Variable Phenotypes Seen with a Homozygous CYP24A1 Mutation: Case Report


Vitamin D–mediated hypercalcemia may be due to benign or malignant conditions. Recently, loss-of-function mutations in the gene CYP24A1, which encodes 25-hydroxyvitamin D3-24-hydroxylase, have been described which result in reduced degradation of the active 1,25-(OH)2 D3, causing hypercalcemia and hypercalciuria. We describe four patients in whom we identified a novel CYP24A1 homozygous germline mutation (NM_000782.4: c.323A>G; p.(His108Arg). Three of the four patients had a long history of recurrent renal stones. One patient had nephrocalcinosis with significant renal impairment. The other three patients had intermittent hypercalcemia, which in two female patients predominantly occurred during pregnancy with severe gestational hypercalcemia. Germline CYP24A1 mutations are a rare but important cause of vitamin D–mediated hypercalcemia and demonstrate a core phenotype of renal stones, hypercalciuria, and PTH-independent hypercalcemia. However, even in the setting of a homozygous CYP24A1 germline mutation, hypercalcemia may be intermittent with a normal PTH level during the periods of normocalcemia resulting in the need for a high degree of clinical suspicion. Measurement of vitamin D metabolites, in particular the 25-(OH)D3/24,25-(OH)2D3 ratio which is elevated in patients with homozygous CYP24A1 germline mutations, may help provide a clue as to the underlying diagnosis. In women with a history of recurrent calcium-containing renal stones or nephrocalcinosis, we would recommend measurement of serum calcium levels prior to conception and each trimester due to the potential for severe adverse effects on mother and baby if an unidentified CYP24A1 mutation is present.


Hypercalcemia occurs in approximately 1.1% of outpatients with increasing prevalence with age [1]. The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy. Less frequent causes include vitamin D–mediated processes (benign or malignant). Loss-of-function mutations of CYP24A1 are a relatively recently described cause of vitamin D–mediated hypercalcemia [2]. CYP24A1 encodes a 25-hydroxyvitamin D3-24-hydroxylase, with loss or inactivating mutations of this gene resulting in elevated 1,25-(OH)2D3 levels and hypercalcemia due to reduced degradation of the active 1,25-(OH)2D3 [2, 3]. Patients with CYP24A1 mutations may present early in life, particularly when given supplements of vitamin D, or as adults, usually presenting with renal stones and less commonly hypercalcemia [4]. CYP24A1-associated hypercalcemia may be mild or intermittent; however, more severe cases of hypercalcemia have been reported including severe gestational hypercalcemia [5,6,7]. Laboratory features include hypercalcemia with a low PTH and high-normal or elevated 1,25-(OH)2D3 levels, whereas 25-(OH)D3 levels may range from low to high [8]. Low 24,25-(OH)2D3 levels have been suggested to help identify patients who may harbor a germline CYP24A1 mutation [9]. We describe four patients with the same novel homozygous mutation, c.323A>G; p.(H108R), in the CYP24A1 gene, and demonstrate the variable phenotype that can occur even with the same genotype.

Case Presentation

Case 1

In 2015, a 58-year-old Māori man was admitted to Waikato hospital, New Zealand, for investigation and treatment of symptomatic hypercalcemia. He had a 35-year history of recurrent renal stones requiring repeated urological intervention, with documented hypercalcemia and hypercalciuria, low serum PTH, and elevated 1,25-(OH)2D3 (Table 1). He had previously been extensively investigated with no cause for his hypercalcemia identified. There was no family history of hypercalcemia or renal stones. In 2005, because of recurrent stones and persistent severe hypercalcemia >3 mmol/L (reference interval [RI] 2.1–2.55 mmol/L), despite a low PTH and negative sestamibi parathyroid scan, his endocrinologist referred him for parathyroid surgery. On four-gland exploration, three enlarged hyperplastic parathyroid glands (138–372 mg) were resected and the fourth, thought to be of normal size, left in situ. Postoperatively his PTH level became undetectable but the hypercalcemia persisted (3.07 mmol/L on postoperative day 3). Serum calcium levels over time are shown in Fig. 1. There was no definite seasonal variation to his calcium levels although his highest serum calcium of 3.89 mmol/L was during March, one of New Zealand’s sunniest months. He was then lost to follow-up until 2015.

