Mutations in CYP24A1 and Idiopathic Infantile Hypercalcemia — NEJM

Original Article

Mutations in CYP24A1 and Idiopathic Infantile Hypercalcemia
Karl P. Schlingmann, M.D., Martin Kaufmann, Ph.D., Stefanie Weber, M.D., Andrew Irwin, B.Sc., Caroline Goos, Ulrike John, M.D., Joachim Misselwitz, M.D., Günter Klaus, M.D., Eberhard Kuwertz-Bröking, M.D., Henry Fehrenbach, M.D., Anne M. Wingen, M.D., Tülay Güran, M.D., Joost G. Hoenderop, Ph.D., René J. Bindels, Ph.D., David E. Prosser, Ph.D., Glenville Jones, Ph.D., and Martin Konrad, M.D.

June 15, 2011 (10.1056/NEJMoa1103864)

Abstract
Background
Vitamin D supplementation for the prevention of rickets is one of the oldest and most effective prophylactic measures in medicine, having virtually eradicated rickets in North America. Given the potentially toxic effects of vitamin D, the recommendations for the optimal dose are still debated, in part owing to the increased incidence of idiopathic infantile hypercalcemia in Britain in the 1950s during a period of high vitamin D supplementation in fortified milk products. We investigated the molecular basis of idiopathic infantile hypercalcemia, which is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis.


Methods
We used a candidate-gene approach in a cohort of familial cases of typical idiopathic infantile hypercalcemia with suspected autosomal recessive inheritance. Identified mutations in the vitamin D–metabolizing enzyme CYP24A1 were evaluated with the use of a mammalian expression system.


Results
Sequence analysis of CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25-dihydroxyvitamin D3 degradation, revealed recessive mutations in six affected children. In addition, CYP24A1 mutations were identified in a second cohort of infants in whom severe hypercalcemia had developed after bolus prophylaxis with vitamin D. Functional characterization revealed a complete loss of function in all CYP24A1 mutations.


Conclusions
The presence of CYP24A1 mutations explains the increased sensitivity to vitamin D in patients with idiopathic infantile hypercalcemia and is a genetic risk factor for the development of symptomatic hypercalcemia that may be triggered by vitamin D prophylaxis in otherwise apparently healthy infants.

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Mutations in CYP24A1 and Idiopathic Infantile Hypercalcemia — NEJM