High Prevalence of Kidney Cysts in Patients with CYP24A1 Deficiency

Abstract Introduction Loss-of-function variants in the CYP24A1 gene cause a rare hereditary disease characterized by reduced 24-hydroxylase enzyme activity, increased serum 1,25-dihydroxycholecalciferol levels, hypercalcemia, hypercalciuria, and nephrocalcinosis and/or nephrolithiasis. Kidney cysts in patients with CYP24A1 deficiency were first reported in a single case study from our center. However, a possible association between CYP24A1 deficiency and kidney cysts has not been described. Methods Retrospective analysis of patients with confirmed or suspected CYP24A1 deficiency and available kidney imaging. Results Among 16 patients with confirmed pathogenic variants, 38% were males and 31% were children, the median age at genetic confirmation was 38 yrs (range 1-66), and none had a family history of cystic kidney disease. Medullary and/or corticomedullary junction cysts were present in all cases. The median age at first detected cyst was 37 yrs (range 3-60). The mean and median number of cysts per patient were 5.3 and 2.5 (range 1-37), respectively. Four out of 5 further patients with suspected but unconfirmed pathogenic variants had cysts. The number of cysts ≥ 5 mm in size was above the 97.5th percentile of an age- and sex-matched control population in 55% and 67% of patients with confirmed and suspected pathogenic variants, respectively. At least 1 cyst (≥ 5 mm in size) was found in 80% of children with confirmed CYP24A1 deficiency. Conclusions These observations strongly suggest an association between CYP24A1 deficiency and kidney cysts. Further studies are needed to evaluate the role of CYP24A1, vitamin D metabolism and/or hypercalciuria in cyst formation, and whether cysts exacerbate CKD or modify nephrocalcinosis and stone risk.