Mild Idiopathic Infantile Hypercalcemia—Part 2: A Longitudinal Observational Study

Abstract

Context

Idiopathic infantile hypercalcemia (IIH) is an uncommon disorder with variable clinical features. The natural history and response to dietary calcium and vitamin D restriction in IIH remains unclear.

Objective

The aim of this study is to describe the clinical and biochemical response to dietary calcium and vitamin D restriction in a genetically characterized cohort of mild IIH.

Methods

This is a longitudinal, observational cohort study of 20 children with mild IIH monitored for a median of 21months. Biochemical measures, dietary assessment, and yearly renal ultrasound results, since the time of diagnosis, were obtained and assessed prospectively every 4 to 6 months.

Results

Median age at initial diagnosis was 4.5 months. Median levels of serum calcium (2.82 mmol/L) and 1,25 (OH)2D (192 pmol/L) were elevated, whereas serum PTH was reduced (10 ng/L). Urinary calcium:creatinine ratio was elevated for some, but not all individuals (median 1.49 mmol/mmol). All patients who were managed with a low-calcium diet showed an improvement in serum and urinary calcium measures, but the serum concentration of 1,25 dihydroxyvitamin D (1,25(OH)2D) and 1,25(OH)2D/PTH ratio remained elevated. In 2 of the 11 subjects, renal calcification worsened. There were no differences in response between individuals with CYP24A1 or SLC34A1/A3 variants.

Conclusion

The clinical presentation of mild IIH is variable, and dietary calcium and vitamin D restriction does not consistently normalize elevated 1,25(OH)2D concentrations or prevent worsening of renal calcification in all cases. Therapeutic options should target the defect in vitamin D metabolism.

Idiopathic infantile hypercalcemia (IIH) is an uncommon metabolic disorder with a wide spectrum of clinical and biochemical severity. The variability of IIH features likely reflects the interaction between the developmental stages of the patient, nutrition, and the underlying metabolic/genetic defect (1). Classically, IIH presents in young infants as severe and symptomatic hypercalcemia, with anorexia, vomiting, dehydration, and nephrocalcinosis (2, 3). Biochemically, these cases are characterized by high serum and urinary calcium levels, elevated concentrations of 1,25 dihydroxyvitamin D (1,25(OH)2D), and suppressed PTH levels. Underlying biallelic mutations in the CYP24A1 as well as SLC34A1 genes were reported recently in many patients with severe IIH, with evidence suggesting that the consequent metabolic defects explained the clinical presentations (4, 5). CYP24A1 encodes for the 24-hydroxylase enzyme, whereas SLC34A1 encodes for the sodium-phosphate co-transporter NaPi-IIa in the kidney; deficiency in these proteins results in decreased deactivation or increased production of 1,25(OH)2D, respectively (4, 5). Based on these identified genes, the term “infantile hypercalcemia-1” (OMIM #143880) when the result of CYP24A1 deficiency and the term “infantile hypercalcemia-2” (OMIM #616969) when the result of SLC34A1 deficiency have been proposed as refinements of the more generic term IIH.

The identification of CYP24A1 and SLC34A1 as causal genes for IIH has led to a rapid expansion of our knowledge regarding this condition. The initial descriptions of IIH implied that this was a limited disorder of infancy that typically resolved after the first year of life (1), but later studies demonstrated that many affected subjects are prone to long-term complications, including impaired renal function and vascular calcification (6-8). More recent reports indicate that about one-third of patients with biallelic CYP24A1 mutations may have a milder phenotype that delays diagnosis until later in childhood or even in adulthood (9, 10). Despite this, much less is known about the underlying causes and natural history of this milder phenotype of IIH (11, 12).

Genetic studies also now suggest that at least some heterozygous carriers of CYP24A1 mutations may be symptomatic and can have hypercalciuria and nephrolithiasis in the context of increased serum concentrations of 1,25(OH)2D, thereby suggesting an intermediate IIH phenotype (8, 13, 14). Furthermore, in some cases, heterozygous carriers of SLC34A1 mutations have been found to have nephrolithiasis, indicating a possible role of haploinsufficiency of this gene in the development of hypercalciuria (15). Similarly, isolated renal calcifications have been described in subjects with heterozygous mutations in SLC34A3, which encodes the related renal sodium-phosphate co-transporter NaPiIIc that accounts for autosomal recessive hereditary hypophosphatemic rickets with hypercalciuria (16).

