Alternative titles; symbols
SNOMEDCT: 34225008; ORPHA: 300547;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.2 | Hypercalcemia, infantile, 1 | 143880 | Autosomal recessive | 3 | CYP24A1 | 126065 |
A number sign (#) is used with this entry because of evidence that infantile hypercalcemia-1 (HCINF1) is caused by homozygous or compound heterozygous mutation in the CYP24A1 gene (126065) on chromosome 20q13.
Infantile hypercalcemia is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. An epidemic of idiopathic infantile hypercalcemia occurred in the United Kingdom in the 1950s after the implementation of an increased prophylactic dose of vitamin D supplementation; however, the fact that most infants receiving the prophylaxis remained unaffected suggested that an intrinsic hypersensitivity to vitamin D might be implicated in the pathogenesis (summary by Schlingmann et al., 2011).
Genetic Heterogeneity
Infantile hypercalcemia-2 (HCINF2; 616963) is caused by mutation in the SLC34A1 gene (182309) on chromosome 5q35.
Suspicion of a genetic basis of hypercalcemia was provided by the family reported first by Smith et al. (1959) and later by Kenny et al. (1963). Two sisters were affected. The authors suggested that the defect might concern vitamin D inactivation. The parents had normal serum calcium levels. The mother, but not the father, became hypercalcemic with a small dose of added vitamin D (Blizzard, 1963; Ehrhardt and Money, 1967).
Hooft et al. (1961) described a family in which a child had idiopathic hypercalcemia and the father had sarcoidosis with hypercalcemia. Autosomal dominant inheritance was suggested by the family reported by Mehes et al. (1975), in which there was an affected father, son, and daughter.
Schlingmann et al. (2011) studied 4 infants from 4 unrelated families, 1 of which was consanguineous, who presented between the ages of 6 and 8 months with typical symptoms of hypercalcemia, including weight loss or failure to thrive, polyuria or dehydration, and muscular hypotonia or lethargy. All 4 infants had received 500 IU of oral vitamin D supplementation daily since birth. Laboratory evaluation revealed profound hypercalcemia, suppressed intact parathyroid hormone (PTH; 168450), and hypercalciuria. Renal ultrasound showed medullary nephrocalcinosis. The authors noted that even after discontinuation of oral vitamin D and institution of a low-calcium diet, serum calcium levels in these patients tended to be continuously mildly elevated during follow-up, and intact PTH levels remained suppressed. Evaluation of 2 asymptomatic sibs of 2 of the patients revealed that 1, who was the monozygotic twin of the affected sib, had an elevated serum calcium level, suppressed intact PTH, hypercalciuria, and medullary nephrocalcinosis. The other sib, who had not been given vitamin D prophylaxis due to his older brother's medical history, was found at 18 months of age to have a serum calcium level in the normal range, suppression of intact PTH, and medullary hyperechogenicity on renal ultrasound.
Phenotypic Variability
Streeten et al. (2011) studied a 47-year-old man who had an episode of nephrolithiasis at 19 years of age and was subsequently asymptomatic until 39 years of age, when hypercalcemia was discovered on routine testing. The patient had a suppressed parathyroid hormone level, elevated levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and low levels of 24,25-dihydroxyvitamin D. After identification of a homozygous mutation in the CYP24A1 gene in this patient (see MOLECULAR GENETICS), Streeten et al. (2011) proposed that in some patients with reduced 24-hydroxylase activity, tissue resistance to 1,25-dihydroxyvitamin D might develop over time, blunting the hypercalcemic response, a concept supported by their patient's normal bone mineral density.
Infantile hypercalcemia is inherited as an autosomal recessive trait (Schlingmann et al., 2011).
Esterification with fatty acids is a protective mechanism against excessive amounts of 1,25-dihydroxyvitamin D. Weisman et al. (1979) suggested that deficiency of the esterification mechanism may underlie infantile hypercalcemia. They suggested that complete absence of normal esterification might cause a severe form of the disorder even when vitamin D intake is not excessive, whereas mild cases may be due to partial deficiency in combination with large intake of vitamin D.
