Heterogeneity is a common ground in familial hypomagnesemia with hypercalciuria and nephrocalcinosis caused by CLDN19 gene mutations.

Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare tubulopathy caused by mutations in the CLDN16 or CLDN19 genes. Patients usuallydevelop hypomagnesemia, hypercalciuria, nephrocalcinosis and renal failure early in life. Patients with CLDN19 mutations may also have ocular abnormalities. Despite clinical variability, factors associated with kidney functionimpairment, especially in patients with CLDN19 mutations, have not been addressed. Retrospective multicenter study of 30 genetically confirmed FHHNC Spanish patients. We analyzed kidney function impairmentconsidering as outcomeschronic kidney disease (CKD) stage3 and annual estimated glomerular filtration rate (eGFR) decline, to identify factors associated with thedifferent phenotypes. Of thirty patients, 27 had mutations in the CLDN19 gene (20 homozygous for the p.G20D mutation) and 3 in the CLDN16. Age at diagnosis was 1.71 (0.67-6.04) years and follow-up time was 8.34 ± 4.30years. No differences in CKD stage3-free survival based on CLDN19 mutation (p.G20D homozygous vs. other mutations) or gender were found, although females seemed to progress faster than males. Patients with more pronounced eGFR decline had higher PTH levels at diagnosis than those with stablekidney function, despite similar initial eGFR. Approximately 60% of CLDN19 patients presented ocular abnormalities. Furthermore, we confirmed high phenotypic intrafamilial variability. In a contemporary cohort of FHHNC patients with CLDN19 mutations, females seemed to progress to CKD-stage3 faster than males. Increased PTH levels at baseline may indicate amore severe renal course. There was high phenotype variability among patients with CLDN19 mutations and kidney function impairment differedeven betweensiblings.