A 23-year-old man with no relevant medical history or active medication presented with gross hematuria and hypogastric pain. Kidney ultrasound revealed medullary hyperechogenicity, suggestive of nephrocalcinosis, and bilateral cysts (Fig 1). A month later, he developed acute renal colic secondary to an obstructive 14 mm stone located in the right pyeloureteral junction, requiring placement of a double J stent. The stone was removed by ureterorenoscopy. Infrared spectroscopy showed the stone to be of mixed type: carbapatite, brushite, and calcium oxalate mono- and dihydrate. Metabolic work-up revealed mild hypercalcemia with suppressed parathyroid hormone (PTH), elevated 24-hour urinary calcium excretion, 25-hydroxyvitamin D level within the reference range, and high 1,25-dihydroxyvitamin D level (Table 1). Family history was negative for nephrolithiasis or cysts and the parents were not consanguineous. Kidney magnetic resonance imaging showed normal-sized kidneys, multiple renal cysts bilaterally, and the absence of liver cysts.•What is the differential diagnosis for this patient’s hypercalcemia, suppressed PTH, and nephrolithiasis?•What additional work-up may confirm this diagnosis?•What treatment options are possible for this patient?Table 1Laboratory FindingsValueReference RangeBlood Creatinine, mg/dL1.160.6-1.3 Calcium, mmol/L2.572.20-2.50 Ionized calcium, mg/dL5.84.44-4.80 Phosphorus, mmol/L1.180.81-1.45 iPTH, pg/mL<315-80 Total 25-hydroxyvitamin D, ng/mL54>30 1,25-hydroxyvitamin D, pg/mL10619.9-79Urine Volume, mL/d1,500 pH6.45.0-7.5 Creatinine, g/d1.860.81-2.01 Calcium, mmol/d8.9<7.5 Oxalate, mg/d38<45 Sodium, mmol/d18040-220Abbreviations: iPTH, intact parathyroid hormone. Open table in a new tab Abbreviations: iPTH, intact parathyroid hormone. This patient has non–parathyroid-related hypercalcemia, of which the most common cause is neoplasia. Both solid tumors and hematologic malignancies may increase bone resorption by various mechanisms: induction of osteolysis by bone metastases, release of osteoclast activating factor in multiple myeloma, secretion of PTH-related protein by some solid tumors (especially squamous cell carcinomas), or production of 1,25-dihydroxyvitamin D (usually by lymphomas).1Guise T.A. Wysolmerski J.J. Cancer-associated hypercalcemia.N Engl J Med. 2022; 386: 1443https://doi.org/10.1056/NEJMcp2113128Crossref PubMed Scopus (8) Google Scholar Nontumor etiologies of non–parathyroid-related hypercalcemia include excessive intake of vitamin D supplements or 1,25-dihydroxyvitamin D3 and increased endogenous production of 1,25-hydroxyvitamin D3 in patients with granulomatous disorders (especially sarcoidosis). Other rare causes of hypercalcemia include lithium therapy, thiazide diuretics, hypervitaminosis A, thyrotoxicosis, pheochromocytoma, adrenal insufficiency, milk-alkali syndrome, and prolonged immobilization. A rare additional cause of high vitamin D levels is a monogenic disorder caused by biallelic (or occasionally monoallelic) pathogenic variants in the gene encoding 25-hydroxyvitamin D3 24-hydroxylase. This enzyme, also known as CYP24A1, catalyzes the conversion of 1,25-dihydroxvitamin D3 and 25-hydroxyvitamin D3 into inactive 24-hydroxylated products that are excreted (Fig 2). CYP24A1 deficiency leads to persistently high levels of 1,25-dihydroxvitamin D3. Loss-of-function variants in CYP24A1 may lead to infantile hypercalcemia type 1 (OMIM 143880), also called hypersensitivity to vitamin D3. This hypersensitivity to vitamin D3 can be severe and potentially fatal in infants after prophylactic vitamin D3 supplementation for the prevention of rickets.2Schlingmann K.P. Kaufmann M. Weber S. et al.Mutations in CYP24A1 and idiopathic infantile hypercalcemia.N Engl J Med. 2011; 365: 410-421https://doi.org/10.1056/NEJMoa1103864Crossref PubMed Scopus (481) Google Scholar Adult patients may present with recurrent calcium kidney stones, with or without nephrocalcinosis. Recently, medullary