Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC): Report of three cases with a novel mutation in CLDN19 gene

Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder that is caused by mutation in the genes coding for tight junction proteins Claudin-16 and Claudin-19. Affected individuals usually develop nephrocalcinosis and progressive renal failure; some of them may have ophthalmologic involvement as well. Phenotypic description of three affected individuals from the same Middle Eastern kindred (two sisters and their cousin) is presented. This includes both clinical and laboratory findings upon initial presentation and subsequent follow-up. Molecular analysis of the CLDN19 gene was performed on the three cases and one set of parents. A novel homozygous missense mutation in CLDN19 (c.241C>T, p.Arg81Cys) was detected in all three affected children. The parents were heterozygous. Clinical and laboratory data in the three children with renal and ocular manifestations of FHHNC are described. Genetic analysis revealed a novel mutation in the CLDN19 gene. FHHNC is a rare cause of nephrocalcinosis, and we believe that it should be considered in the presence of nephrocalcinosis with hypercalcuria and hypermagnesuria.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: variable phenotypic expression in three affected sisters from Mexican ancestry

“…Although the disease is usually a pediatric diagnosis, in the three sisters herein reported, etiologic diagnosis was delayed until their fourth decade of life. Interestingly the mutation identified in this family, a glycine to asparagine substitution, at position 20 (p.Gly20Asp) of the protein, 2,8,9 has been almost exclusively reported in families from Spain and Southwest France origin, where a founder effect was established. 9 To our knowledge, this is the first report of a Mexican family with FHHNC and although for the p.Gly20Asp mutation endogamy and a founder effect has been described for the disease parental consanguinity was denied in the family reported herein.…”

“…CLDN19 is expressed with highest levels in the kidney and the eye 2,9 being both, renal and ocular manifestations in the affected sisters in agreement with previous reports. 2,8,9 The above-mentioned endorse the described phenotypic variability, 10 making difficult to define a clear genotype-phenotype correlation. 3 Interestingly, the heterozygous mother, although did not exhibited clinical and ultrasound manifestations of renal disease, showed a significant hypercalciuria even higher than their three affected daughters and normal but low reference values of serum magnesium, thus being discarded as a possible donor.…”

Claudins in Renal Physiology and Pathology

“…Patients with CLDN19 mutations frequently display severe ocular abnormalities (myopia, pigmentary retinitis, macular coloboma, strabismus, astigmatism, nystagmus, macular scars, macular degeneration, anisocoria, retinochoroiditis) [50,51,57,58,68], contrasting with milder and rarer ocular abnormalities reported with CLDN16 mutations (strabismus, myopia, astigmatism, hypermetropia) [45]. CLDN19 is expressed in human fetal retinal pigment epithelium; claudin 19 may be involved in the development and the function of retinal pigment epithelium and retinal neurogenesis [69,70].…”

AsPNA

“…Acute kidney injury occurred in 1.4 % of the patients. Al-Shibli et al described a novel missense mutation (Arg81Cys) in the claudin-19 gene in three female siblings with familial hypomagnesemia with hypercalciuria and nephrocalcinosis, who presented with nephrocalcinosis and myopia [155].…”