Table 1 Summary of cases homozygous for novel c.323A>G; p.(His108Arg) mutation CYP24A1 gene
Fig. 1

Adjusted total serum calcium levels over time in Case 1. Reference interval shown in shaded box

By 2015, moderate renal impairment was present (serum creatinine 131 μmol/L; eGFR 49 mL/min/1.73 m2). While his 1,25-(OH)2D3 levels were now within the reference interval (attributed to his deterioration in renal function) (Fig. 2), a CYP24A1 mutation was suspected and assessment of vitamin D metabolites performed (Table 1). The abnormal ratio prompted a mutational analysis of the CYP24A1 gene. Polymerase chain reaction and Sanger sequencing of DNA from peripheral blood leukocytes demonstrated a novel homozygous change in CYP24A1 (NM_000782.4: c.323A>G; p.(His108Arg) with associated homozygous non-pathogenic SNPs across CYP24A1 consistent with a large region of homozygosity, suggesting consanguineous inheritance. In silico analyses predict this mutation to be disease-causing (Mutation Taster [10] and damaging SIFT [11]). The mutation is present heterozygously in the ExAC database with an allele frequency of 1.65 × 10−5 and in gnomAD with an allele frequency of 0.000008207. The American College of Medical Genetics and Genomics (ACMG) classifies this variant as being of uncertain significance (class 3).

Fig. 2

Vitamin 1,25-(OH)2D3 levels over time in case 1(results shown as proportion of the upper limit of reference interval [where 1.0 is upper limit of the reference interval] due to several assay changes over time)

Oral fluconazole was commenced at 50 mg alternate days as an inhibitor of cytochrome P450-dependent enzyme systems such as vitamin D hydroxylation. Due to a lack of response, the dose was increased and he was admitted to ensure compliance. Serum calcium levels increased and fluconazole was stopped. A separate inpatient trial of ketoconazole 200 mg TDS again showed a rapid increase in calcium levels (Fig. 3). He was started on rifampicin as a recent report suggested a benefit from this agent [12] but despite a promising early response (adjusted total serum calcium decreasing from 2.94 to 2.65 mmol/L within 24 h), rifampicin was unable to be continued due to the development of nausea and vomiting.

Fig. 3

Inpatient trial of ketoconazole 200 mg TDS (started after day 0 bloods) in case 1 demonstrating a rapid rise in calcium levels in response to treatment with return to baseline after cessation. Reference interval shown in shaded box. Duration of ketoconazole shown in black

Case 2

A 33-year-old Māori man was referred for hypercalcemia. At age 19 years, he was noted to have an elevated serum calcium at 3.06 mmol/L (RI 2.1–2.55 mmol/L) with normal phosphate and undetectable PTH. His next available calcium level 5 years later was normal (2.4 mmol/L). At the age of 31 years, he developed renal colic and several small renal stones were identified at which time he again was normocalcemic. At initial assessment, his serum calcium was mildly increased with a normal phosphate and suppressed PTH (Table 1) but a repeat level 2 months later demonstrated a normal calcium and normal PTH level (calcium 2.37 mmol/L with a PTH 1.6 pmol/L [PTH RI 1.6–6.9 pmol/L]). There was no family history of hypercalcemia, renal stones, or consanguinity or personal history of vitamin D–containing supplement use. Due to clinical suspicion of a CYP24A1 mutation, DNA extraction from peripheral blood leukocytes with polymerase chain reaction and Sanger sequencing performed and he was identified as carrying a homozygous variant in the CYP24A1 gene (NM_000782.4: c.323A>G; p.(His108Arg). Advice was given regarding the importance of hydration status (aiming to drink at least 2.5–3 L per day), avoiding vitamin D supplements (including cod liver oil) and excess sun.

