CYP24A1 mutation leading to nephrocalcinosis

Abstract

A 45-year-old man recently came to our attention, who had originally presented with renal colic at the age of 10 years. He subsequently re-presented with a further episode of renal colic and symptomatic hypercalcemia at the age of 45 years, which resulted in an intensive and invasive search for an occult malignancy. A biochemical phenotype of hypercalcemia (serum calcium 2.81 mmol/l, serum phosphate 1.15 mmol/l), suppressed parathyroid hormone (14 ng/l), and hypercalciuria (urinary calcium 8.8 mmol/24 h) was noted. There was no history of vitamin D supplementation. Total vitamin D levels were normal (117 nmol/l). Renal imaging revealed bilateral medullary nephrocalcinosis (Figures 1 and 2). A family history also identified his sister as a renal stone former. His parents had no clinical phenotype. On this basis, an inherited cause of hypercalciuric renal stones seemed much more likely than a malignancy. We confirmed a homozygous E143del mutation, segregating from each parent, who were not known to be consanguineous, in CYP24A1. Although mutations in CYP24A1 may be rare, there is growing evidence that phenotypes of mutations in this gene may include adult presentations of renal stone disease and nephrocalcinosis. A trial of ketoconazole is indicated in order to control the hypercalcemia. Consideration of CYP24A1 mutations as a cause of renal stone disease should be given and a familial pattern of stone formation should be looked for. Figure 1 | Renal ultrasound scan demonstrating medullary nephrocalcinosis.Figure 2 | Computed tomography scan showing bilateral nephrocalcinosis.

LC-MS/MS for Identifying Patients with CYP24A1 Mutations

“…Depending on calcium and phosphorus demands, D (10, 11 ). Inactivating mutations of CYP24A1 (cytochrome P450, family 24, subfamily A, polypeptide 1) cause hypercalcemia, hypercalciuria, and increased 1,25(OH) 2 D concentrations (12)(13)(14)(15)(16)(17)(18)(19)(20). In studies describing LC-MS/MS assays for 24,25(OH) 2 D quantification, the relationship between 25(OH)D and 24,25(OH) 2 D has been used as a nutritional marker for assessment of optimum vitamin D supplementation (21 ).…”

24-Hydroxylase Deficiency Due to CYP24A1 Sequence Variants: Comparison With Other Vitamin D−mediated Hypercalcemia Disorders

“…In 2011, Schlingmann et al [ 1 ] first associated CYP24A1 variants with IIH. With the subsequent recognition of late-onset disease in adults (characterized by hypercalcemia, NC, nephrolithiasis, or a combination) [ 3 , 7 , 9 , 12 , 14 , 21 , 38 , 41 ] and studies that showed only select cases of IIH were associated with CYP24A1 sequence variants [ 4 ], it is important to characterize this disorder as 24HD, which in its most severe form may cause IIH. This distinction is important because not all patients with 24HD will have IIH and vice versa.…”

“…Hypercalciuria has been noted in patients with 24HD [ 3 , 4 , 7 , 22 ]. In our cohort, more 24HD patients presented with hypercalciuria compared with all other groups (88.9% vs 55.6%).…”

CYP24A1 and SLC34A1 genetic defects associated with idiopathic infantile hypercalcemia: from genotype to phenotype

“…IIH is not restricted to infancy and its clinical manifestations may appear later into adult life. In this case, the sub-clinical long-term hypercalcemia/ hypercalciuria causes kidney stones disease in adulthood with a more severe damage of kidney function [47][48][49]. Affected adults may also develop extra-renal manifestations, including Ca deposits in the joints [50] and in the cornea, a low bone mineral density and osteoporosis, principally related to the increase of the osteoclast activity [51][52][53].…”