Once a diagnosis of IIH is established, contemporary management of these patients is to restrict dietary calcium intake and limit vitamin D intake and sunlight exposure with the anticipation that hypercalcemia and hypercalciuria will resolve over time. However, there remain significant gaps in our understanding of the natural history of these milder phenotypes including biochemical profile, risk for renal calcification, and modifying genetic factors. Moreover, the long-term impact of calcium and vitamin D restriction remains unclear (17, 18).

The aim of this longitudinal observational study is to describe the clinical and renal ultrasound findings as well as the biochemical response to dietary calcium and vitamin D restriction in a genetically characterized cohort of subjects with mild IIH.

Methods

Study Participants and Study Design

This is a longitudinal observational cohort study of children between 6 months and 17 years of age with confirmed IIH followed in the Calcium Clinic at the Hospital for Sick Children (SickKids) in Toronto, Canada, between January 2018 and January 2020. Eligibility criteria included: documentation of serum calcium levels (total and/or ionized) above the upper limit of the reference range for age, elevated (or high normal) serum 1,25(OH)2D concentrations, and low (or low normal) serum PTH levels. Once IIH was confirmed, calcium and vitamin D restriction was initiated. Subjects were excluded if other causes of hypercalcemia had been identified. The study was approved by the Research Ethics Board at SickKids. Standard institutional informed consent and assent procedures were followed in accordance with the Declaration of Helsinki.

Data Collection and Clinical Assessment

Details of the clinical symptoms, medical and family history, dietary assessment, renal ultrasound, and biochemical measures from the time of first recognition of hypercalcemia were collected from baseline medical records and again prospectively between January 2018 and June 2020 at each follow-up visit. A dietary assessment for daily calcium and vitamin D intake was completed by a registered dietitian using percent dietary reference intakes (DRIs) of calcium and vitamin D for age (19, 20) at each visit. Follow-up visits were completed every 4 to 6 months and renal ultrasound was repeated every 1 to 2 years depending on the preceding report. Genetic analyses were performed by Prevention Genetics using the Nephrocalcinosis Sequencing Panel, as previously reported in the companion paper (Part 1) (21).

Biochemical Methods

Conventional techniques were used by the Department of Pediatric Laboratory Medicine at SickKids to measure serum calcium, ionized calcium, phosphate, alkaline phosphatase (ALP), albumin, creatinine, and random urinary calcium:creatinine (Ca:Cr) ratio. Serum 25-hydroxyvitamin D (25(OH)D) was measured by liquid chromatography-tandem mass spectrometry and intact PTH was measured on the IDS-ISYS Multi-Discipline automated analyzer (Immunodiagnostic System, Boldon, UK) (22). Serum 1,25(OH)2D was measured using the Diasorin Liaison XL assay (Liaison, Saluggia, VC, Italy) at the Department of Clinical Laboratory at Mount Sinai Hospital in Toronto, Ontario. All results were compared with age- and sex-specific reference ranges (23, 24). 1,25(OH)2D/PTH ratio and 1,25(OH)2D/25(OH)D ratio (1α-hydroxylase activity) was assessed over time and compared with a healthy control population as described in our companion paper (Part 1) (21).

Dietary Calcium and Vitamin D restriction: Goals and Implementation

Once IIH was confirmed, patients were placed on a calcium- and vitamin D-restricted diet by partially or fully switching to a formula containing very low concentrations of calcium and no vitamin D (Calcilo XD) for younger infants, or by eliminating or reducing vitamin D supplements and reducing the amount of dietary calcium for older infants, toddlers, and children. The dietary restriction was achieved by reducing the dietary calcium intake by 20% to 40% of DRI (19, 20). After that, further adjustments of dietary intake of calcium and vitamin D were made every 2 to 6 months with the assistance of a registered dietician on the basis of serum and urinary calcium levels as well as PTH levels.