Case 3

In 2011, an 18-year-old Māori woman was referred due to hypercalcemia (3.39 mmol/L) at 16 weeks gestation. No previous calcium results were available and she was not taking any vitamin D-containing supplements. She had no family history of hypercalcemia, renal stones or consanguinity. PTH was suppressed (Table 1). Initial investigations failed to identify a cause for the hypercalcemia. She required multiple admissions over the course of her pregnancy for intravenous normal saline infusions to try to control her hypercalcemia. A healthy baby was delivered at 36 + 1/40 by emergency C-section for premature rupture of membranes. There was no neonatal hyper- or hypocalcemia or hypoglycemia. Maternal calcium normalized by 2 weeks postpartum.

The patient was lost to follow-up and re-presented in 2018 at 19 + 3/40 in her second pregnancy with symptomatic hypercalcemia (calcium 3.36 mmol/L). PTH was again suppressed. She received vigorous saline hydration and throughout the remainder of the pregnancy aggressive oral hydration (5–6 L per day) with intermittent intravenous normal saline (approximately 3 L every 4 days) with strict instructions to avoid the sun and excess vitamin D and dietary advice on a low calcium diet. A healthy baby was delivered by normal vaginal delivery at 36/40 gestation. No neonatal hypocalcemia occurred and only transient hypoglycemia (glucose 2.0 mmol/L). Maternal hypercalcemia resolved by 11 days postpartum and she has remained normocalcemic. Genetic testing identified a germline homozygous variant in the CYP24A1 gene (NM_000782.4: c.323A>G; p.(His108Arg).

Case 4

A 33-year-old G2P0 Māori woman was assessed at 33 weeks gestation for hypercalcemia and hypertension. She had a background of intermittent severe abdominal/loin pain associated with microscopic hematuria at age 15 and 17 years requiring opiate analgesia but no definite renal calculi were identified. On both occasions, she was normocalcemic. At the age of 28 years, she was admitted for urosepsis associated with multiple renal calculi (requiring lithotripsy and stenting). At that time, she had an elevated calcium level up to 2.94 mmol/L with a low PTH. There was no family history of hypercalcemia, renal stones, or consanguinity.

During the current pregnancy, she presented with acute pyelonephritis and possible renal colic at 26/40 gestation and was noted to have a serum calcium level of 3.03 mmol/L. Peak calcium was 3.2 mmol/L with a normal phosphate and a suppressed PTH (Table 1). She was not receiving vitamin D–containing supplements. Saline rehydration was undertaken but an emergency lower segment Cesarean section was performed at 35 + 2/40 for severe atypical pre-eclampsia and a non-reassuring cardiotocography with fetal bradycardia and decreased variability. There was no neonatal hypocalcemia but transient hypoglycemia (2.1 mmol/L), which readily responded to dextrose gel. While breastfeeding, maternal calcium levels gradually declined after delivery but were still elevated at 2.64 mmol/L 3 weeks postpartum. She was then lost to follow-up. At 14 months postpartum, her calcium was normal (2.40 mmol/L) with a normal PTH (1.7 pmol/L [PTH RI 1.6–6.9 pmol/L]) and has since remained normal. Sequencing of leukocyte DNA demonstrated a germline homozygous variant in the CYP24A1 gene (NM_000782.4: c.323A>G; p.(His108Arg). Both of the patient’s parents consented to have serum calcium levels and genetic testing performed. Both were normocalcemic and each was found to be heterozygous for the CYP24A1 gene variant (NM_000782.4: c.323A>G; p.(His108Arg).

All four patients were from the same region of New Zealand and identified as the same ethnic group. On the discussion of familial relationships, it was determined that they were likely all distantly related.


We describe four cases with the same novel CYP24A1 germline mutation. Case 1 describes a patient with a protracted history of hypercalcemia and recurrent renal stones requiring multiple urological interventions. Even on the initial investigation, he was considered likely to have a vitamin D–mediated etiology. However, as CYP24A1 mutations had not been described at that time, the diagnosis was not made and the patient underwent repeated extensive investigation and inappropriate parathyroid surgery. The long history parallels that described by Jacobs et al. [13]. In our case, we observed a possible reduction in 1,25-(OH)2D3 levels over time (Fig. 3) which may have paralleled his deterioration in renal function or simply be due to variations in substrate availability i.e. 25-(OH)D3 levels. As such, a normal 1,25-(OH)2D3 does not necessarily exclude a CYP24A1 mutation, particularly if there is 25-(OH)D3 deficiency and/or significant renal impairment.

