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MEDTECH Genetic Variant in Vitamin D Metabolism Pathway Linked to Infantile Hypercalcemia
A 10-month-old boy presented with vomiting, weight loss, and hypercalcemia, leading to a diagnosis of 24-hydroxylase deficiency caused by a homozygous variant in the CYP24A1 gene. This case highlights the importance of considering genetic disorders in the differential diagnosis of infantile hypercalcemia and demonstrates the complex interplay between vitamin D metabolism and calcium homeostasis.
Key Points:
- The patient presented with projectile vomiting, weight loss, and hypercalcemia (13.2 mg/dL).
- Initial laboratory findings included suppressed PTH (6 pg/mL) and normal levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D.
- Medullary nephrocalcinosis was detected on abdominal ultrasonography.
- The ratio of 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D was elevated (170 ng/ng; reference range 7-35).
- Genetic testing revealed a homozygous variant in CYP24A1 (c.1226T>C; p.L409S).
- CYP24A1 encodes 24-hydroxylase, which is responsible for inactivating vitamin D metabolites.
- The identified variant results in reduced enzymatic activity, leading to increased 1,25-dihydroxyvitamin D levels and hypercalcemia.
- Acute management involved saline diuresis and transition to a low-calcium, vitamin D-free formula.
- Long-term management includes dietary calcium and vitamin D restriction, sun protection, and hydration.
- Rifampin was used off-label to induce an alternative vitamin D catabolic pathway mediated by CYP3A4.
- The patient’s calcium levels normalized with treatment, and growth improved.
- Persistent, stable nephrocalcinosis remained a concern.
HCN Medical Memo
When evaluating infants with hypercalcemia, consider genetic testing for CYP24A1 variants, especially in cases with normal or elevated 1,25-dihydroxyvitamin D levels and suppressed PTH. Management should focus on calcium and vitamin D restriction, with potential for novel treatments like rifampin to induce alternative vitamin D catabolic pathways.
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