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bartter syndrome ( bs ) , first described by bartter and colleagues in 1962 , is a group of rare autosomal recessive disorders , characterized by renal salt wasting , normal blood pressure , hypokalemic metabolic alkalosis with hyperreninemic hyperaldosteronism , and hyperplasia of the juxtaglomerular apparatus1 ) .
it is caused by impairment in sodium chloride reabsorption in the medullary thick ascending limb of the loop of henle , and is characterized by its genetic and phenotypic heterogeneity2 ) .
bs is clinically categorized as antenatal bs and classic bs , and also categorized into 5 genetic subtypes .
underlying mutant genes for bs types i through v are the slc12a1 gene encoding the sodium - potassium - chloride cotransporter ( nkcc2 ) for type i , the kcnj1 gene encoding the apical inwardly rectifying potassium channel ( romk ) for type ii , the clcknb gene encoding the basolateral chloride channel ( clc - kb ) for type iii , the bsnd gene encoding the -subunit for clc - ka and clc - kb for type iv , and the casr gene encoding the basolateral calcium sensing receptor for type v3 ) . in a nationwide cohort for korean children with bs ,
clcnkb mutations have been reported to be most common mutations , and there was no evidence of genotype - phenotype correlation3 ) . in a cohort study , the korean pediatric patients with clcnkb mutations manifested from antenatal bs to mixed bartter - gitelman phenotypes3 ) .
in other populations , it has been also known that the clinical phenotype in patients with clcnkb mutations can be highly variable , and clinical overlap of symptoms between bs and gitelman syndrome ( gs ) is observed45 ) .
we identified a novel missense mutation in clcnkb in a korean patient with atypical manifestations including severe chronic hypomagnesemia , hypokalemia , and hypercalciuria with nephrocalcinosis .
a 10-year - old male patient was referred to our hospital due to persistent hypokalemia and hypomagnesemia .
he was born at 39 weeks gestational age by normal spontaneous vaginal delivery with a birth weight of 3,500 g. he had a family history significant for chronic hepatitis b in his mother and a cousin who underwent heart transplantation for unknown reasons .
his height and weight were in the 50th percentile , and blood pressure was within normal range . neurologic examination showed no abnormalities .
however , laboratory and imaging findings showed severe hypomagnesemia , hypokalemia , hypocalcemia with hypercalciuria , elevated renin and aldosterone levels , and bilateral nephrocalcinosis .
renal wasting of magnesium and potassium was suspected , but an exact diagnosis was not made . since then , he had been treated with oral potassium and magnesium supplements , amiloride , and spironolactone for 6 years . despite oral and intermittent intravenous magnesium supplements
genetic testing for familial hypomagnesemia with hypercalciuria and nephrocalcinosis ( fhhnc ) performed after 3 years of treatment was negative . at the age of 10 years , he was transferred to our hospital due to acute heart failure .
he was diagnosed with acute myocarditis , and was managed with veno - arterial extracorporeal membrane oxygenation ( va - ecmo ) for 13 days .
fortunately , his cardiac function recovered , though a definite etiology for the acute myocarditis was not identified .
after successful weaning off of ecmo , he was transferred to the general ward and our pediatric nephrology department was consulted for evaluation of his chronic , persistent hypokalemia and hypomagnesemia .
his height was 145 cm ( 50th percentile ) and body weight 36.5 kg ( 50th percentile ) .
mmol / l , potassium 3.2 mmol / l , and total co2 20.2 mmol / l .
magnesium 1.1 meq / l , blood urea nitrogen 6.7 mg / dl , creatinine 0.32 mg / dl .
urine specific gravity was 1.007 and there was no hematuria or proteinuria . in the spot urine sample ,
tubular resorption of phosphate was 92.5% and the transtubular potassium gradient was 14.48 in spite of persistent hypokalemia .
his clinical findings suggested a diagnosis of inherited renal tubulopathy , but his clinical manifestations were not straightforward , leading to confusion with regard to the subgroup diagnosis : bs type iii , bs type v , gs or fhhnc were all suspected .
after a thorough history taking , we discovered his antenatal history of polyhydramnios , which favored a diagnosis of bs type iii . ultimately , we analyzed the causative genes for bs type iii , bs type v , gs and fhhnc ( clcnlkb , casr , slc12a3 , and cldn16 , respectively ) .
while the genetic studies for cldn16 , slc12a3 and casr were all negative , a heterozygous mutation in the clcknb gene was detected ; c.139g > a causing p.gly(ggg)465glu(gag ) in exon 13 ( fig .
this is not a known mutation of the clcknb gene , and his clinical findings and in silico prediction suggested that this would very likely be pathogenic .
the online programme  polyphen-2  classifies this amino acid exchange as probably damaging with a score 0.997 ( sensitivity , 0.41 ; specificity , 0.98 ) . after genetic confirmation of the diagnosis of bs type iii , indomethacin therapy was started at a dosage of 0.05 mg / kg / day , and gradually increased up to 0.2 mg / kg / day without significant side effects .