Management of CYP24A1 mutation carriers includes a diet low in calcium and vitamin D and avoidance of sun exposure. Other treatments used to inhibit 25(OH)D-1-hydroxylase include azoles such as fluconazole and ketoconazole [13,14,15,16] as this enzyme still appears to be active despite the hypercalcemia and suppressed PTH. Short-term use of these agents has appeared successful but concern regarding potential hepatotoxicity may limit ketoconazole use [17]. Fluconazole appears promising despite being a less potent 1-alpha hydroxylase inhibitor [16], although there is a lack of long-term data. In our trial in one case, calcium levels increased with both fluconazole and ketoconazole. While this deterioration initially appeared counterintuitive, these agents may also inhibit CYP3A4, which provides an alternative inactivating pathway for 1,25-(OH)2D3 metabolism [12] and is the likely reason for the observed deterioration. Rifampicin is a potent inducer of CYP3A4; the increased inactivation of 1,25-(OH)2D3 would be expected to decrease the calcium level [12]. Unfortunately, despite early suggestion of benefit, rifampicin was not tolerated. Other CYP3A4 enzyme inducers, such as carbamazepine and phenytoin, were not considered and have a low therapeutic index and therefore the potential for serious side effects.

Case 2, similar to case 1, presented with renal stones. However, unlike case 1, the hypercalcemia was intermittent and when normocalcemic, the PTH level was normal (although at the lower end of the reference interval) therefore illustrating that a normal calcium and PTH level do not necessarily exclude an underlying homozygous CYP24A1 mutation in a patient with recurrent renal stones. As such, a review of historical calcium levels is important and serial calcium (and PTH) measurements should be performed if there is high clinical suspicion for a CYP24A1 mutation. Unfortunately, measurements of vitamin D metabolites were not available for this case but we would recommend measurement of vitamin D metabolites in this setting if available. 24,25-(OH)2D3 levels are typically low in the presence of an underlying germline homozygote CYP24A1 mutation and the 25-(OH)D3 vitamin D/24,25 -(OH)2D3 ratio is elevated [9] (Table 1).

Cases 3 and 4 describe gestational hypercalcemia due to a homozygous germline CYP24A1 mutation. Hypercalcemia in pregnancy is rare, is more often due to primary hyperparathyroidism, and carries significant risk to the mother and baby [18]. Pregnancy-induced changes in calcium metabolism have been reviewed in detail by Kovacs [19]. To summarize, in normal pregnancy due to the fall in albumin, total serum calcium declines, but ionized calcium remains normal. Whereas PTH levels typically decline early in gestation before returning to the mid-normal range by term, PTHrP levels rise over the pregnancy (likely derived from placental and breast tissue) and peak in the third trimester [19]. Circulating maternal 1,25-(OH)2D3 levels increase, particularly due to increased renal production (rather than placental production), whereas 25-(OH)D3 levels are stable throughout [19]. Calcium absorption from the gut doubles from early in pregnancy [19]. Twenty-four hour urine calcium excretion increases from the end of the first trimester to the upper end of normal or mildly elevated levels, due to the increased intestinal calcium absorption, whereas fasting urine calcium levels are low and can result in the clinician missing hypercalciuria [19].

Hypercalcemia of pregnancy associated with a homozygous CYP24A1 mutation was first described in 2015 by Dinour et al. [20]. However, in that case, the hypercalcemia was not identified until the postpartum period and the patient had been receiving both supplemental vitamin D and taking antacids. Similar to our cases, most reports of gestational hypercalcemia due to a CYP24A1 mutation had a long history of calcium-containing renal stones with normal or borderline elevated serum calcium levels when not pregnant.

