CYP24A1 – Infantile Hypercalcemia Type 1

Infantile Hypercalcemia Type 1 (HCINF1) is an autosomal recessive disorder marked by PTH-independent hypercalcemia, hypercalciuria and nephrocalcinosis due to defective inactivation of 1,25-dihydroxyvitamin D. The disorder stems from bi-allelic loss-of-function variants in CYP24A1, which encodes the vitamin D 24-hydroxylase responsible for catabolism of active vitamin D metabolites. Affected patients may present in infancy or adulthood with renal stones, nephrocalcinosis and elevated serum calcium and 1,25(OH)2D levels ([PMID:36625425]). Clinical recognition is critical to avoid complications of chronic hypercalcemia and to guide management focused on limiting vitamin D exposure and calcium intake.

Extensive genetic screening across multiple cohorts has identified CYP24A1 variants in over 50 unrelated probands. In a cohort of 185 patients with hypercalcemia and hypercalciuria, 25 harbored biallelic CYP24A1 mutations ([PMID:34721296]). A study of 72 hypercalcemic individuals found 20 with recessive CYP24A1 variants, mostly associated with nephrolithiasis or nephrocalcinosis ([PMID:26214117]). An Italian series reported bi-allelic mutations in 8 of 12 patients from 7 families ([PMID:27394135]), and two Chinese infants carried novel compound heterozygous variants ([PMID:30633617]).

The variant spectrum includes missense, nonsense, frameshift and splice-site mutations. Notable recurrent alleles include c.1186C>T (p.Arg396Trp) and c.989C>T (p.Thr330Met), with hotspots at p.Leu148Pro and p.Arg439Cys in European and Italian cohorts. A single‐nucleotide deletion c.1426_1427del (p.Cys477LeufsTer14) and splice-donor changes such as c.449+2T>C have also been reported, expanding the pathogenic landscape.

Segregation analysis in affected families supports recessive inheritance. For example, a 33-year-old proband with long-standing hypercalcemia and two first-degree relatives all carried homozygous CYP24A1 variants and shared clinical features of nephrocalcinosis ([PMID:34551392]). Overall, at least two additional affected relatives have segregated CYP24A1 variants consistent with disease.

Functional studies corroborate loss of 24-hydroxylase activity as the pathogenic mechanism. Site-directed mutagenesis in a two-hybrid JEG-3 cell assay demonstrated that p.Leu409Ser retains only ~32% of wild-type enzyme activity ([PMID:25375986]). Structural modeling and enzyme kinetics reveal impaired substrate binding and reduced Vmax across multiple missense mutants. Knock-out and overexpression models confirm that CYP24A1 deficiency leads to accumulation of 1,25(OH)2D and hypercalcemic phenotypes.

Beyond coding variants, non-coding structural elements in the CYP24A1 3′UTR alter mRNA folding and impair translation, producing a semifunctional enzyme in six patients lacking coding-region mutations ([PMID:36625425]). This highlights the need for comprehensive analysis of untranslated regions when genetic tests are negative despite biochemical evidence of HCINF1.

In conclusion, the CYP24A1–HCINF1 association is Definitive based on >50 probands, multi-family segregation, and concordant functional data. Genetic testing for CYP24A1 should be pursued in patients with unexplained hypercalcemia, nephrocalcinosis or renal stones, as early diagnosis informs avoidance of vitamin D oversupplementation and guides targeted therapies. Key Take-home: Biallelic CYP24A1 loss-of-function variants cause autosomal recessive infantile hypercalcemia type 1, and comprehensive genetic and functional assessment enables precise diagnosis and management.

References

• Frontiers in Endocrinology • 2021 • Overlapping Phenotypes Associated With CYP24A1, SLC34A1, and SLC34A3 Mutations: A Cohort Study of Patients With Hypersensitivity to Vitamin D PMID:34721296
• The Journal of Clinical Endocrinology & Metabolism • 2015 • CYP24A1 Mutations in a Cohort of Hypercalcemic Patients: Evidence for a Recessive Trait PMID:26214117
• Nephron • 2016 • Mutational Spectrum of CYP24A1 Gene in a Cohort of Italian Patients with Idiopathic Infantile Hypercalcemia PMID:27394135
• Endocrinology, Diabetes & Metabolism Case Reports • 2021 • Infantile hypercalcaemia type 1: a vitamin D-mediated, under-recognised cause of hypercalcaemia PMID:34551392
• Journal of Bone and Mineral Research • 2023 • 3' Untranslated Region Structural Elements in CYP24A1 Are Associated With Infantile Hypercalcemia Type 1 PMID:36625425
• The Journal of Biological Chemistry • 2005 • Alternative splicing of vitamin D-24-hydroxylase: a novel mechanism for the regulation of extrarenal 1,25-dihydroxyvitamin D synthesis PMID:15788398

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