The goal of the dietary calcium and vitamin D restriction was to maintain serum calcium, PTH, ALP levels, and urinary Ca:Cr ratio within reference range for age while targeting the serum 25(OH)D concentration to be from 50 to 75 nmol/L according to the Global Consensus Recommendations on prevention of nutritional rickets (19). The patients’ families saw the same dietician at each follow-up visit and were in frequent contact in between clinic visits to make dietary adjustments as necessary.

When the biochemical profile normalized and the renal ultrasound showed no evidence or progression of renal calcification, a stepwise liberalization of dietary calcium and vitamin D restriction by approximately 10% to 20% to 100% DRI was offered to the families.

Renal Ultrasound

As part of our standard clinical practice, patients have a renal ultrasound repeated every 1 to 2 years. The ultrasound examinations were performed by experienced pediatric sonographers and reported by experienced pediatric radiologists. Analysis included assessment for renal calcification, such as renal calculi and/or signs of nephrocalcinosis. The data were collected, both retrospectively and prospectively, for this study cohort.

Statistics

Descriptive statistics were calculated for demographic, clinical, and laboratory test variables. Mean or median and range (minimum and maximum values) were provided for continuous variables. Numbers and proportions were calculated for categorical variables. Because most data were not normally distributed, nonparametric statistical methods were applied. Comparison of continuous variables at different time points was done with paired sample Wilcoxon test. A P value < .05 was considered significant. All analyses were performed using GraphPad Software Version 8.4 0.2 (GraphPad Software, San Diego, CA, USA).

Results

Patient Population

Between January 2018 and January 2020, 36 patients were diagnosed with IIH at SickKids. Before enrollment into the study, IIH appeared to have resolved in 8 patients in that serum calcium, 1,25(OH)2D, and PTH levels normalized without further dietary restrictions and renal ultrasound showed no evidence of renal calcification. Twenty-eight patients continued to meet inclusion criteria and were all approached to participate in this study. A total of 20 patients (11 males, 9 females) with a median age of 16 months at the time of study entry were included in this study. The observational period was a median of 21 months (range, 8-156 months). Genetic variants were identified in 13 of the 20 participants (21), including SLC34A1 variants (3 heterozygous, 1 compound heterozygous), SLC34A3 variant (1 heterozygous patient), and CYP24A1 variant (1 homozygous patient and 1 heterozygous patient). Other identified variants included the following genes: SLC4A1, SLC3A1, SLC12A1, SLC26A1, CLCN5, CLDN19, ATP6V0A4, and CASR. The identified variants and the variant classification are summarized in online Supplemental Table 1 (25) and described in more detail in the companion paper Part 1 (21). Each proband with a gene variant is denoted by a unique proband number (P1-P13) found in online Supplemental Table 1 (25) as well as in the companion paper Part 1 (21).

Clinical Characteristics at Initial Diagnosis of Hypercalcemia

Clinical characteristics, dietary calcium, and vitamin D intake as well as calcium-related biochemical measures at initial diagnosis of IIH are summarized in Table 1. Diagnosis of IIH was at a median age of 4.5 months. Eleven patients presented with poor weight gain (median percentile weight 16%, height 19%) and/or poor feeding (including P2, P3, P5, P6, P10, P11, and P12), 4 with recurrent vomiting (including P6 and P12), and 2 with constipation (including P13) as the only symptom. In 6 patients, hypercalcemia or renal calcification was found incidentally, for example during evaluation of seizure-like episodes (P3) or hypertension (P9 and P11). In 10 participants, IIH was identified during the course of significant medical or surgical conditions. These diagnoses included Sotos syndrome (P2); developmental delay (n = 2, including P10); dysmorphic features (n = 2, including P10); suspected seizure disorders (n = 2, no identified variant); vertebral anomalies, anal atresia, cardiovascular anomalies, tracheoesophageal fistula, esophageal atresia, renal and/or radial anomalies, and limb defects association (P12); posterior urethral valves and hydronephrosis (n = 1, no identified variant); diaphragmatic hernia (P11); and prematurity (n = 5, including P1, P10, P11) including chronic lung disease of prematurity (n = 2, including P11). In 10 participants, IIH was the only medical condition. Eleven patients had evidence of renal calcification on ultrasound obtained within 1 year of initial recognition of hypercalcemia, whereas 7 had documented nephrolithiasis and 5 were found to have medullary nephrocalcinosis (see Tables 1-3 from companion paper Part 1 (21) for more details).

