Isolated nephrocalcinosis due to compound heterozygous mutations in renal outer medullary potassium channel

Abstract

Identification of a monogenic etiology is possible in a proportion of patients with childhood-onset nephrolithiasis or nephrocalcinosis. Bartter syndrome (BS), a hereditary tubulopathy characterized by polyuria, hypokalemic alkalosis and growth retardation that rarely presents with isolated nephrocalcinosis. Patients with defect in renal outer medullary potassium channel, encoded by the KCNJ1 gene causing BS type 2, typically present during the neonatal period. We describe a 14-yearold girl with mild late-onset BS type 2 with reported pathogenic compound heterozygous variations in exon 2 of KCNJ1 (c.146G > A and c.657C > G). This patient presented with isolated medullary nephrocalcinosis due to hypercalciuria; absence of hypokalemia and metabolic alkalosis was unique. This case highlights the importance of screening the KCNJ1 gene in patients with hypercalciuria and nephrocalcinosis, even in older children.

Whole-exome sequencing and variant spectrum in children with suspected inherited renal tubular disorder: the East India Tubulopathy Gene Study

“…Interestingly NC2 presented with only nephrocalcinosis and hypercalciuria and the diagnosis was purely based on genetic testing. The LP homozygous variant identified in NC2 (c.146G>A) had been previously reported in a similar case report of isolated nephrocalcinosis and hypercalciuria from India albeit in a compound heterozygous form (c.146G>A and c.657C>G) [35]. Although our numbers were small, larger international cohorts of paediatric stone disease / nephrocalcinosis have also shown similar diagnostic yield from genetic testing, ranging between 7 to 30 % [36,37].…”

Impact of claudin‐10 deficiency on amelogenesis: Lesson from a HELIX tooth

“…For example, the alteration of the K + ‐dependent Na + /Ca 2+ exchanger isoform 4 ( SLC24A4 ) into mouse maturation ameloblasts by an excess of fluoride in the drinking water was shown to impair amelogenesis 89 . Furthermore, patients with syndromes associated with hypokalemia, such as the Bartter's syndrome, were reported to display Amelogenesis imperfecta 90,91 . It is, therefore, likely that the hypokalemia measured in the patients with the HELIX syndrome may contribute to higher enamel fragility.…”

“…89 Furthermore, patients with syndromes associated with hypokalemia, such as the Bartter's syndrome, were reported to display Amelogenesis imperfecta. 90,91 It is, therefore, likely that the hypokalemia measured in the patients with the HELIX syndrome may contribute to higher enamel fragility.…”

A novel mutation of KCNJ1 identified in an affected child with nephrolithiasis

“…The channel is gated by intracellular pH in the neutral range and reach half-maximal activation at a pH of 6.8. The gating is driven by the protonation of lysine within KRR [ 10 ], which is assembled by amino acid residues at positions 22, 61, and 292 in the transmembrane region [ 7 ]. Structural disturbance of KRR shifts the pKa of the lysine residue away from the neutral pH range and leads to channel inactivation.…”