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

Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal disease caused by mutations in genes for the tight junction transmembrane proteins Claudin-16 (CLDN16) and Claudin-19 (CLDN19). We present the first case report of a Mexican family with three affected sisters carrying a p.Gly20Asp mutation in CLDN19 whose heterozygous mother showed evident hypercalciuria and normal low magnesemia without any other clinical, laboratory, and radiological symptoms of renal disease making of her an unsuitable donor. The affected sisters showed variable phenotypic expression including age of first symptoms, renal urinary tract infections, nephrolithiasis, nephrocalcinosis, and eye symptoms consisting in retinochoroiditis, strabismus, macular scars, bilateral anisocoria, and severe myopia and astigmatism. End stage renal disease due to renal failure needed kidney transplantation in the three of them. Interesting findings were a heterozygous mother with asymptomatic hypercalciuria warning on the need of carefully explore clinical, laboratory, kidney ultrasonograpy, and mutation status in first degree asymptomatic relatives to avoid inappropriate kidney donors; an evident variable phenotypic expression among patients; the identification of a mutation almost confined to Spanish cases and a 3.5 Mb block of genomic homozygosis strongly suggesting a common remote parental ancestor for the gene mutation reported.

Claudins in Renal Physiology and Pathology

“…Age at onset ranges from 0 to more to 30 years for CLDN16 [45,49,50,[52][53][54][55][56] and CLDN19 mutations [50,51,57,58] and the diagnosis can be delayed.…”

“…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].…”

“…Histories of nephrolithiasis, nephrocalcinosis, and/or hypercalciuria can be observed in heterozygous family members not affected by FHHNC [45,58,66,67,76] however other causes of these affections are not documented in cases reported.…”

“…However, there is a clinical heterogeneity of disease severity in families even among patients bearing the same CLDN16 [45,62,77,78] and CLDN 19 mutation [58].…”

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis: clinical and molecular characteristics

“…A founder effect has been indicated for the recurrent G20D mutation in Spanish and French families [ 14 , 19 , 37 ]. Recently a Mexican family of Spanish origin with three FHHNC-affected sisters homozygous for this mutation was reported, which suggests a remote common ancestor [ 42 ].…”