Atypical presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis in a patient with a new claudin-16 gene mutation

Júlia Guasti P Vianna,Antonio Carlos Seguro,Michell Roncete De Bortoli,Everlayny Fiorot Costalonga,Thiago Gabriel Simor,Weverton Machado Luchi,Pamella Senna

doi:10.5414/cncs109595

Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disorder caused by mutations in genes that encode renal tight junction proteins claudin-16 or claudin-19, which are responsible for magnesium and calcium paracellular reabsorption in the thick ascending limb of Henle’s loop. Progressive renal failure is frequently present, and most of the patients require renal replacement therapy still during adolescence. In this case report, we describe a new homozygous missense mutation on CLDN16 gene (c.592G>C, Gly198Arg) in a 24-year-old male patient diagnosed with FHHNC after clinical investigation due to incidental detection of altered routine laboratorial tests, who was firstly misdiagnosed with primary hyperparathyroidism. In addition, it illustrates an atypical presentation of this disease, with late onset of chronic kidney disease, improving the phenotype-genotype knowledge of patients with FHHNC.

Highlights

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive renal tubular disorder, with unknown prevalence, caused by mutations on CLDN16 or CLDN19 genes firstly described by Michelis et al [1] in 1972 (Michelis-Castrillo syndrome)
Claudin-16 and claudin-19 are expressed on the thick ascending limb of Henle’s loop and are responsible for paracellular resorption of ~ 60% of Mg2+ and 20 – 30% of Ca2+ filtered by the kidneys, driven by transepithelial voltage gradient lumen-positive created in this segment (Figure 2) [2]
Claudin-16 is exclusively expressed in the kidneys, differing from claudin-19, which is expressed in retina and peripheral neurons [4]

Summary

Introduction

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive renal tubular disorder, with unknown prevalence, caused by mutations on CLDN16 (chromosome 3q28) or CLDN19 (chromosome 1p34.1) genes firstly described by Michelis et al [1] in 1972 (Michelis-Castrillo syndrome). These genes codify the tight junction proteins claudin-16 and -19, respectively, responsible for the regulation of the paracellular reabsorption of magnesium (Mg2+) and calcium (Ca2+) at the thick ascending limb of Henle’s loop. A 20-year-old Brazilian man was referred for medical investigation after the incidental finding of increased serum creatinine level (Cr: 1.67 mg/dL). After PTX At diagnosis Follow-up Reference (20 years) (22 years) (24 years) (25 years) values

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Discussion