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since the identification of cyp24a1 mutations in children with idiopathic infantile hypercalcaemia , the spectrum of phenotypes attributable to cyp24a1 variants has been expanded , with cyp24a1 mutations identified in cases of idiopathic calcium stone formation and nephrocalcinosis [ 14 ] .
cyp24a1 encodes the vitamin d 24-hydroxylase enzyme , which catalyses the hydroxylation of the biologically active form of vitamin d ( 1,25-dihydroxy vitamin d3 ) , and its precursor ( 25-hydroxy vitamin d3 ) , to inactive forms for excretion .
mutations in cyp24a1 inhibit these functions , resulting in increased levels of active vitamin d , and subsequent persistent hypercalcaemia .
mutations in cyp24a1 may also lead to increased levels of 25-hydroxy vitamin d. this led investigators to trial treatment with ketoconazole , a p450 enzyme inhibitor which also inhibits vitamin d - synthesizing enzymes ( including 25-hydroxylases and 1--hydroxylase ) . in patients with mutations in cyp24a1 , ketoconazole may be a useful therapy to prevent hypercalcaemia and hypercalciuria and their systemic complications .
report an adult male with a splice - site mutation in cyp24a1 in whom they demonstrated , after 2 months of treatment with ketoconazole ( 200 mg tds ) , a significant reduction in urinary calcium excretion and a modest reduction in serum calcium .
also describe the treatment of a renal stone former with a cyp24a1 mutation with ketoconazole ( up to 800 mg / day ) , showing a reduction in 1,25 dihydroxy vitamin d , serum calcium and urine calcium levels .
although these reports are encouraging , the long - term use of ketoconazole , especially at high doses , in subjects with cyp24a1 mutations is not advisable due to toxicity of the drug ( https://www.gov.uk/drug-safety-update/oral-ketoconazole-do-not-prescribe-or-use-for-fungal-infections-risk-of-liver-injury-outweighs-benefits ) , with more recent mhra warnings in respect of its use as medical therapy of endogenous cushing 's syndrome .
we report a male english patient who had originally presented with renal colic at 10 years of age and had a history of recurrent renal stones .
he subsequently re - presented with symptomatic hypercalcaemia [ with suppressed pth ( 14 ng / l ) and hypercalciuria ( 8.8 mmol/24 h ) , aged 45 years ] .
there was no history of vitamin d supplementation , although he occasionally uses tanning beds .
body imaging , serum electrophoresis , tumour makers and serum angiotensin - converting enzyme were all normal .
he was treated empirically with an aggressive iv fluid regime and oral prednisolone , resulting in partial correction of serum calcium likely ascribable largely to the iv fluids ( figure  1 ) .
no malignancy was found , but renal imaging revealed bilateral nephrocalcinosis and an inherited cause of hypercalciuric renal stones was therefore postulated .
levels of 25-hydroxy vitamin d were raised at 168 nmol / l , and magnesium levels were normal ( 0.83 mmol / l ) ; following recovery of a presumed hypercalcaemia - induced acute kidney injury , he had persistent evidence of chronic kidney disease ( ckd ) with egfr of 33 ml / min/1.73 m ( ckd stage g3ba1 ) . using pcr and sanger sequencing , we confirmed a known pathogenic homozygous p.e143del mutation , segregating from each parent , in cyp24a1 ( figure  1a ) .
the parents were not known to be consanguineous . this mutation has been previously described by schlingmann et al .   and others and has an allele frequency of 0.06% reported in the exome aggregation consortium ( exac ) database ( http://exac.broadinstitute.org/ ) generated from whole exome sequencing data of > 60 000 individuals . 

( a ) sequence chromatograms are shown for index case and parents , identifying p.e143del mutation and confirming segregation .
( b ) clinical course of patient and response of serum calcium ( adjusted for albumin , reference range 2.22.6 mmo / l ) and 1,25 dihydroxy vitamin d levels ( using an validated immunoassay ( http://www.idsplc.com/en-gb/products/ids-isys-125-dihydroxy-vitamin-d-is-2400 ) , reference range 20120 pmol / l ) to therapy with variable prednisolone dose ( mg ) and fluconazole 50 mg od .
( a ) sequence chromatograms are shown for index case and parents , identifying p.e143del mutation and confirming segregation .