and/or corticomedullary junction cysts (a mean of 5.3 cysts per patient) were reported in 16 patients with CYP24A1 deficiency (half of whom had nephrolithiasis as the presenting symptom).3Hanna C. Potretzke T.A. Cogal A.G. et al.High prevalence of kidney cysts in patients with CYP24A1 deficiency.Kidney Int Rep. 2021; 6: 1895-1903https://doi.org/10.1016/j.ekir.2021.04.030Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar The mechanisms of cystogenesis remain unknown, but sustained hypercalciuria and/or exposure to increased calcitriol levels could contribute to kidney cyst development. The diagnosis of CYP24A1 deficiency should be suspected in patients with bilateral kidney cysts, high levels of 1,25-dihydroxvitamin D3, nephrocalcinosis, and kidney stones composed of carbapatite, brushite, and/or oxalate calcium dihydrate, which are typically associated with hypercalciuria. Chest imaging, measurement of serum levels of angiotensin-converting enzyme, and eye examination were performed to rule out sarcoidosis. Genetic testing using a next-generation sequencing targeted gene panel revealed a homozygous variant in the CYP24A1 gene predicted to lead to a substitution of tryptophan for arginine at amino acid 396 (p.Arg396Trp); this variant has been previously reported to result in complete loss of function.2Schlingmann K.P. Kaufmann M. Weber S. et al.Mutations in CYP24A1 and idiopathic infantile hypercalcemia.N Engl J Med. 2011; 365: 410-421https://doi.org/10.1056/NEJMoa1103864Crossref PubMed Scopus (481) Google Scholar The patient’s parents were both heterozygous for the variant. The management of CYP24A1 deficiency remains challenging. The patient received dietary counseling on the need to increase water intake; reduce intake of salt, protein, and oxalate; and maintain a diet moderately rich in calcium to enhance bone formation. The patient was also counseled to avoid vitamin D supplements and sun exposure.4Figueres M.L. Linglart A. Bienaime F. et al.Kidney function and influence of sunlight exposure in patients with impaired 24-hydroxylation of vitamin D due to CYP24A1 mutations.Am J Kidney Dis. 2015; 65: 122-126https://doi.org/10.1053/j.ajkd.2014.06.037Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Thiazide diuretics must be used with caution when treating hypercalciuria, as they may worsen or cause hypercalcemia. Use of imidazole derivatives such as ketoconazole or fluconazole to partially inhibit CYP27B1 (to decrease calcitriol levels) or rifampin (to increase CYP3A4 activity), has shown short-term benefits, but the long-term safety of such therapies remains uncertain.5Nguyen M. Boutignon H. Mallet E. et al.Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to ketoconazole treatment.J Pediatr. 2010; 157: 296-302https://doi.org/10.1016/j.jpeds.2010.02.025Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 6Sayers J. Hynes A.M. Srivastava S. et al.Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole.Clin Kidney J. 2015; 8: 453-455https://doi.org/10.1093/ckj/sfv028Crossref PubMed Scopus (56) Google Scholar, 7Brancatella A. Cappellani D. Kaufmann M. et al.Long-term efficacy and safety of rifampin in the treatment of a patient carrying a CYP24A1 loss-of-function variant.J Clin Endocrinol Metab. 2022; 107: e3159-e3166https://doi.org/10.1210/clinem/dgac315Crossref Scopus (2) Google Scholar CYP24A1 deficiency secondary to a homozygous pathogenic variant. Valentine Gillion, MD, Karin Dahan, MD, PhD, Cristina Anca Dragean, and Nathalie Demoulin, MD. None. The authors declare that they have no relevant financial interests. The authors declare that they have obtained written consent from the patient reported in this article for publication of the information about him that appears within this Quiz. Received October 19, 2022. Evaluated by an external reviewer, with direct editorial input from an Editorial Intern and the Engagement Editor. Accepted in revised form November 17, 2022.