An Unusual Case of BSND Gene–Related (Type IV) Bartter Syndrome Presenting as Antenatal Bartter Syndrome: A Case Report and Review of Literature : Maternal-Fetal Medicine

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Case Report

An Unusual Case of BSND Gene–Related (Type IV) Bartter Syndrome Presenting as Antenatal Bartter Syndrome: A Case Report and Review of Literature

Shajan, Aleena M.1; Kumar, Manish2; Navaneethan, Preethi1; Danda, Sumita3; Beck, Manisha M.1,∗

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Maternal-Fetal Medicine ():10.1097/FM9.0000000000000182, January 26, 2023. | DOI: 10.1097/FM9.0000000000000182
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Polyhydramnios is diagnosed when the amniotic fluid index in singleton pregnancies exceeds 25 cm or is greater than 95th centile for the gestational age. Causes of polyhydramnios include the presence of congenital fetal anomalies (eg, anencephaly and cleft palate), multiple gestation, maternal diabetes, placental tumors, and fetal anemia. The prevalence of polyhydramnios is 1% to 2%, and it is associated with adverse perinatal outcomes including preterm labor and prematurity.

In 30% to 60% of cases, the cause of polyhydramnios is not known.1 Antenatal Bartter syndrome is a rare autosomal recessive disorder of the renal tubules, resulting in early-onset severe polyhydramnios. Bartter syndrome affects the transport of sodium chloride in the fetal thick ascending loop of Henle and distal convoluted tubule.2 This, in turn, leads to fetal urinary losses of sodium, potassium, and chloride. Fetal polyuria due to salt wasting leads to polyhydramnios. Treatment is challenging needing lifelong fluid and electrolyte replacement and the use of nonsteroidal anti-inflammatory drugs, such as indomethacin.3 Written consent to publish the clinical information in the journal was received.

Case presentation

A 28-year-old gravida 3, para 2, living 1 and stillbirth 1 pregnant woman presented at 10 weeks for routine antenatal care. This was a consanguineous couple whose first pregnancy was uneventful, with the delivery of a baby boy weighing 3.24 kg, who remains healthy. In her second pregnancy, she experienced preterm labor at 26 weeks because of severe polyhydramnios and delivered a fresh stillborn baby boy weighing 0.970 kg. There were no fetal anomalies on scan or on gross examination of the stillborn baby.

In the couple’s third and current pregnancy, the first trimester dating scan corresponded to her dates. At 20 weeks of gestation, a morphology scan was performed and reported as normal. The patient’s glucose tolerance test at 22 weeks was also normal.

At 23 weeks of gestation, clinical examination was suspicious of polyhydramnios, so a follow-up ultrasound was performed, which showed an amniotic fluid index of 30 cm. Fetal biometry corresponded to the gestational age, and there were no gross fetal anomalies to explain the polyhydramnios. The placenta appeared normal, ruling out the presence of a chorioangioma. Peak systolic velocity of the middle cerebral artery was not suggestive of fetal anemia. A glucose tolerance test was subsequently repeated and was normal.

In view of the unexplained polyhydramnios, antenatal Bartter syndrome was suspected. During counseling, it was explained that a genetic defect in the fetus was the likely cause of the polyhydramnios and the need for a fetal DNA analysis was stressed for confirmatory diagnosis. The parents rejected genetic testing at that time because of financial constraints but consented for fetal DNA banking along with biochemical evaluation of the amniotic fluid.

Amniocentesis was performed and an amniotic fluid sample was collected to carry out a chloride blood test. Fetal DNA was extracted from the fluid and was banked. Amniotic fluid chloride levels were found to be elevated at 119 mmol/L (95–105 mmol/L). Maternal urine spot chloride levels were also found to be elevated at 360 mmol/L (98–107 mmol/L). A provisional diagnosis of fetal Bartter syndrome was made.

Indomethacin, 200 mg/d orally, was commenced to prevent the onset of preterm labor from 25 weeks onwards. Serial scans were run to check amniotic fluid index levels, fetal growth, and cervical length. Maternal urine spot chloride levels started showing a downward trend (187 mmol/L). From 28 weeks onward, close fetal surveillance was commenced and maintained using serial scans, to rule out constriction of the ductus arteriosus (as the patient was on indomethacin). Indomethacin was stopped at 31 weeks.

The patient presented with threatened preterm labor at 32 weeks. Two doses of antenatal steroids were given to accelerate fetal lung maturity. At 33 weeks and 2 days, a baby girl was delivered, weighing 1.95 kg and with a good Apgar score. The baby was admitted to the neonatal intensive care unit for monitoring and care. Neonatal urine sodium and chloride levels were high, 118 mmol/L and 120 mmol/L, respectively. Capillary blood gas analysis, however, showed no evidence of hypokalemic hypochloremic metabolic alkalosis.

