Hypercalcemia due to CYP24A1 mutations: a systematic descriptive review.

Area of Science:

• Endocrinology
• Genetics
• Metabolic Disorders

Background:

• CYP24A1 encodes 24-hydroxylase, crucial for vitamin D metabolism.
• Loss-of-function mutations lead to vitamin D-dependent hypercalcemia.
• Existing literature shows variability in disease presentation, symptoms, and treatment outcomes.

Purpose of the Study:

• Investigate clinical heterogeneity in CYP24A1-related hypercalcemia.
• Assess the phenotype of monoallelic carriers.
• Compare the efficacy of different hypocalcemic therapies.

Main Methods:

• Systematic literature review of studies from CYP24A1 variant identification to December 2020.
• Inclusion of clinical trials and case reports on CYP24A1 variant carriers.
• Analysis of genetic data, allele frequencies, and clinical outcomes.

Main Results:

• 221 patients from 50 studies were analyzed.
• Infantile hypercalcemia (76%) and nephrocalcinosis (<0.0001) were common presentations.
• Monoallelic carriers showed increased risks of nephrolithiasis (19.4%) and symptomatic hypercalcemia (5.6%).

Conclusions:

• CYP24A1 loss-of-function causes an age-dependent phenotype, worsened by factors like pregnancy.
• Biallelic carriers exhibit more severe features, but monoallelic carriers face elevated risks.
• Therapeutic approaches showed high variability, precluding definitive treatment recommendations.