( b ) clinical course of patient and response of serum calcium ( adjusted for albumin , reference range 2.22.6 mmo / l ) and 1,25 dihydroxy vitamin d levels ( using an validated immunoassay ( http://www.idsplc.com/en-gb/products/ids-isys-125-dihydroxy-vitamin-d-is-2400 ) , reference range 20120 pmol / l ) to therapy with variable prednisolone dose ( mg ) and fluconazole 50 mg od . while fluconazole is not the most potent inhibitor of 1-hydroxylase ( and of adrenal 11,-beta- and 17,- hydroxylases ) , it is far less toxic and more widely available than ketoconazole .
indeed , it is now being used for the medical management of surgically intractable cushing 's syndrome [ 5 , 6 ] .
we therefore hypothesized that it would likely be a clinically useful treatment for this patient .
low - dose fluconazole ( 50 mg orally daily ) was commenced , allowing reduction and then complete discontinuation of oral prednisolone .
while on this therapy , 1,25 dihydroxy vitamin d levels fell from inappropriately high levels of 118 to 69 pmol / l ( over a period of 98 days ) , 25-hydroxy vitamin d levels remained elevated following treatment ( 175 nmol / l ) , confounded in part by tanning bed use by the patient . prior to steroid treatment ,
serum calcium levels ( adjusted for albumin ) were 3.27 mmol / l and fell to 2.612.71 mmol / l following fluid resuscitation ( prednisolone effect ) .
introduction of fluconazole allowed calcium levels to stabilize , and prednisolone treatment was discontinued ( figure  1b ) with a fall in urine calcium levels to 5.2 mmol/24 h. there have been no noted side effects of the drug , in particular no liver toxicity , and we propose to maintain the patient on this therapy , with appropriate monitoring of liver function tests . we have instructed the patient to avoid tanning beds and to avoid inadvertent vitamin d supplementation from dietary supplements and drinks .
there is growing evidence that cyp24a1 mutations , although rare , can underlie adult presentations of renal stone disease / nephrocalcinosis , and consideration of cyp24a1 mutations as the underlying cause should be given .
a recent genetic screen of 256 renal stone patients identified just 1 patient ( 0.4% ) with a homozygous cyp24a1 mutation . once identified , a therapy to prevent the associated hypercalcaemia , which may be complicated by hypercalciuria , renal stones and nephrocalcinosis should be considered .
long - term steroids are not a targeted treatment of this condition , and indeed in some patients with cyp24a1 mutations , the serum calcium may be resistant to lowering by steroids .
in addition , seasonal sunlight exposure   ( and tanning beds ) may exacerbate serum calcium levels .
they are heterocyclic ring compounds and are generally classified as either imidazoles ( e.g. ketoconazole ) or triazoles ( e.g. fluconazole ) , containing two or three nitrogen atoms , respectively , in the azole ring .
they exhibit their antifungal action through inhibition of lanosterol 14-alpha demethylase , a cytochrome p450 enzyme important for the synthesis of a fungal plasma membrane constituent .
recognition that these agents could inhibit other cytochrome p450-dependent enzyme systems , such as those involved in vitamin d hydroxylation , led to the use of ketoconazole as a treatment for hypercalcaemia .
administration of ketoconazole has been successfully used for the treatment of hypercalcaemia associated with hyperparathyroidism and sarcoidosis . in patients with cyp24a1 mutations ,
although these reports are encouraging , the use of ketoconazole in subjects with cyp24a1 mutations could be potentially problematic due to potentially serious adverse effects including hepatotoxicity .
the risk of hepatotoxicity is considerably less with newer triazole agents , such as fluconazole .
schuster et al . have screened various azole compounds for selective inhibition of vitamin d hydroxylases .
while fluconazole was not the most potent 1-hydroxylase inhibitor , due to its favourable side - effect profile , we hypothesized that it would be a clinically useful treatment for patients with mutations in cyp24a1 .
we closely monitored our patient for efficacy of the drug and potential toxic effects and conclude that fluconazole is well tolerated and is effectively controlling the hypercalcaemia , without the use of steroids , by directly reducing 1,25 dihydroxy vitamin d levels .
we can not completely exclude confounding environmental effects that may have caused a fall in 1,25 dihydroxy vitamin d and serum calcium , but we are not aware of any significant changes in the patient 's behaviour ; indeed , the patient persisted with tanning bed use .
another important caveat is that we can not predict the long - term outcome or whether intolerance to the drug will occur or whether there might be long - term cumulative hepatoxicity .
the results presented in this paper have not been published previously in whole or part , except in abstract format .
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--hydroxylase ) thereby reducing levels of 1,25dihydroxy vitamin d.