The couple underwent further genetic counseling, to which the parents agreed, with an emphasis on genetic confirmation of Bartter syndrome by testing the banked fetal DNA. Clinical exome sequencing was performed on the fetal DNA, and maternal cell contamination was simultaneously ruled out. A homozygous single base pair deletion in exon 3 of the BSND gene (barttin CLCNK-type accessory subunit β) (ENST00000651561.1) described as c.452del (p.Pro151LeufsTer27) was identified. This results in a frameshift and premature truncation of the protein at 27 amino acids downstream to codon 151. The observed variation has previously been reported in a patient affected with Bartter syndrome type IV and classified as pathogenic as per American College of Medical Genetics guidelines.4 The parents were counseled regarding the need for parental validation, but it was declined.

The couple were informed about the guarded prognosis of Bartter syndrome type IVa. As parental validation was not performed, a recurrence risk could not be ascertained. However, because the previous pregnancy had displayed a similar presentation, the parents were advised that the probable risk in each pregnancy was 25%.

The baby had polyuria from birth and was managed with nasogastric feeds of 60 mL/kg and intravenous fluids with normal saline at 80 mL/kg. Newborn hearing screening was performed at 24 hours and on day 4, when the baby was diagnosed as having bilateral sensory neural deafness. The baby was discharged with advice for nasogastric tube feeding of 220 mL/(kg ⋅ d) and a repeat audiology screening after 4 weeks.


There are two ways in which Bartter syndrome can present: the antenatal type and the classic type. The antenatal type presents with fetal polyuria, polyhydramnios, and preterm labor. The classic form presents in childhood with failure to thrive and electrolyte imbalances.5

There are 5 subtypes of Bartter syndrome, based on the mutant gene involved. Types I and II, are caused by mutations in the SLC12A2 gene and KCNJ1 gene, respectively. Chloride channel Kidney A and B (CLCNKA and B) are proteins, predominantly expressed in distal nephron segments of the kidney and the inner ear. Type III is less severe than types I and II, it presents later in life, and it is associated with mutation in the CLCNKB gene.5

Type IV is associated with mutations in the BSND gene, causing severe renal tubular dysfunction and sensorineural deafness. The BSND gene encodes the protein barttin, an essential β subunit for these chloride channels. Biallelic pathogenic variants of BSND hamper the function of chloride channels leading to deranged renal salt reabsorption and potassium recycling in the inner ear. Individuals carrying homozygous or compound heterozygous BSND pathogenic variants have an inability to concentrate urine in utero along with sensorineural hearing loss in severe cases. This leads to polyuria and polyhydramnios in antenatal life. Our case, presenting in the antenatal period, was molecular proven type IV Bartter syndrome. Type V is associated with a gain-of-function mutation in the CASR gene, resulting in hypocalcemia and hypomagnesemia.5 Types I and II are typically present antenatally while type IV may present rarely as antenatal Bartter syndrome.6

Diagnosis of antenatal Bartter syndrome is important because it allows the early initiation of appropriate therapy. Indomethacin is known to be effective in controlling polyhydramnios in such cases.7 It is also helpful in protecting the neonate against fluid losses and electrolyte imbalances.8 One of the main concerns with its use, however, is the premature closure of the ductus arteriosus, especially if used beyond 30 to 32 weeks.

Amniotic fluid biochemistry has been used by some for the prenatal diagnosis of Bartter syndrome, especially amniotic fluid chloride levels.9 However, there have been conflicting reports about their utility. Some authors propose the use of maternal urine biochemistry in aiding prenatal diagnosis.7

Here, we identified elevated chloride levels in the amniotic fluid and increased maternal urinary spot chloride levels. Because the parents could not afford genetic diagnosis antenatally, provisional diagnosis was made on the basis of these tests. This helped us initiate indomethacin therapy in the antenatal period. Moreover, on initiation of indomethacin therapy, the maternal urinary spot chloride levels showed a decreasing trend.

Hence, we suggest that amniotic fluid chloride levels can be used as an alternative to genetic testing, for the diagnosis of antenatal Bartter syndrome, especially in low-resource settings where genetic tests are either not available or beyond the reach of parents because of financial constraints. Early diagnosis enables timely initiation of appropriate maternal therapy with indomethacin and guides the fluid and electrolyte management of the newborn. Moreover, the response to therapy can be monitored using maternal urinary spot chloride levels.

The strength of our study is that to the best of our knowledge, this is the first case report of type IV BSND-related Bartter presenting as ABS. A limitation was that we were unable to perform the parental validation test to confirm whether the parents were carriers of the pathogenic variant diagnosed in the neonate.



Conflicts of Interest


Data Availability

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.


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Antenatal Bartter’s syndrome; BSND gene; Sensorineural hearing loss; Polyhydramnios; Prenatal diagnosis; Amnioreduction; Clinical exome sequencing

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