Mutations in CYP24A1, encoding the vitamin D 24-hydroxlase enzyme, are known to cause a range of clinical phenotypes and presentations including idiopathic infantile hypercalcaemia and adult-onset nephrocalcinosis and nephrolithiasis. In the context of raised or borderline high serum calcium levels, suppressed PTH and persistently elevated 1,25 dihydroxy vitamin D levels, this rare condition should be considered. We present a case where this biochemical pattern was seen and mutations in CYP24A1 were confirmed. We were able to successfully control serum calcium levels and reduce urinary calcium excretion by treatment with low-dose fluconazole, which inhibits vitamin D-synthesizing enzymes (including 25-hydroxylases and 1-α-hydroxylase) thereby reducing levels of 1,25–dihydroxy vitamin D.

IntroductionThe genetics underlying the idiopathic hypercalciuria leading to calciumcontaining renal stones remains elusive. The discovery of rare monogenic tubulopathies, often leading to hypercalciuria, has increased our understanding of tubular physiology and patho-physiology. However, insights into idiopathic calcium stone formation have not been gained from these disorders. The aim of this study is to examine CYP24A1 mutations in cohorts of patients with calcium nephrolithiasis. Materials and MethodsWe examined two cohorts of stoneforming patients for mutations in CYP24A1, which encodes the vitamin D24-hydroxylase enzyme. The first cohort had a biochemical phenotype of suppressed parathyroid hormone and high normal serum calcium, whilst the second cohort had a hypercalciuria phenotype. We did not identify bi-allelic sequence variants in CYP24A1 in our cohorts. ResultsIn cohort 1, we identified 9 known sequence variants. In cohort 2 we identified 7 known sequence variants. Conclusion CYP24A1 mutations remain a rare cause of calcium nephrolithiasis and hypercalciuria.

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.