Endocrine Abstracts

Introduction: 24-hydroxylase, encoded by a CYP24A1 gene, is a crucial enzyme entailed in catabolism of vitamin D. Loss-of-function mutations of CYP24A1 result in hypercalcemia, not adequately concomitant high levels of 1,25(OH)2D and low PTH levels. The variety of clinical manifestations depends on age – mutations can lead to fatal infantile hypercalcemia among neonates (typically precipitated by supplementation of vitamin D), whereas adults’ symptoms are usually mild. The differential diagnosis of PTH-independent hypercalcemia includes i.a. malignancy and granulomatous diseases.

Case Presentation: We report a case of a 58-year-old woman with a history of parathyroid adenoma leading to hypercalcemia, hypercalciuria and unsuppressed PTH concentration. Preoperatively, in ultrasonography, technetium-99m (99mTc) sestamibi scintigraphy, followed by biopsy, the suspected mass adjoining the upper pole of left lobe of thyroid gland was found. The patient underwent parathyroidectomy (histopathology report confirmed parathyroid adenoma), significant decrease in serum calcium was observed. Three years after the parathyroidectomy, the patient was admitted to the Department of Endocrinology because of hypercalcemia, and recurrent primary hyperparathyroidism was suspected. However, the results of biochemical tests (calcium 2.88 mmol/l (reference range 2.15-2.50 mmol/l)), PTH (intact) 7.75 pg/ml (reference range 15–65 pg/ml) and slightly elevated 1,25(OH)2D serum concentration (90.6 pg/ml (reference range 25-86.5 pg/ml)) demonstrated PTH-independent hypercalcemia. Further investigation required the exclusion of the most common causes of PTH-independent hypercalcemia (granulomatous diseases, hypercalcemia of malignancy, vitamin D intoxication) - the results of diagnostic tests did not reveal the cause of elevated calcium concentration. Subsequently, vitamin D metabolites were measured using liquid chromatography with tandem mass spectrometry (LC/MS-MS), revealing high 25(OH)D3 (72.62 ng/ml), low 24,25(OH)2D3 (0.09 ng/ml) and elevated 25(OH)D3 / 24,25(OH)2D3 ratio (806.9 (reference range 7.0-23.6)) – suggesting the defect in vitamin D catabolism. The molecular analysis of CYP24A1 gene was conducted using Next-Generation Sequencing (NGS), two pathogenic variants were identified p.(Arg396Trp) and p.(Glu143del) (rs114368325 and rs777676129).

Conclusions: Presented case shows the importance of accurate clinical evaluation of hypercalcemia. Rarely multiple causes of hypercalcemia may coexist, which complicates the diagnostic process. In patients with PTH-independent hypercalcemia, the measurement of vitamin D metabolites using LC-MS/MS analytical technique, followed by genetic testing (e.g. NGS technology), may help to identify carriers of CYP24A1 mutations.