Persistent hypercalcaemia associated with two pathogenic variants in the CYP24A1 gene and a parathyroid adenoma-a case report and review.

Introduction: 24-Hydroxylase, encoded by the CYP24A1 gene, is a crucial enzyme involved in the catabolism of vitamin D. Loss-of-function mutations in CYP24A1 result in PTH-independent hypercalcaemia with high levels of 1,25(OH)2D3. 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. Aim of the study: We report a rare case of an adult with primary hyperparathyroidism and loss-of-function mutations in the CYP24A1 gene and a review of similar cases. Case presentation: 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)2D3 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)D3, low levels of 24,25(OH)2D3 and elevated 25(OH)2D3/24,25(OH)2D3 ratios, suggesting a defect in vitamin D catabolism. Molecular analysis of the CYP24A1 gene using the NGS technique revealed two pathogenic variants: p.(Arg396Trp) and p.(Glu143del) (rs114368325 and rs777676129, respectively). Conclusions: 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 CYP24A1 mutations. Subsequent molecular testing may contribute to establishing the exact frequency of pathogenic variants of the CYP24A1 gene and introducing personalized treatment.

Iodine supplementation during pregnancy of hypothyroid women treated with L-thyroxine neither influences neonatal TSH nor prevents decrease in maternal free thyroid hormone concentrations in second and third trimesters.

INTRODUCTION: Pregnant women require about 250 µg of iodine daily. Hypothyroid women treated with L-thyroxine do not utilise iodine, and metabolism of L-thyroxine tablets is an additional source of iodine for their foetuses. The aim of the study was to evaluate the influence of iodine supplementation in hypothyroid pregnant women treated with L-thyroxine on neonate TSH concentration and maternal thyroid parameters. MATERIAL AND METHODS: Ninety-two pregnant women with primary hypothyroidism on adequate thyroid hormone replacement were voluntarily divided into two groups: "thyroxine" (n = 38) treated with L-thyroxine only, and "thyroxine + iodine" (n = 54) treated additionally with 150 µg/day of iodine since 10th gestational week. Primary outcomes were the maternal thyroid function tests (TSH, fT4, fT3) and neonatal TSH concentrations at the 3-4th day of life. Urinary iodine concentration was measured at first and third trimester to compare iodine status in both groups. RESULTS: Iodine supplementation significantly increased median urinary ioduria in the third trimester (from 95.15 µg/L to 151.50 µg/L), but did not prevent the decrease of maternal fT4 and fT3 concentrations in the second and third trimester. Median neonate TSH concentration in both groups was within normal range, but was 33% higher in the "thyroxine + iodine" than in the "thyroxine" group (1.91 mU/L vs. 1.34 mU/L). Moreover, 8.77% of newborns in the "thyroxine + iodine" group had TSH > 5 mIU/L. CONCLUSIONS: We did not find evidence for a positive influence of iodine supplementation on thyroid function of either hypothyroid pregnant women sufficiently treated with L-thyroxine or their neonates. (Endokrynol Pol 2016; 67 (4): 367-374).