Table 1.

Clinical and biochemical characteristics and dietary assessment at time of initial IIH Diagnosis before dietary restriction (n = 20)

Demographics	Median	Range (minimum-maximum)
Age (mo)	4.5	0-63
Weight (percentile)	16.2	0-70
Height (percentile)	20.6	0-99
Clinical characteristics			n (%)
Renal calcification			11 (55)
Additional chronic medical or surgical condition			10 (50)
Poor feeding			8 (40)
Recurrent vomiting			4 (20)
Weight loss or failure to thrive			4 (20)
Irritability			4 (20)
Seizure-like activity			4 (20)
Constipation			3 (15)
Arterial hypertension			3 (15)
Muscular hypotonia			2 (10)
Abdominal pain			1 (5)
Polyuria/polydipsia or signs of dehydration			1 (5)
Dietary assessment	Median	Range (minimum-maximum)	Reference
Daily calcium intake (%DRI)	99	42-269	a
Daily vitamin D intake (%DRI)	42	3-172	b
Laboratory findings	Median	Range (minimum-maximum)	Reference range
Total serum calcium (mmol/L)	2.82	2.63-3.04	2.08-2.64 (1-12 mo) 2.22-2.54 (>12 mo)
Ionized calcium (mmol/L)	1.38	1.32-1.59	1.22-1.37
iPTH (ng/L)	10	<5-24	16-88
Creatinine (µmol/L)	23	<13-49	8-89c
Albumin (g/L)	43	33-53	35-48
Urine Ca:Cr ratio (mmol/mmol)	1.49	<0.14 -8.6	< 2.5 (0-6 mo) <1.8 (6-12 mo) <0.6 (>12 mo)
25(OH)D (nmol/L)	81	29-120	70-250
1,25(OH)2D (pmol/L)	192	113-461	48-190
Phosphate (mmol/L)	1.89	0.88-2.54	1.51-2.72 (0- 12 mo) 1.38-2.19 (1-5 y) 1.02-1.79 (13-16 y)
Magnesium (mmol/L) (n = 14)	0.87	0.65-0.94	0.81-1.27
Alkaline phosphatase (z-score)	-0.81	-3.66 to 2.36	-2 to 2

Abbreviations: 1,25(OH)2D, 1,25 dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; Ca:Cr, calcium:creatinine; DRI, dietary reference intake; IIH, idiopathic infantile hypercalcemia; iPTH, intact PTH.

^a 20.

^b 21.

^c Variable, depending on age and sex (25).

Clinical and Biochemical Response to Dietary Calcium and Vitamin D Restriction

All participants were started on dietary restriction of calcium and vitamin D after initial diagnosis of IIH (Fig. 1A and 1B). Four time points are reported: initial IIH diagnosis before the initiation of calcium/vitamin D restriction (initial), first follow-up visit after initiation of dietary restriction (first follow-up), genetic testing (genetics), and latest follow-up visit (latest follow-up). A stepwise reduction in calcium intake with a calcium DRI below 100 was achieved by all subjects at their latest follow-up, and when compared with their initial time point, calcium DRI was found to be significantly reduced (Fig. 1A). Vitamin D intake was low for age for most individuals even at initial diagnosis, before initiation of any dietary changes. Although more variable over time and adjusted based on laboratory 25(OH)D levels, vitamin D DRI was significantly reduced below 100 for all subjects at latest follow-up when compared with their initial time point (Fig. 1B).

Figure 1.

