Late-Onset Bartter Syndrome Type II Due to a Novel Compound Heterozygous Mutation in KCNJ1 Gene: A Case Report and Literature Review.

Background: Bartter syndrome (BS) type II is a rare autosomal recessive renal tubular disorder caused by mutations in the KCNJ1 gene, which encodes the apical renal outer medullary potassium (ROMK) channel in the thick ascending limb (TAL) of Henle's loop. BS type II is typically considered as a disorder of infancy and seldom seen in adults. Case Presentation: A 34-year-old woman was admitted with generalized body numbness and hand convulsions, without growth retardation. Laboratory tests revealed hypokalemic metabolic alkalosis, hyperreninemic hyperaldosteronism, and nephrocalcinosis. She was misdiagnosed during the initial diagnosis process and was finally diagnosed with late-onset BS type II via genetic testing through next-generation sequencing combined with Sanger sequencing. A novel compound heterozygous p.Leu207Ile/p. Cys308Arg variant in exon 5 of the KCNJ1 gene from her parents was identified and speculated to be a potential pathogenic gene variation. Conclusion: We report a case of late-onset BS type II with a novel compound heterozygous mutation in KCNJ1. Both variants are novel and have never been reported. Our report will have a significant impact on the diagnosis of BS in other patients without typical clinical presentations and emphasizes the importance of genetic investigation.

Hypocalcemia as the Initial Presentation of Type 2 Bartter Syndrome: A Family Report.

CONTEXT: Bartter syndrome (BS) is a group of rare autosomal-recessive tubulopathies characterized by hypokalemic, hypochloremic metabolic alkalosis in which the primary defect is a deficiency of transporters involved in sodium chloride reabsorption. Type 2 BS results from a defect in the renal outer medullary potassium channel encoded by the KCNJ1 gene. Type 2 BS presents with polyhydramnios, intrauterine growth retardation, prematurity, failure to thrive, polyuria, hypercalciuria, and life-threatening episodes of dehydration. Hypocalcemia is a very rare presenting symptom of BS, with only a few published cases reporting it as the initial manifestation of type 2 BS. OBJECTIVE: To describe a child who presented with hypocalcemic seizure at the age of 2.3 years that was first related to vitamin D deficiency and high-phosphate soft drink consumption. METHODS: Whole exome sequencing (WES) was used to evaluate the biochemical abnormalities of the proband. RESULTS: We identified a previously described homozygous missense mutation c.212C>T, p.T71M in the KCNJ1 gene associated with type 2 BS. Six additional family members with the same mutation and diagnosed clinically with BS are also reported, 2 presenting with hypocalcemia associated with vitamin D deficiency. CONCLUSION: This report expands the clinical spectrum associated with KCNJ1 mutations and emphasizes the role of WES in unsolved cases of hypocalcemia when genetic disease is suspected. It also highlights the hazardous effects of phosphate-containing soft drinks on calcium metabolism.

Eight novel KCNJ1 variants and parathyroid hormone overaction or resistance in 5 probands with Bartter syndrome type 2.

PURPOSE: Bartter syndrome type 2 (BS2) is an autosomal recessive renal tubular disorder, which is caused by the mutations in KCNJ1. This study was designed to analyze and describe the genotype and clinical features of five Chinese probands with BS2. METHODS: Identify KCNJ1 gene variants by the next generation sequencing and evaluate their mutation effects according to 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines. RESULTS: Ten variants including eight novel ones of KCNJ1 gene were found, the most common type was missense variant. The common symptoms and signs from high to low incidence were: polydipsia and polyuria (5/5), one of them (1/5) presented with diabetes insipidus; maternal polyhydramnios and premature delivery (4/5); growth retardation (3/5). Two patients presented with hypochloremic metabolic alkalosis and hypokalemia; whereas the acid-base disturbance was absent in the others. One patient had evident parathyroid hormone (PTH) resistance (hypocalcemia, hyperphosphatemia and markedly elevated PTH levels), three presented with PTH overacting (hypercalcemia, hypophosphatemia and mild elevated PTH levels), and one showed normal blood calcium and phosphorus concentrations with high-normal PTH levels. All patients had nephrocalcinosis and/or hypercalciuria, and one of them complicated with nephrolithiasis. Indomethacin has significant therapeutic effect on the growth retardation, polydipsia and polyuria and treatment was associated with a decrease in urine calcium excretion, normalization of electrolyte disturbance and PTH parameters. CONCLUSIONS: Ten variants of KCNJ1 gene were identified in five Chinese probands. These patients had atypical BS phenotype lacking evident metabolic alkalosis and/or manifesting with PTH overaction/resistance, which reminds clinicians to carefully differentiate BS2 with other parathyroid disorders. This is the first report of BS2 from Chinese populations.

Mutation analysis of KCNJ1 gene and investigation of phenotype in 5 Chinese patients with Bartter syndrome type 2 / 中华肾脏病杂志

Objective@#To identify and analyze the variants of the KCNJ1 gene in five Chinese patients with Bartter syndrome type 2 (BS2), and to describe their clinical features as well as treatment results.@*Methods@#Data and blood samples of five BS2 patients and their relatives confirmed by Qingdao Municipal Hospital from June 2012 to January 2019 were collected. Whole-exome-sequencing (WES) based on the second generation high throughput sequencing was performed to detect variants. The 2015 American College of Medical Genetics and Genomics Standards and Guidelines were applied to analyze the pathogenicity of the variants. The clinical features and laboratory results were retrospectively studied. The response to treatment and follow-up data were reviewed.@*Results@#Ten variants including six novel ones of KCNJ1 gene were identified through WES and verified by Sanger dideoxy sequencing. Missense variants accounted for the highest proportion. The common symptoms and signs of five BS2 patients from high to low incidence were polydipsia and polyuria (5/5), one of them (1/5) presented with diabetes insipidus; maternal polyhydramnios and premature delivery (4/5); growth retardation (3/5). Initially, two patients presented with hypochloremic metabolic alkalosis and hypokalemia, whereas the acid-base disturbance was absent in the others. One patient experienced hyperkalemia. In terms of calcium-phosphorus metabolism, one patient had evident parathyroid hormone (PTH) resistance (hypocalcemia, hyperphosphatemia and markedly elevated serum intact PTH levels), three presented with PTH overacting (hypercalcemia, hypophosphatemia and mild elevated serum intact PTH levels), and one showed normal blood calcium and phosphorus concentrations with high-normal serum intact PTH levels. All patients had nephrocalcinosis or hypercalciuria, and one of them complicated with nephrolithiasis. Indomethacin helped to correct the growth retardation, halt polydipsia polyuria, decrease the elevated urinary calcium excretion, and normalize electrolyte disturbance as well as PTH parameters in some patients.@*Conclusions@#This investigation identifies ten variants of KCNJ1 gene, including six ones that have not been previously reported, which will enrich the human gene mutation database (HGMD). These patients in our study have atypical BS phenotype, so that careful differentiation from other parathyroid diseases will be required for clinicians.