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Kidney Week

Abstract: PO1357

Childhood-Onset Nephrocalcinosis in Twins Caused By Biallelic Mutations in CYP24A1 Gene: A Long Journey to a Genetic Diagnosis

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Tan, Xin Yee, Cleveland Clinic, Cleveland, Ohio, United States
  • Roberts, Mary-Beth, Cleveland Clinic, Cleveland, Ohio, United States
  • Nurko, Saul, Cleveland Clinic, Cleveland, Ohio, United States
  • Wang, Xiangling, Cleveland Clinic, Cleveland, Ohio, United States

24-hydroxylase deficiency is a rare autosomal recessive disorder caused by mutations in CYP24A1 gene, characterized by hypercalcemia,hypercalciuria and nephrolithiasis.Establishing a genetic diagnosis,while important to guide management and family counseling,can be challenging.We hereby report a case of twins with childhood-onset nephrocalcinosis and chronic hypercalcemia caused by biallelic mutations of CYP24A1,which took years to be diagnosed.

Case Description

A 26 year-old female presented for preconception evaluation for a history of childhood-onset nephrocalcinosis and chronic hypercalciuric hypercalcemia.Patient reported similar history in identical twin sister.They had exome sequencing( ES) eight years ago after negative genes panel test which revealed a heterozygous variant of unknown significance(c.1186C>T)in CYP24A1.A reanalysis of ES was performed four years ago which demonstrated no changes.Work up revealed hypercalciuric hypercalcemia,low 25(OH)vitamin D, elevated 1,25(OH)vitamin D and 24,25(OH)vitamin D,and suppressed PTH(fig.1).Ratio of 25(OH)D-to-24,25-(OH)2D,a new biochemical test for 24-hydroxylase deficiency,suggested biallelic mutations in CYP24A1 gene. ES reanalysis at this time reclassified the c.1186C>T variant as pathogenic and disclosed a novel intronic variant (c.544-17G>A )which was predicted to cause splicing pattern change with multiple silico algorithms. Parental tests confirmed these two variants were in trans configuration consistent with autosomal recessive inheritance pattern.A thorough counselling included low recurrence risk for her children while high risk for her to develop severe hypercalcemia during pregnancy.She has been closely monitored with low calcium and vitamin D diet,sun avoidance and adequate hydration during current pregnancy with no complications to date.


CYP24A1 gene related hypercalcemia is rare and challenging to diagnose even with ES.This case suggests the benefits of ES regular reanalysis for clinically suspected patients with inconclusive genetic findings.The novel intronic mutation identified in this case broadens the genetics spectrum of 24-hydroxylase deficiency.

Figure 1