Co-occurrence of pathogenic CYP24A1 gene variants and primary hyperparathyroidism: a diagnostic challenge.
4 affiliations
- 1Department of Clinical and Experimental Medicine, University of Pisa, Pisa, 56126, Italy.
- 2Endocrine Unit 2, University Hospital of Pisa, Pisa, 56124, Italy.
- 3Laboratory of Molecular Genetics, University Hospital of Pisa, Pisa, 56126, Italy.
- 4Department of Surgical, Medical and Molecular Pathology and Critical Care Area, University of Pisa, Pisa, 56126, Italy.
Abstract
Hypercalcemia is mostly caused by primary hyperparathyroidism (PHPT) or malignancy. Less commonly, hypercalcemia results from vitamin D-dependent mechanisms. Pathogenic variants in CYP24A1, which encodes the 24-hydroxylase responsible for inactivating 1,25(OH)₂D₃, can lead to hypercalciuria, nephrolithiasis/nephrocalcinosis, and hypercalcemia, typically with suppressed PTH. When CYP24A1-related disease coexists with PHPT, their biochemical features may overlap, potentially masking a vitamin D catabolic defect and complicating postoperative interpretation of hypercalcemia. We report 2 unrelated patients with moderate-to-severe hypercalcemia in whom PHPT and CYP24A1 variants coexisted. The first patient was a 26-yr-old man with longstanding nephrolithiasis who initially had hypercalcemia with an inappropriately normal PTH level and imaging consistent with a hyperfunctioning parathyroid lesion, treated with parathyroidectomy (PTx). Several years later, PTH-suppressed hypercalcemia and elevated 25(OH)D₃ and 1,25(OH)₂D₃ concentrations was detected despite the absence of vitamin D supplementation. Genetic testing revealed a heterozygous pathogenic CYP24A1 variant (p.Leu409Ser), consistent with partial 24-hydroxylase deficiency. The second patient was a 59-yr-old woman with severe PHPT requiring surgery and later experienced life-threatening hypercalcemia (19.8 mg/dL) requiring hemodialysis, marked calcium fluctuations, particularly after calcium and calcitriol exposure following a second surgery, nephrocalcinosis, and progressive renal impairment. Genetic testing identified compound heterozygous CYP24A1 variants (p.Glu143del and p.Gln82Arg). These cases broaden the clinical spectrum of combined PHPT and CYP24A1-related disease and highlight that persistent or recurrent hypercalcemia after PTx, particularly when PTH is suppressed, may prompt evaluation for CYP24A1 defects, with potential implications for vitamin D avoidance and long-term renal surveillance.
Related
- A case of renal hypouricemia type 1 associated with compound heterozygous URAT1/SLC22A12 variants A209V and F379L: clinical evidence for their pathogenic significance
- Hypomagnesemia in Hypoparathyroidism, Sensorineural Deafness, and Renal Dysplasia Syndrome Caused by Pathogenic Variants of GATA3
- Pathogenic variants in myoferlin (MYOF) cause arrhythmogenic cardiomyopathy
- Occurrence, persistence and pathogenic potential of Bacillus cereus sensu lato strains isolated during processing of two plant-based desserts
- Preoperative parathyroid imaging in CKD-related secondary hyperparathyroidism: a systematic review and diagnostic test accuracy network meta-analysis.
BibTeX
@article{valentina2026cooccurrence,
title = {{Co-occurrence of pathogenic CYP24A1 gene variants and primary hyperparathyroidism: a diagnostic challenge.}},
author = {Simone Della Valentina and Laura Pierotti and Chiara Sardella and Anna Dal Lago and Maria Adelaide Caligo and Agnese Giamborino and Filomena Cetani},
journal = {JBMR plus},
year = {2026},
month = oct,
doi = {10.1093/jbmrpl/ziag164},
url = {https://europepmc.org/article/MED/42928911},
note = {CC BY},
}
RIS
TY - JOUR
TI - Co-occurrence of pathogenic CYP24A1 gene variants and primary hyperparathyroidism: a diagnostic challenge.
AU - Simone Della Valentina
AU - Laura Pierotti
AU - Chiara Sardella
AU - Anna Dal Lago
AU - Maria Adelaide Caligo
AU - Agnese Giamborino
AU - Filomena Cetani
PY - 2026
DA - 2026/10/09
JO - JBMR plus
DO - 10.1093/jbmrpl/ziag164
UR - https://europepmc.org/article/MED/42928911
AB - Hypercalcemia is mostly caused by primary hyperparathyroidism (PHPT) or malignancy. Less commonly, hypercalcemia results from vitamin D-dependent mechanisms. Pathogenic variants in CYP24A1, which encodes the 24-hydroxylase responsible for inactivating 1,25(OH)₂D₃, can lead to hypercalciuria, nephrolithiasis/nephrocalcinosis, and hypercalcemia, typically with suppressed PTH. When CYP24A1-related disease coexists with PHPT, their biochemical features may overlap, potentially masking a vitamin D catabolic defect and complicating postoperative interpretation of hypercalcemia. We report 2 unrelated patients with moderate-to-severe hypercalcemia in whom PHPT and CYP24A1 variants coexisted. The first patient was a 26-yr-old man with longstanding nephrolithiasis who initially had hypercalcemia with an inappropriately normal PTH level and imaging consistent with a hyperfunctioning parathyroid lesion, treated with parathyroidectomy (PTx). Several years later, PTH-suppressed hypercalcemia and elevated 25(OH)D₃ and 1,25(OH)₂D₃ concentrations was detected despite the absence of vitamin D supplementation. Genetic testing revealed a heterozygous pathogenic CYP24A1 variant (p.Leu409Ser), consistent with partial 24-hydroxylase deficiency. The second patient was a 59-yr-old woman with severe PHPT requiring surgery and later experienced life-threatening hypercalcemia (19.8 mg/dL) requiring hemodialysis, marked calcium fluctuations, particularly after calcium and calcitriol exposure following a second surgery, nephrocalcinosis, and progressive renal impairment. Genetic testing identified compound heterozygous CYP24A1 variants (p.Glu143del and p.Gln82Arg). These cases broaden the clinical spectrum of combined PHPT and CYP24A1-related disease and highlight that persistent or recurrent hypercalcemia after PTx, particularly when PTH is suppressed, may prompt evaluation for CYP24A1 defects, with potential implications for vitamin D avoidance and long-term renal surveillance.
SN - 2473-4039
ER -