Dataset Information

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 male and 31% were children, the median age at genetic confirmation was 38 years (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 years (range 3-60). The mean and median number of cysts per patient were 5.3 and 2.5 (range 1-37), respectively. Four 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 chronic kidney disease or modify nephrocalcinosis and stone risk.

SUBMITTER: Hanna C

PROVIDER: S-EPMC8258502 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose To define the magnetic resonance (MR) imaging prevalence of pancreatic cysts in a cohort of patients with autosomal dominant polycystic kidney disease (ADPKD) compared with a control group without ADPKD that was matched for age, sex, and renal function. Materials and Methods In this HIPAA-compliant, institutional review board-approved study, all patients with ADPKD provided informed consent; for control subjects, informed consent was waived. Patients with ADPKD (n = 110) with mutations identified in PKD1 or PKD2 and control subjects without ADPKD or known pancreatic disease (n = 110) who were matched for age, sex, estimated glomerular filtration rate, and date of MR imaging examination were evaluated for pancreatic cysts by using axial and coronal single-shot fast spin-echo T2-weighted images obtained at 1.5 T. Total kidney volume and liver volume were measured. Univariate and multivariable logistic regression analyses were conducted to evaluate potential associations between collected variables and presence of pancreatic cysts among patients with ADPKD. The number, size, location, and imaging characteristics of the cysts were recorded. Results Patients with ADPKD were significantly more likely than control subjects to have at least one pancreatic cyst (40 of 110 patients [36%] vs 25 of 110 control subjects [23%]; P = .027). In a univariate analysis, pancreatic cysts were more prevalent in patients with ADPKD with mutations in PKD2 than in PKD1 (21 of 34 patients [62%] vs 19 of 76 patients [25%]; P = .0002). In a multivariable logistic regression model, PKD2 mutation locus was significantly associated with the presence of pancreatic cysts (P = .0004) and with liver volume (P = .038). Patients with ADPKD and a pancreatic cyst were 5.9 times more likely to have a PKD2 mutation than a PKD1 mutation after adjusting for age, race, sex, estimated glomerular filtration rate, liver volume, and total kidney volume. Conclusion Pancreatic cysts were more prevalent in patients with ADPKD with PKD2 mutation than in control subjects or patients with PKD1 mutation. (©) RSNA, 2016 Online supplemental material is available for this article.

Project description:The CYP24A1 gene encodes a mitochondrial 24-hydroxylase that inactivates 1,25(OH)2 D. Loss-of-function mutations in CYP24A1 cause hypercalcemia, nephrolithiasis and nephrocalcinosis. We describe a woman with CYP24A1 deficiency and recurrent gestational hypercalcemia. Her first pregnancy, at age 20, resulted with the intrauterine demise of twin fetuses. Postpartum, she developed severe hypercalcemia (14 mg/dL), altered mental status, and acute pancreatitis. Her PTH was suppressed (6 pg/mL) and her 1,25(OH)2 D was elevated (165 and 195 pg/mL on postpartum day 1 and 5, respectively). Between one and three months postpartum, her serum calcium decreased from 11.4 to 10.2 mg/dL while her 1,25(OH)2 D level decreased from 83 to 24 pg/mL. Her 24-hour urine calcium was 277 mg. Six months postpartum, she became pregnant again. At 14 weeks, her albumin-corrected calcium level was 10.4 mg/dL and her 1,25(OH)2 D level exceeded 200 pg/mL. To establish the diagnosis of CYP24A1 deficiency, we showed her 24,25(OH)2 D level to be undetectable (<2 ng/mL). Exon sequencing of the CYP24A1 gene revealed a homozygous, 8-nucleotide deletion in exon 8, causing an S334V substitution and premature termination due to a frame shift (c.999_1006del, p.Ser334Valfs*9). To prevent hypercalcemia, she was advised to discontinue prenatal vitamins, avoid sun exposure and calcium-rich foods, and start omeprazole and a calcium binder (250 mg K-Phos-neutral with meals). Despite these measures, both hypercalcemia (11.5 mg/dL) and acute pancreatitis recurred. Labor was induced and a healthy, normocalcemic boy was delivered. In the absence of lactation, maternal hypercalcemia resolved within 2 months. This report shows that CYP24A1-deficient subjects may be normocalcemic at baseline. Hypercalcemia may be unmasked by pregnancy through the routine use of calciferol-containing prenatal vitamins, increased 1-alpha hydroxylation of VitD by the placenta and maternal kidney, and production of PTHrP by the uteroplacental unit. CYP24A1 deficiency should be considered in patients with unexplained vitamin D-mediated hypercalcemia. © 2016 American Society for Bone and Mineral Research.