In 4 probands and 2 asymptomatic sibs with idiopathic infantile hypercalcemia from 4 unrelated families, including a Turkish family of known consanguinity, Schlingmann et al. (2011) analyzed 4 candidate genes involved in vitamin D metabolism and identified homozygosity or compound heterozygosity for 6 different mutations in the CYP24A1 gene (126065.0001-126065.0006, respectively). Analysis of CYP24A1 in 4 unrelated German patients who developed symptomatic hypercalcemia in infancy after receiving 1 or more oral doses of 600,000 IU of vitamin D2, 2 of whom were previously reported (Misselwitz and Hesse, 1986), revealed homozygosity or compound heterozygosity for 2 CYP24A1 mutations in 3 patients (126065.0005; 126065.0007). In 1 of the German patients, a heterozygous complex deletion in CYP24A1 was identified, but no other mutation was detected by sequence analysis.
In a 47-year-old man with a history of nephrolithiasis at 20 years of age and asymptomatic hypercalcemia discovered at 39 years of age, Streeten et al. (2011) identified homozygosity for a 3-bp deletion in the CYP24A1 gene (E143del; 126065.0002). The authors noted that this mutation had previously been identified in patients with infantile hypercalcemia, suggesting variable severity and possibly age-related phenotypic change. Schlingmann et al. (2011) commented that this case widened the phenotypic spectrum found in patients with CYP24A1 defects and suggested that the penetrance of such mutations might well be incomplete; they noted that information on lifestyle, nutrition, and vitamin supplementation in the patient described by Streeten et al. (2011) might identify a potential trigger for the development of clinical symptoms in adulthood.
Blizzard, R. M. Personal Communication. Baltimore, Md. 1963.
Ehrhardt, A. A., Money, J. Hypercalcemia--a family study of psychologic functioning. Johns Hopkins Med. J. 121: 14-20, 1967.
Hooft, C., Vermassen, A., Eeckels, R., Vanheule, R. Familial incidence of hypercalcemia. Extreme hypersensitivity to vitamin D in an infant whose father suffered from sarcoidosis. Helv. Paediat. Acta 16: 199-210, 1961. [PubMed: 13715699]
Kenny, F. M., Aceto, T., Jr., Purisch, M., Harrison, H. E., Blizzard, R. M. Metabolic studies in a patient with idiopathic hypercalcemia of infancy. J. Pediat. 62: 531-537, 1963. [PubMed: 14031980] [Full Text: https://doi.org/10.1016/s0022-3476(63)80010-4]
Mehes, K., Szelid, Z., Toth, P. Possible dominant inheritance of the idiopathic hypercalcemic syndrome. Hum. Hered. 25: 30-34, 1975. [PubMed: 1150292] [Full Text: https://doi.org/10.1159/000152705]
Misselwitz, J., Hesse, V. Hypercalcemia following prophylactic vitamin D administration. Kinderarztl Prax. 54: 431-438, 1986. [PubMed: 3490596]
Schlingmann, K. P., Jones, G., Konrad, M. Reply to Streeten et al. and Ji and Shen. (Letter) New Eng. J. Med. 365: 1742-1743, 2011.
Schlingmann, K. P., Kaufmann, M., Weber, S., Irwin, A., Goos, C., John, U., Misselwitz, J., Klaus, G., Kuwertz-Broking, E., Fehrenbach, H., Wingen, A. M., Guran, T., Hoenderop, J. G., Bindels, R. J., Prosser, D. E., Jones, G., Konrad, M. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. New Eng. J. Med. 365: 410-421, 2011. [PubMed: 21675912] [Full Text: https://doi.org/10.1056/NEJMoa1103864]
Smith, D. W., Blizzard, R. M., Harrison, H. E. Idiopathic hypercalcemia. A case report with assays of vitamin D in the serum. Pediatrics 24: 258-269, 1959. [PubMed: 13674824]
Streeten, E. A., Zarbalian, K., Damcott, C. M. CYP24A1 mutations in idiopathic infantile hypercalcemia. (Letter) New Eng. J. Med. 365: 1741-1742, 2011. [PubMed: 22047572] [Full Text: https://doi.org/10.1056/NEJMc1110226]
Weisman, Y., Harell, A., Edelstein, S. Infantile hypercalcemia: a defect in the esterification of 1,25-dehydroxyvitamin D? Med. Hypotheses 5: 379-382, 1979. [PubMed: 459990] [Full Text: https://doi.org/10.1016/0306-9877(79)90019-7]