Infantile Hypercalcemia and Hypercalciuria: New Insights into a Vitamin D-Dependent Mechanism and Response to Ketoconazole Treatment

doi:10.1016/j.jpeds.2010.02.025

The Journal of Pediatrics

Volume 157, Issue 2, August 2010, Pages 296-302

https://doi.org/10.1016/j.jpeds.2010.02.025 Get rights and content

Objective

To analyze vitamin D metabolism and response to ketoconazole, an imidazole derivative that inhibits the vitamin D-1-hydroxylase, in infants with idiopathic hypercalcemia, and hypercalciuria.

Study design

Twenty infants (4 days-17 months) with hypercalcemia, severe hypercalciuria, and low parathyroid hormone level, (10 had nephrocalcinosis), including 10 treated with ketoconazole (3-9 mg/kg/day), were followed to the age of 2 to 51 months. Vitamin D receptor expression (VDR), 24-hydroxylase activity, and functional gene polymorphisms of vitamin D metabolism regulators VDR(rs4516035), 1-hydroxylase(rs10877012), 24-hydroxylase(rs2248359), FGF23(rs7955866), Klotho(rs9536314, rs564481, rs648202), were evaluated.

Results

Serum calcium levels, which occurred faster in the ketoconazole group (0.7 ± 0.2 versus 2.4 ± 0.6 months; P = .0076), and urinary calcium excretion (2.5 ± 0.5 versus 4.2 ± 1.7 months) normalized in all patients. Serum 1,25-(OH)2D levels were high normal and positively correlated to 25-(OH)D levels. Serum 24,25-(OH)2D levels were low normal, and skin fibroblasts from 1 patient showed defective up-regulation of the 24-hydroxylase by 1,25-(OH)2D despite normal VDR binding ability. An abnormally low prevalence of haplotype CC/CC for H589H/A749A in Klotho gene was found in patients and family members.

Conclusions

Ketoconazole is a potentially useful and safe agent for treatment of infantile hypercalcemia. Abnormal vitamin D metabolism is suggested as the mechanism, possibly involving defective up-regulation of the 24-hydroxylase by 1,25-(OH)2D3, and the klotho-FGF23 axis.

Section snippets

Methods

Twenty Caucasian children (12 girls and 8 boys, aged 4 days-17 months) with idiopathic infantile hypercalcemia and hypercalciuria were included in the study because of their serum calcium and urinary calcium/creatinine ratio that was higher than upper reference ranges for the age (2.70 mmol/L and 1.5 mmol/mmoL, respectively). The exclusion criteria included: serum 25-(OH)D levels greater than the threshold of vitamin D overload (100 ng/mL); data, from genetic analysis, scanner, or clinical

Results

Patients' mean age at diagnosis was 65 days (range, 4 days-17 months). The diagnosis had been established fortuitously after a systematic medical check-up (n = 7) or because of growth retardation, feeding difficulties, or weight loss (n = 6), urinary infection (n = 2), or more severe clinical symptoms of hypercalcemia, like dehydratation, decreased appetite, vomiting, lethargy, and hypotonia (n = 5). None of the 9 infants aged <3 weeks, but 10 of the 11 older infants, had unilateral or

Discussion

Infantile benign idiopathic hypercalcemia has been known for >50 years.3, 4, 5 Its mechanism remains poorly understood and the effectiveness of treatment has not been precisely evaluated. Although half the infants we studied had moderately retarded growth and 10 had nephrocalcinosis at diagnosis, all had body weight and length in the normal range, and only 2 still had abnormalities on ultrasound scanning at the end of the survey. Ketoconazole treatment has been shown to decrease serum calcium

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Citation Excerpt :
The successful therapeutic use of ketoconazole initially were described in patients with hyperparathyroidism, granulomatous disorders, and hypercortisolism.80 Several studies evaluated the use of ketoconazole in hypercalcemic patients with CYP24A1 mutations.79,81,82 Although the therapeutic efficacy of ketoconazole in these studies was encouraging, use in the long term might be problematic because of its side effects and toxicity.83

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: The authors declare no conflicts of interest.

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Original ArticleInfantile Hypercalcemia and Hypercalciuria: New Insights into a Vitamin D-Dependent Mechanism and Response to Ketoconazole Treatment

Objective

Study design

Results

Conclusions

Section snippets

Methods

Results

Discussion

J Pediatr

Am J Clin Nutr

J Biol Chem

Kidney Int

J Steroid Biochem Mol Biol

J Biol Chem

Med Hypotheses

Arch Pediatr

Elevated plasma 1,25-dihydroxyvitamin D concentrations in infants with hypercalcemia and an elfin facies

N Engl J Med

The blood chemistry in idiopathic hypercalcemia

Arch Dis Child

Biochemical studies in idiopathic hypercalcaemia of infancy

Arch Dis Child

Prednisolone and cellulose phosphate treatment in idiopathic infantile hypercalcaemia with nephrocalcinosis

J Paediatr Child Health

Idiopathic infantile hypercalcemia: rapid response to treatment with calcitonin

Child Nephrol Urol

Oral bisphosphonate therapy for vitamin D intoxication of the infant

Pediatrics

Ketoconazole-induced reduction in serum 1,25-dihydroxyvitamin D and total serum calcium in hypercalcemic patients

J Clin Endocrinol Metab

Original Article
Infantile Hypercalcemia and Hypercalciuria: New Insights into a Vitamin D-Dependent Mechanism and Response to Ketoconazole Treatment