Dietary calcium and vitamin D intake (including supplements) during observation period. (A) Dietary calcium intake in percent of daily reference intake (DRI) for age. (B) Vitamin D intake from diet and supplement in % of DRI for age. Results for all participants are provided on the left (n = 20), results for participants with identified SLC34A1/A3 or CYP24A1 variant are provided separately on the right. Initial: the time point where IIH was diagnosed for each individual before starting dietary calcium or vitamin D restriction. First follow-up: 4 to 6 months after dietary restriction was initiated. Genetics: study entry and time point of genetic testing (median 10 months after initial). Latest follow-up: most recent follow up on ongoing calcium and/or vitamin D restriction (median 21 months after initial). Median value for each timepoint is indicated with horizontal line. *Initial and latest follow-ups are compared with paired sample Wilcoxon test.

Median weight percentiles improved from 16th percentile at initial presentation to 38th percentile at latest follow-up (P = .0396).

There was a significant decrease in serum calcium (Fig. 2A) into the upper normal range as well as an improvement in urinary Ca:Cr ratio and a significant increase in PTH level (Fig. 2B) into the reference range when comparing initial with latest follow-up time point. However, there was no significant change in 1,25(OH)2D levels (Fig. 2C), and the urinary Ca:Cr ratio (Fig. 2D) and 1,25(OH)2D/PTH ratio remained increased (Fig. 3A). Most patients had chronic persistent mild hypercalcemia and persistent or intermittent mild hypercalciuria. There was no significant change in serum creatinine and serum albumin over time, which remained within sex- and age-dependent reference range for all individuals.

Figure 2.

Biochemical response to dietary calcium and vitamin D restriction. (A) Serum calcium level. (B) PTH level. (C) 1,25(OH)2D level. (D) Urinary Ca:Cr ratio. Results for all participants are provided on the left (n = 20) and results for participants with identified SLC34A1/A3 or CYP24A1 variant are provided separately on the right. LLN, lower limit of normal; ULN, upper limit of normal. ⁺ULN indicated for individuals >12 months. Initial: the time point where IIH was diagnosed for each individual before starting dietary calcium- or vitamin D restriction. First follow-up: 4 to 6 months after dietary restriction was initiated. Genetics: study entry and time point of genetic testing (Median 10 months after initial). Latest follow-up: Most recent follow-up on ongoing calcium and/or vitamin D restriction (median 21 months after initial). Median for each timepoint is indicated with horizontal line. Median value for each timepoint is indicated with horizontal line. *Initial and latest follow-ups are compared with paired sample Wilcoxon test.

Figure 3.

Vitamin D metabolite ratio over time. (A) 1,25(OH)2D/PTH ratio over time and (B) 1,25(OH)D/25(OH)D ratio over time. ULN, upper limit of normal based on (A) 78 and (B) 83 healthy controls described in more detail in our companion paper (Part 1). Results for all participants are provided on the left (n = 20); results for participants with identified SLC34A1/A3 or CYP24A1 variant are provided separately on the right. Initial: the time point where IIH was diagnosed for each individual before starting dietary calcium or vitamin D restriction. First follow up: 4 to 6 months after dietary restriction was initiated. Genetics: study entry and time point of genetic testing (median 10 months after initial). Latest follow-up: most recent follow-up on ongoing calcium and/or vitamin D restriction (median 21 months after initial). Median for each timepoint is indicated with horizontal line. Median value for each timepoint is indicated with horizontal line. *Initial and latest follow-ups are compared with paired sample Wilcoxon test.

Symptoms of hypercalcemia resolved in most subjects within 4 to 6 months of initiation of the dietary restrictions. However, 4 patients required additional short-term treatment as hypercalcemia worsened (serum calcium levels about 3 mmol/L or above) and symptoms increased. Two patients (including P3) required IV hyperhydration (one of whom also received calcitonin), whereas the other 2 patients (including P13) received 1 to 2 doses of pamidronate with subsequent normalization of serum calcium levels.

Seven participants had a trial of liberalizing their calcium and vitamin D intake during the study period, but in all cases the IIH biochemical profile including hypercalcemia and lower PTH level reoccurred within 2 to 4 months so patients were restarted on the restricted diet.

