ESPN 53rd Annual Meeting

ESPN 2021


 
Novel compound heterozygous mutations of CLDN16 gene in two siblings with nephrocalcinosis, hypomagnesemia and hypercalciuria
LOVRO LAMOT 1 IVAN JAKOPčIć 1 HANA MATKOVIć 1 IVANKA KOS 1 KRISTINA VRLJIčAK 1

1- DEPARTMENT OF PEDIATRICS, UNIVERSITY OF ZAGREB SCHOOL OF MEDICINE, UNIVERSITY HOSPITAL CENTRE ZAGREB, ZAGREB, CROATIA
 
Introduction:

The pathological condition underlying nephrocalcinosis in children is not always evident and requires a detailed history and work-up. Most commonly it is not associated with specific symptoms, while only a small number of children can present with recurrent urinary tract infection (rUTI). Yet, when accompanied with hypercalciuria and hypomagnesemia, it should raise a suspicion of an inherited disease, and therefore genetic testing is warranted. 

Material and methods:

Case report.

Results:

We report a case of sister (11 years) and brother (7 years) born to nonconsanguineous, healthy parents. The girl initially presented rUTI at the age of 4, while renal ultrasound revealed bilateral nephrocalcinosis. A screening renal ultrasound was performed in her brother at the age of 4 months with the same findings. Further evaluation revealed hypercalciuria, hypomagnesaemia, hypermagnesuria, hyperparathyroidism, hyperuricemia and decreased GFR in both siblings, with no other extrarenal manifestations. Finally, targeted gene sequencing (Blueprint Nephrolitiasis panel with 35 genes) identified a novel heterozygous frameshift variant c.332_333del, p.(Thr111Lysfs*15) and a heterozygous missense variant c.358T>C, p.(Cys120Arg) in CLDN16 gene, confirming the diagnosis of Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC).

Conclusions:

FHHNC is is a rare autosomal recessive tubular disease caused by mutations in CLDN16 and CLDN19 genes encoding for the tight-junction proteins expressed in the thick ascending limb of Henles loop, where they form an essential complex for the paracellular reabsorption of magnesium and calcium. Many patients display a marked decline in GFR at the time of diagnosis, and about one-third progress to chronic renal failure during adolescence. While most of them harbor loss-of-function mutations in both alleles, phenotypic variability has been shown even in siblings with the same homozygous mutation, emphasizing the likely contribution of epigenetic factors to the disease development. In this context, to achieve a wider health impact, reporting of novel disease-causing mutations is of high importance in order to establish phenotype-genotype correlations, facilitate appropriate treatment and inform disease outcome.