitonin and RET mutation were normal (ruled out MEN2A). Therapeutic approach was surgical excision of adrenal pheochromocytoma followed by parathyroidectomy. We report a case of pheochromocytoma with primary hyperparathyroidism (cause: left inferior parathyroid adenoma) in a patient of VHL (Renal clear cell carcinoma, pancreatic cystadenoma, epidydymal cysts and medullary and spinal hemangioblastoma). Hypercalcemia seen in patients of VHL is either due to bone metastasis/PTHrP/IL-6 secretion from RCC or due to PTHrP/PTH/calcitonin secretion from pheochromocytoma and rarely due to associated parathyroid adenoma. Literature search revealed four case reports of parathyroid adenoma with VHL. In only one of these, VHL had pheochromocytoma associated with parathyroid adenoma (1). Conclusion: Ours is the 2nd such case reported in literature of primary hyperparathyroidism in a genetically confirmed case of VHL with pheochromocytoma. This case highlights the overlap of tumorigenesis in two rare genetically divergent syndromes and importance of long-term follow-up for sequential development of new tumors. Reference: Arao T, Okada Yet al. A case of VHL disease with bilateral pheochromocytoma, renal cell carcinoma, pelvic tumor, spinal hemangioblastoma and primary hyperparathyroidism. Endocr J. 2002 Apr;49(2):181–8.