Vitamin D Metabolite Ratios

Although the 1,25(OH)2D/PTH ratio improved in all individuals over time, it remained above the normal reference range (Fig. 3A). By contrast, there were no changes in the 1,25(OH)2D/25(OH)D ratio (1α-hydroxylase activity) over time, and many patients remained above the reference range (Fig. 3B).

Clinical and Biochemical Response to Calcium Restriction Based on Identified Genetic Variant

Genetic findings of subjects and their family members are discussed in detail in the companion paper (Part 1) (21). Results of participants with identified SLC34A1/A3 or CYP24A1 variant are provided separately for Figs. 1-3 with a uniform color code (Figs. 1-3). Representing the biochemical findings at clinical presentation as well as the response to dietary restrictions in Figs. 1-3 suggested no differences between patients with identified CYP24A1 or SLC34A1/A3 variants compared with other IIH subjects. Statistical analyses were not undertaken because of the small sample size.

Renal Changes in Response to Calcium and Vitamin D Restriction

Over the course of this longitudinal study, renal calcification resolved in 4 patients, whereas 2 patients had evidence of worsening of existing renal calcification despite good compliance with dietary calcium and vitamin D restriction. In 5 patients, renal calcification remained stable over the course of this longitudinal study. Nine patients had no evidence of renal calcification during the study period. We were unable to identify any clinical, genetic, or biochemical features that could distinguish the 4 subjects whose renal calcification resolved from the 2 subjects with worsening renal calcification. All subjects had ongoing hypercalciuria, although only mild in 1 of the 2 cases that showed progressive renal calcification.

Discussion

This genetically characterized cohort of children with milder manifestations of IIH shows a different spectrum of clinical and biochemical findings to that reported in subjects who present with classical, more severe IIH. Clinically, these subjects presented with more subtle signs and symptoms of hypercalcemia such as feeding difficulties, constipation, and poor weight gain rather than recurrent vomiting, failure to thrive, and significant dehydration usually seen in more severe cases. In one-third of the cases, hypercalcemia was discovered as an incidental finding during work up for hypertension and/or seizure-like episodes. One-half had at least 1 additional significant medical or surgical condition likely unrelated to IIH, hypercalcemia, or hypercalciuria.

All subjects were managed by restriction of dietary calcium and vitamin D during the duration of this study period (median 21 months). These restrictions were achieved by limiting intake of foods that have a high calcium content, including most dairy products or switching to a very low-calcium formula. Nutritional supplements and vitamin D supplements were reduced or eliminated to achieve serum 25(OH)D concentrations of 50 to 75 nmol/L and to prevent development of secondary hyperparathyroidism. Compliance with dietary modifications was challenging in some cases, especially in the first year of life, when infants depend on formula and breast milk as basic nutrition and the subsequent slow introduction of solids that also has to be tailored not only to achieve a lower calcium and vitamin D intake, but to provide sufficient energy and protein intake to maintain appropriate growth at the same time. Compliance to dietary recommendations was excellent in most cases. Nonetheless, the overall the response of the patients to this approach was only partially successful.

Although dietary restrictions led to reductions in serum calcium levels in most subjects, the majority of patients continued to show mild, but persistent hypercalcemia and intermittent or persistent mild hypercalciuria and inappropriately elevated serum concentrations of 1,25(OH)2D. Although the 1,25(OH)2D/PTH ratio improved in all individuals over time, the ratio remained above normal in all subjects (Fig. 3A). Most patients with a SLC34A1/A3 variant had serum phosphate and ALP levels that were generally normal, with only intermittent episodes of mild hypophosphatemia and hyperphosphatasemia for age (see companion paper Part 1) (21). Evidence of osteopenia was identified in the radiographs of some of these subjects, raising concern that dietary restriction in combination with ongoing elevated 1,25(OH)2D levels might facilitate increased calcium mobilization from bone and contribute to ongoing bone loss.

Seven participants who achieved normal serum calcium and PTH levels during the observation period were allowed to liberalize their calcium intake during the study period, but in all cases hypercalcemia and the biochemical profile of IIH recurred within 2-4 months, supporting the persistence of the underlying defect in mineral metabolism.

