SAT-368 CYP24A1 Mutation Masking Malignancy Mediated Hypercalcemia

Abstract

Background: Mutations in CYP24A1, resulting in reduced conversion of 1,25(OH)2D to its inactive metabolite 24,25-(OH)2D3,are rare causes of parathyroid hormone (PTH)-independent hypercalcemia. While manifestations may range from the severe idiopathic infantile hypercalcemia due to biallelic mutations, heterozygous loss-of-function mutations causing milder phenotypes are increasingly reported in adults. Elevated 1,25(OH)2D and hypercalciuria often accompanied by a history of nephrolithiasis are characteristic. Worsening hypercalcemia, under conditions such as pregnancy or sunlight exposure that enhance 1,25(OH)2D and 25(OH)D production, respectively, has been described in CYP24A1 mutations. We describe a patient with hypercalcemia and a history of lymphoma who was found to have elevated 25-OH-D3 and low 24,25-(OH)2D3 levels, suggesting a mutation in CYP24A1. Clinical Case: An 80 year-old Caucasian male with history of indolent non-Hodgkin lymphoma diagnosed in 2016,well controlled after several courses of chemotherapy,was referred for recurrent hypercalcemia. Laboratory studies showed levels of 1,25(OH)2D of 78 (18–72 pg/mL) and PTH 22 (10–65 pg/mL) with calcium ranging from 10.3 to 12.6 (8.5–10.1mg/dL), an undetectable PTHrP, 25(OH)D level of 32.9 (30–100 ng/mL), and 24-hour urinary calcium of 378mg. He was treated with high dose prednisone for presumed 1,25(OH)2D-mediated hypercalcemia. Despite initial good response, hypercalcemia became progressively difficult to control requiring escalating doses of steroids. Repeat 1,25(OH)2D levels improved to 30–40 pg/mL, but subsequently rebounded to >150. Oncologic re-evaluation found low-grade follicular lymphoma in inguinal lymph nodes,which were thought to be the source of 1,25(OH)2D overproduction. Detailed history and records review, however, revealed that onset of hypercalcemia dated back to 2006, concurrent with the development of several episodes obstructive uropathy due to stones. These events preceded the diagnosis of lymphoma by a decade, and resulted in CKD stage 4. Family history is notable for nephrolithiasis in his fatherand son. We suspected CYP 24A1 mutation. Vitamin D metabolite analysis demonstrated a 25-OH-D3 of 27 (20-50ng/mL) and 24,25-(OH)2D3 of 0.56 ng/mL with a ratio elevated to 48.21 (<25), indicative of a defect in vitamin D degradation that potentially exacerbates oversupply of 1,25(OH)2D, mediated via its reduced metabolism. Genetic evaluation is in progress. After initiation of treatment with Rituximab, his serum calcium levels declined along with regression of his lymphoma. Conclusion: Although mutations in CYP24A1 are an uncommon cause of hypercalcemia, they should be considered in the differential diagnosis of elevated 1,25(OH)2D levels without a clear source, as confirming this diagnosis strongly impacts treatment decisions and clinical outcome.