Previously, five patients with CYP24A1-mediated hypercalcemia in pregnancy have been described [5,6,7, 20, 21] (Table 2). Two papers described the same case [5, 7] and one paper described three sisters, two of whom had gestational hypercalcemia with seven pregnancies between the two sisters [6]. In the case reported by Kwong and Woods, calcium levels remained normal during the first two trimesters [5, 7]. This is similar to the report by Hedberg et al. in which one sister in her 4th pregnancy had a normal calcium at 14/40 gestation, rising from 18/40 and peaking at 26/40 [6]. Of note, Hedberg et al. also reported hypoglycemia in some of the neonates, postulated to be due to the stimulation of insulin secretion by calcium [6]. Transient mild hypoglycemia was also noted in two of the three births in our series. Similar to the hyperparathyroidism literature, hypertension in pregnancy was common in this cohort (Table 2). A second trimester intrauterine death occurred in one woman who also developed pancreatitis in both pregnancies [5, 7].

Table 2 Summary of cases in pregnancy

In case 4, we were able to sequence the parents and both were heterozygous for the CYP24A1 mutation. Both parents had normal calcium status and no history of renal stones. The homozygous mutation in case 1 and pattern of nearby SNPs suggest that his parents were consanguineous. Unfortunately, both parents of case 1 were deceased and we were unable to test other first-degree relatives. Given all patients were the same ethnicity it is likely that the CYP24A1 c.323A>G; p.(His108Arg) allele is a founder mutation in the indigenous Māori population. Māori comprise approximately 17.3% of the population in our region. Most literature suggests an autosomal recessive pattern of inheritance for CYP24A1 mutations [4]. However, Tebben and colleagues did show a phenotype in some heterozygote carriers (of certain alleles) suggesting an autosomal dominant inheritance pattern with incomplete penetrance [14]. Based on very limited data, we found no evidence that heterozygotes for this allele had any clinical phenotype.


Awareness of CYP24A1 mutations as a cause for hypercalcemia with recurrent calcium-containing renal stones is important to avoid misdiagnosis and inappropriate treatment, including parathyroid surgery. However, as sustained hypercalcemia may not always be present, a high degree of clinical suspicion is required. Measurement of vitamin D metabolites, if available, is recommended, in particular the 25-(OH)D3/24,25-(OH)2D3 ratio, which is elevated in this setting. As demonstrated, careful monitoring needs to be undertaken if using azoles to treat this condition, due to the potential for a paradoxical increase in calcium levels. In the setting of a woman with a history of potentially calcium-containing renal stones and/or nephrocalcinosis, we suggest measurement of serum calcium prior to conception and even if the preconception serum calcium is normal in this setting, continued monitoring each trimester for the potential development of gestational hypercalcemia due to the possibility of severe implications for both mother and baby.


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MSE—conception and design of the project, arranging testing and interpretation of results, drafting the manuscript and critical revision, and approval of the final version.

SDT—acquisition of data (biochemistry) and interpretation, revising the manuscript for critically important intellectual content, and final approval of the version to be published.

SA—acquisition of data (genetics) and interpretation, revising the manuscript for critically important intellectual content, and final approval of the version to be published.

JS—acquisition of data (genetics) and interpretation, revising the manuscript for critically important intellectual content, and final approval of the version to be published.

JVC—conception and design of the project, revising the manuscript for critically important intellectual content, and final approval of the version to be published.

JAUT—testing and interpretation of results, revising the manuscript for critically important intellectual content, and final approval of the version to be published.

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Correspondence to Marianne S. Elston.

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The local institutional review board (Waikato District Health Board) granted permission for the study. Written, informed consent was obtained from all patients for investigation and publication. Ethics approval for gene sequencing was given by the Newcastle and North Tyneside Research Ethics Committee, UK 2003/163.

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Elston, M.S., Du Toit, S., Alkanderi, S. et al. Variable Phenotypes Seen with a Homozygous CYP24A1 Mutation: Case Report. SN Compr. Clin. Med. 2, 995–1002 (2020).

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  • Hypercalcemia
  • Vitamin D
  • Vitamin D3 24-hydroxylase
  • Hypercalciuria
  • Kidney calculi