AUTHOR=Leszczyńska Dorota , Szatko Alicja , Latocha Julia , Kochman Magdalena , Duchnowska Maria , Wójcicka Anna , Misiorowski Waldemar , Zgliczyníski Wojciech , Glinicki Piotr 

TITLE=Persistent hypercalcaemia associated with two pathogenic variants in the CYP24A1 gene and a parathyroid adenoma—a case report and review

JOURNAL=Frontiers in Endocrinology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1355916

DOI=10.3389/fendo.2024.1355916

ISSN=1664-2392

ABSTRACT=<sec><title>Introduction</title><p>24-Hydroxylase, encoded by the <italic>CYP24A1</italic> gene, is a crucial enzyme involved in the catabolism of vitamin D. Loss-of-function mutations in <italic>CYP24A1</italic> result in PTH-independent hypercalcaemia with high levels of 1,25(OH)<sub>2</sub>D<sub>3</sub>. The variety of clinical manifestations depends on age, and underlying genetic predisposition mutations can lead to fatal infantile hypercalcaemia among neonates, whereas adult symptoms are usually mild.</p></sec><sec><title>Aim of the study</title><p>We report a rare case of an adult with primary hyperparathyroidism and loss-of-function mutations in the <italic>CYP24A1</italic> gene and a review of similar cases.</p></sec><sec><title>Case presentation</title><p>We report the case of a 58-year-old woman diagnosed initially with primary hyperparathyroidism. Preoperatively, the suspected mass adjoining the upper pole of the left lobe of the thyroid gland was found via ultrasonography and confirmed by 99mTc scintigraphy and biopsy as the parathyroid gland. The patient underwent parathyroidectomy (a histopathology report revealed parathyroid adenoma), which led to normocalcaemia. After 10 months, vitamin D supplementation was introduced due to deficiency, and the calcium level remained within the reference range. Two years later, biochemical tests showed recurrence of hypercalcaemia with suppressed parathyroid hormone levels and elevated 1,25(OH)<sub>2</sub>D<sub>3</sub> concentrations. Further investigation excluded the most common causes of PTH-independent hypercalcaemia, such as granulomatous disease, malignancy, and vitamin D intoxication. Subsequently, vitamin D metabolites were measured using LC–MS/MS, which revealed high levels of 25(OH)D<sub>3</sub>, low levels of 24,25(OH)<sub>2</sub>D<sub>3</sub> and elevated 25(OH)<sub>2</sub>D<sub>3</sub>/24,25(OH)<sub>2</sub>D<sub>3</sub> ratios, suggesting a defect in vitamin D catabolism. Molecular analysis of the <italic>CYP24A1</italic> gene using the NGS technique revealed two pathogenic variants: p.(Arg396Trp) and p.(Glu143del) (rs114368325 and rs777676129, respectively).</p></sec><sec><title>Conclusions</title><p>The diagnostic process for hypercalcaemia becomes complicated when multiple causes of hypercalcaemia coexist. The measurement of vitamin D metabolites using LC–MS/MS may help to identify carriers of <italic>CYP24A1</italic> mutations. Subsequent molecular testing may contribute to establishing the exact frequency of pathogenic variants of the <italic>CYP24A1</italic> gene and introducing personalized treatment.</p></sec>