Atypical phenotype of type I Bartter syndrome accompanied by focal segmental glomerulosclerosis

Abstract

Type I Bartter syndrome (BS) is caused by mutations of the Na-K-2Cl cotransporter (NKCC2)-encoding SLC12A1 gene. The clinical phenotype of this severe form of BS is characterized by polyhydramnios, premature delivery, failure to thrive, and nephrocalcinosis, and the diagnosis is usually made during the antenatal-neonatal period. This report concerns a 29-year-old Japanese man with atypical type I BS due to a compound heterozygous mutation of the SLC12A1 gene. He was born after full-term pregnancy complicated by polyhydramnios. He first presented with asymptomatic proteinuria at the age of 20 years and was diagnosed with BS based on laboratory data. There were signs of moderate proteinuria, mild renal dysfunction and nephrocalcinosis. Renal biopsy showed focal segmental glomerulosclerosis (FSGS), and genetic testing revealed novel mutations of A555V and G809V in the SLC12A1 gene. The patient's sister showed the same clinical course, laboratory test abnormalities and gene mutations. Our patient had a type I BS with an atypical clinical course, which was diagnosed when he was 20 years old. Laboratory findings indicated phenotypic variability in this disease, and the presence of nephropathy suggested that FSGS might be one of the lesions causing end-stage renal failure in this disease.

A patient with Dent disease and features of Bartter syndrome caused by a novel mutation of CLCN5

“…It has been proposed that increased RAS activity and elevated angiotensin II contribute to the development of glomerulosclerosis [11]. Indeed, several patients with Bartter syndrome developed FGS [11,13]. These findings suggest that patients with Dent disease with features of Bartter syndrome may be susceptible to progression to renal dysfunction.…”

Focal segmental glomerulosclerosis in a boy with Dent-2 disease

“…There are several reports of FSGS associated with Dent-1 [1], Lowe syndrome [3], Gitelman syndrome [4], Bartter syndrome [5], and inherited distal renal tubular acidosis, all of which indicate that tubular dysfunction may cause FSGS as suggested by Copelovitch et al…”

A patient with Bartter syndrome accompanying severe growth hormone deficiency and focal segmental glomerulosclerosis

“…The other interesting point in our patient was the presence of nephrotic-range proteinuria. In the literature, there are limited numbers of patients with Bartter or Gitelman syndrome who also had proteinuria [6,10,16]. Six of them showed FSGS in renal biopsy as well as juxtaglomerular apparatus hyperplasia, interstitial fibrosis, and vascular wall hypercellularity, as expected in Bartter or Gitelman syndrome [6,[17][18][19].…”

“…In the literature, there are limited numbers of patients with Bartter or Gitelman syndrome who also had proteinuria [6,10,16]. Six of them showed FSGS in renal biopsy as well as juxtaglomerular apparatus hyperplasia, interstitial fibrosis, and vascular wall hypercellularity, as expected in Bartter or Gitelman syndrome [6,[17][18][19]. Suggested pathogenetic mechanisms of proteinuria and FSGS are stimulation of the renin-angiotensin system activation (RAS) and increased angiotensin II in response to chronic hyperfiltration due to salt-losing nephropathy [6,16,20].…”

“…The third type, the most severe, involves combined loop and distal convoluted tubule dysfunction and is now referred to as antenatal Bartter syndrome with sensorineural deafness. Molecular genetic studies show that five genes are responsible for these diseases, which lead, directly or indirectly, to either transporter or channel loss of function [4][5][6][7].…”