Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinosis: A Case Report of Compound Heterozygous Variants in the CLDN16 Gene Inherited From Symptomatic Heterozygous Carriers
- 1Nephrology Unit, Department of Medicine-DIMED, University of Padua, Padua, Italy
- 2Clinical Genetics Unit, Department of Women and Children’s Health, University of Padua, Padua, Italy
Abstract
Introduction: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder characterized by renal magnesium wasting, hypercalciuria, and early onset of nephrocalcinosis, complicated by progressive chronic renal failure in childhood or adolescence. The disorder is caused by CLDN16 or CLDN19 genes’ pathogenic variants.
Case Presentation: We describe a 22-year-old female patient with a clinical diagnosis of FHHNC in infancy. Detailed clinical evaluation revealed a complex phenotype with early nephrocalcinosis, recurrent self-resolving renal colic episodes, persistent hypomagnesemia, and secondary hyperparathyroidism (HPP). High oral doses of magnesium were required to treat the FHHNC, causing significant gastrointestinal side effects, particularly diarrhea, leading to further magnesium losses. Upon transfer to our adult nephrology unit, the proband’s blood was subjected to genetic analysis using next-generation sequencing with multigene panel testing.
Results: Genetic analysis of the proband revealed compound heterozygous variants in the CLDN16 gene: a novel splice-site variant NC_000003.12 (NM_006580.4):c.382+1G>C in the canonical donor splice consensus sequence, classified as likely pathogenic inherited from the mother with HPP phenotype; a rare missense variant NM_006580.4:c.500G>C p.(Trp167Ser) inherited from the father with hypercalciuria. Due to poor tolerability of conventional oral magnesium salts, she was switched to a Sucrosomial magnesium formulation, which significantly improved her gastrointestinal tolerance and adherence.
Conclusion: The novel splice-site variant c.382+1G>C and the previously unreported missense variant p.(Trp167Ser) in CLDN16 expand the mutational spectrum associated with FHHNC. Regarding the mother’s phenotype, a symptomatic carrier of a recessive autosomal disease, our finding suggests the importance of genotype-phenotype analysis in identifying mild forms of FHHNC.
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BibTeX
@article{ceol2026familial,
title = {{Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinosis: A Case Report of Compound Heterozygous Variants in the CLDN16 Gene Inherited From Symptomatic Heterozygous Carriers}},
author = {Monica Ceol and Elena Sgrò and Franca Anglani and Giovanna Priante and Lucia Federica Stefanelli and Martina Cacciapuoti and Leonardo Salviati and Federico Nalesso and Dorella Del Prete},
journal = {Case Reports in Nephrology and Dialysis},
year = {2026},
month = oct,
doi = {10.1159/cnd/abxag006},
url = {https://doi.org/10.1159/cnd/abxag006},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinosis: A Case Report of Compound Heterozygous Variants in the CLDN16 Gene Inherited From Symptomatic Heterozygous Carriers
AU - Monica Ceol
AU - Elena Sgrò
AU - Franca Anglani
AU - Giovanna Priante
AU - Lucia Federica Stefanelli
AU - Martina Cacciapuoti
AU - Leonardo Salviati
AU - Federico Nalesso
AU - Dorella Del Prete
PY - 2026
DA - 2026/10/07
JO - Case Reports in Nephrology and Dialysis
DO - 10.1159/cnd/abxag006
UR - https://doi.org/10.1159/cnd/abxag006
AB - Introduction: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder characterized by renal magnesium wasting, hypercalciuria, and early onset of nephrocalcinosis, complicated by progressive chronic renal failure in childhood or adolescence. The disorder is caused by CLDN16 or CLDN19 genes’ pathogenic variants. Case Presentation: We describe a 22-year-old female patient with a clinical diagnosis of FHHNC in infancy. Detailed clinical evaluation revealed a complex phenotype with early nephrocalcinosis, recurrent self-resolving renal colic episodes, persistent hypomagnesemia, and secondary hyperparathyroidism (HPP). High oral doses of magnesium were required to treat the FHHNC, causing significant gastrointestinal side effects, particularly diarrhea, leading to further magnesium losses. Upon transfer to our adult nephrology unit, the proband’s blood was subjected to genetic analysis using next-generation sequencing with multigene panel testing. Results: Genetic analysis of the proband revealed compound heterozygous variants in the CLDN16 gene: a novel splice-site variant NC_000003.12 (NM_006580.4):c.382+1G>C in the canonical donor splice consensus sequence, classified as likely pathogenic inherited from the mother with HPP phenotype; a rare missense variant NM_006580.4:c.500G>C p.(Trp167Ser) inherited from the father with hypercalciuria. Due to poor tolerability of conventional oral magnesium salts, she was switched to a Sucrosomial magnesium formulation, which significantly improved her gastrointestinal tolerance and adherence. Conclusion: The novel splice-site variant c.382+1G>C and the previously unreported missense variant p.(Trp167Ser) in CLDN16 expand the mutational spectrum associated with FHHNC. Regarding the mother’s phenotype, a symptomatic carrier of a recessive autosomal disease, our finding suggests the importance of genotype-phenotype analysis in identifying mild forms of FHHNC.
SN - 2296-9705
ER -