oral magnesium and potassium supplements were maintained as well , with regular follow - up of laboratory tests and growth parameters .
the present study was performed in accordance with the ethical standards of the institutional review board and with the helsinki declaration .
according to the related defective genes , inherited renal tubular disorders associated with impaired renal conversion of salt , calcium , and magnesium are classified as bs , gs , isolated renal magnesium loss or fhhnc , and these disorders exhibit a broad spectrum of clinical pictures , often overlapping one another3 ) .
apart from bs , gs , and fhhnc were two other important hereditary tubulopathies included in the differential diagnosis in this case .
fhhnc ( omim248250 ) is caused by mutations in the cldn16 or cldn19 gene encoding the tight junction proteins , claudin-16 and claudin-19 , respectively678 ) .
a complete loss - of - function mutation of the cldn16 gene is known to be associated with a more rapid decline in renal function9 ) .
our patient had been initially suspected as having fhhnc , but after his referral to our hospital and being newly informed about the antenatal history of polyhydramnios , we suspected bs as the most likely diagnosis .
while the antenatal history of polyhydramnios , early age of onset , hypercalciuria , and nephrocalcinosis were all more compatible with bs , our patient also manifested persistent hypomagnesemia , one of the typical characteristics that distinguishes gs from other tubulopathies .
a number of previous studies point out that hypomagnesemia is present in almost all cases of gs , and is rare or absent in bs1011 ) . in our patient ,
severe hypomagnesemia was persistent in spite of the supplementation of magnesium and resulted in clinical symptoms .
after the genetic diagnosis , oral indomethacin was given to the patient , and hypomagnesemia was improved with reduced dose of magnesium supplementation .
bs type iii ( omim607364 ) , often known as classic bs , is caused by the dysfunction of clc - kb at the basolateral membrane of the thick ascending limb10 ) . among other types of inherited tubulopathies
, it comprises the most heterogeneous clinical presentation , as compared to gs phenotypes11 ) .
there was a report of a novel missense mutation of clcnkb in a japanese patient of gitelman - like phenotype with diuretic insensitiviry to thiazide administration4 ) .
a diuretic test using furosemide and thiazide as well as clinical findings has been used to make a differential diagnosis between bs and gs , but there were some reports that showed the discrepancies between the diuretic test and genotype45 ) .
the heterogeneity of bs type iii is probably attributed to the diversity in genetic defects and to the possible cooperation of clc - kb with other cotransporters and/or channels1011 ) .
andrini et al.10 ) described functional consequences of clcknb mutations and suggested that all clc - kb mutants show impaired membrane expression , and a minority of the mutants combine with a reduced expression and with an altered ph - dependent channel gating .
the cooperation of clc - kb with other membrane proteins such as the clc - ka chloride channel or potassium - chloride cotransporter in the basolateral membrane of thick ascending limb epithelial cells has also been proposed as evidence for phenotypic variation1012 ) .
there was a report a patient with bs type iii caused by a novel mutation and single nucleotide polymorphisms ( snps ) in clcnkb gene , and there is a possibility that a clcnkb mutation combined with snps can cause the atypical clinical findings in bs13 ) .
together , these findings suggest that the clinical distinction of inherited tubular disorders is not clear - cut and that the correlation between the underlying genetic mutation and the clinical phenotype is not universal . the phenotypic variation of hereditary tubular disorders has been consistently discussed over the past few decades , and there have been debates on how to clinically distinguish them from one another .
although it has been widely accepted that bs type iii most commonly presents as classical bs , it may exhibit heterogeneous phenotypes overlapping with gs or fhhnc in a minority of patients , probably owing to variable functional consequences of mutations and the channel 's possible interplay with other membrane cotransporters and channels10 ) .
herein , we described our experience with such a case ; a pediatric patient with atypical clinical findings caused by a novel clcnkb gene mutation .
bartter syndrome ( bs ) is an inherited renal tubular disorder characterized by low or normal blood pressure , hypokalemic metabolic alkalosis , and hyperreninemic hyperaldosteronism . 
 type iii bs is caused by loss - of - function mutations in clcnkb encoding basolateral clc - kb . 
 the clinical phenotype of patients with clcnkb mutations has been known to be highly variable , and cases that are difficult to categorize as type iii bs or other hereditary tubulopathies , such as gitelman syndrome , have been rarely reported . 
 we report a case of a 10-year - old korean boy with atypical clinical findings caused by a novel clcnkb mutation . 
 the boy showed intermittent muscle cramps with laboratory findings of hypokalemia , severe hypomagnesemia , and nephrocalcinosis . 
 these findings were not fully compatible with those observed in cases of bs or gitelman syndrome . 
 the clcnkb mutation analysis revealed a heterozygous c.139g > a transition in exon 13 [ p.gly(ggg)465glu(gag ) ] . 
 this change is not a known mutation ; however , the clinical findings and in silico prediction results indicated that it is the underlying cause of his presentation .