Additionally, 20% of the cohort experienced at least 1 episode of worsening or symptomatic hypercalcemia that required more aggressive medical intervention, which highlights the importance of monitoring these patients frequently. Last, dietary restriction resulted in resolution or improvement in renal calcification in only 4 subjects, whereas 2 individuals experienced worsening of renal involvement during the study period. These findings therefore indicate that only a partial biochemical response is possible with dietary restriction that does not correct underlying pathophysiological factors.

This study does have some relevant limitations. The sample size of this single-center study is small and part of this longitudinal study is based on retrospective data collection with limitations. The median observation period was 21 months; further clinical course of our patients has to be determined. There are no obvious differences in biochemical profiles between the different genetic variants nor in their response to calcium/vitamin D restriction. However, as discussed in detail in our companion paper, Part 1 (21), 8 patients were found to have a variance of uncertain significance according to the American College of Medical Genetics and Genomics scoring system (26, 27). Despite family member testing and extensive clinical analysis, it remains unclear which of these variances of uncertain significance are disease causing; therefore, no mutation specific conclusions can be drawn based on this study. Because of the limited number of subjects in our study, and the relatively short duration of observation, it was not possible for us to determine whether hypercalcemia and/or hypercalciuria are ameliorated with age.

Further study of this question is needed. It remains unclear, in particular for patients with other complex medical conditions, whether the chronic medical condition and or its treatment result in biochemical findings identical to those seen in otherwise healthy infants with mild IIH.

Nevertheless, to our knowledge, this study is the first describing a longitudinal follow-up of patients with IIH and characterized genetic findings as well as their biochemical and clinical response to dietary calcium and vitamin D restriction as current standard of care. These findings have relevant implications for the diagnosis and management of children with IIH. Dietary calcium and vitamin D restriction achieves all the goals only in a minority of patients (35%), but there remains ongoing concern about renal outcomes as well as possible bone loss and osteopenia. In those in whom dietary calcium and vitamin D restriction is not successful and/or is challenging for the family, other treatment options should be considered.

In the selection of further treatment options, differentiation between different genetic causes of IIH, especially CYP24A1 or SLC34A1/SLC34A3, may be important. In the companion paper (Part 1), evidence suggests that a comprehensive vitamin D metabolite analysis may help to distinguish different genetic causes of IIH and genetic testing as well as assessment of family members should be considered when CYP24A1 or SLC34A1/A3 variants are suspected (21).

For infantile hypercalcemia-1 resulting from CYP24A1 loss-of-function mutations, medications that either reduce expression or activity of CYP27B1 (eg, ketoconazole, fluconazole) (28, 29) or induce expression of CYP3A4 (eg, rifampin) (30) as an alternative metabolic pathway for inactivation of vitamin D metabolites can be considered. In contrast to patients with CYP24A1 defects, some authors suggest phosphate supplementation with the goal of normalizing calcium and vitamin D metabolism in patients with infantile hypercalcemia-2 resulting from SLC34A1 and SLC34A3 defects (5). However, the safety and efficacy of long-term phosphate supplementation in patients with SLC34A1 and SLC34A3 defects who have normal serum phosphorus levels will need to be clarified in future studies.

Conclusion

Based on this longitudinal, observational cohort study, the clinical and biochemical spectrum of this milder cohort of IIH subjects is broad, and none of these features differentiates the underlying genetic causes. The clinical course remains variable and the current standard-of-care treatment with dietary calcium and vitamin D restriction in many cases is unable to reduce elevated 1,25(OH)2D levels and hypercalcemia or restrain hypercalciuria and renal involvement. The significance of these changes will need to be assessed over a longer term. For patients with persistent or worsening renal calcification, other treatment options should be considered.

Glossary

Abbreviations

1,25(OH)2D

1,25 dihydroxyvitamin D

25(OH)D

25-hydroxyvitamin D

ALP

alkaline phosphatase

Ca:Cr

calcium:creatinine

DRI

dietary reference intake

IIH

idiopathic infantile hypercalcemia

Additional Information

Disclosures: None of the authors has any conflicts of interests to declare.

Data Availability

Some or all data generated or analyzed during this study are included in this published article or in the data repositories listed in References.