Bartter syndrome, an autosomal recessive congenital disorder of renal tubular function, is characterized by hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronism [1], and can be classified into five sub‐types based on the causal gene. Type I Bartter syndrome (MIM #601678) is caused by pathogenic variants of the SLC12A1 gene, which encodes the furosemide‐sensitive Na+‐K+‐2Cl− cotransporter expressed in the thick ascending limb of the loop of Henle [1]. Neonates affected by this disorder typically present with polyuria, vomiting, dehydration, and electrolyte imbalances, for which genetic testing can enable a definitive diagnosis [1].
During pregnancy, fetal polyuria can lead to polyhydramnios, and previous reports have indicated that elevated chloride (Cl) concentrations [1] and reductions in the levels of alpha‐fetoprotein (AFP) in amniotic fluid [2] may aid in prenatal diagnosis. Herein, we report two patients in which fetal Bartter syndrome was suspected based on polyhydramnios and characteristic amniotic fluid findings, thereby facilitating early postnatal genetic confirmation.
Case 1 is that of a 30‐year‐old primigravida with congenital hearing loss, who had been treated for sub‐clinical hypothyroidism. Polyhydramnios (amniotic fluid index [AFI], 38 cm) was detected at 25 weeks of gestation, and she was referred at 26 weeks. Ultrasonography revealed severe polyhydramnios (Figure S1A) with normal fetal anatomy, and there was no evidence of abnormalities in maternal glucose metabolism. Intravenous ritodrine hydrochloride was administered to treat pre‐term labor. At 30 weeks, the AFI had increased to 55 cm, necessitating five sessions of amnioreduction by 33 weeks, with a total of 10 900 mL of fluid being removed. Analysis of the amniotic fluid revealed elevated levels of Cl (118 mmol/L; reference: 106–114 mmol/L) and reductions in the levels of AFP (358 ng/mL; median at 32 weeks: approximately 1000 ng/mL) [3], findings taken to be indicative of fetal Bartter syndrome (Table 1). At 33 weeks, amniotic membrane separation had extended to the umbilical cord insertion, raising concerns regarding compromised circulation, and thereby prompting emergency cesarean section, delivering a 2160 g male infant with Apgar scores of 9 at 1 and 5 min. Postnatally, the neonate developed polyuria, hyponatremia, hypomagnesemia, and hypokalemia. Genetic analysis identified compound heterozygous SLC12A1 variants [NM_000338.2:c.1522G>A: p.(Ala508Thr) and c.2095delG: p.(Asp699Thrfs*2)]. The variant c.1522G>A has previously been reported as likely pathogenic, and c.2095delG as pathogenic, confirming the infant's diagnosis of type I Bartter syndrome [4, 5].
TABLE 1.
Amniotic fluid biochemistry of the two patients.
| Case | Sampling GA (weeks) | Cl (mmol/L) | AFP (ng/mL) | Total protein (g/dL) | γ‐GTP (IU/L) |
|---|---|---|---|---|---|
| 1 | 32w3d | 118 a | 358 b | 0.3 a | 1640 a |
| 2 | 25w4d | 118 a | 1515 c | 0.5 a | 2280 a |
Reference ranges: Cl, 106–114 mmol/L; total protein, > 1.0 g/dL; γ‐GTP, varies by gestational age.
Median at 32 weeks: AFP, ~1000 ng/mL.
Median at 25 weeks: AFP, ~12 000 ng/mL.
Case 2 is that of a 24‐year‐old primigravida with no relevant history, who presented with polyhydramnios (AFI: 35 cm). Following the initiation of ritodrine, she was transferred to our institution, with subsequent ultrasonography revealing severe polyhydramnios (Figure S1B) with a normal fetal anatomy. Similarly, maternal glucose metabolism was established to be normal. Between gestational weeks 25 and 27, the patient underwent three sessions of amnioreduction, collectively removing 6950 mL of fluid. Amniotic fluid analysis revealed elevated levels of Cl (118 mmol/L) and reductions in those of AFP (1515 ng/mL; median at 25 weeks: ~12 000 ng/mL) [3], thereby providing evidence of fetal Bartter syndrome (Table 1). At 27 weeks, profuse genital bleeding occurred following amnioreduction, and detection of placental abruption upon ultrasonography prompted emergency cesarean section, with delivery of a 968 g male infant with Apgar scores of 9 at 1 and 5 min. Postnatally, the neonate developed polyuria, hyponatremia, and hypokalemia, with genetic analysis revealing the presence of the compound heterozygous SLC12A1 variants c.2095delG: p.(Asp699Thrfs*2) and c.864 + 1G>A, the former of which has previously been reported to be pathogenic [5], and the latter is classified as pathogenic according to the ACMG/AMP guidelines (PVS1, PM2, PM3, and PP3). On the basis of these findings, the patient was diagnosed with type I Bartter syndrome.
1. Discussion
These patients serve to highlight the clinical utility of biochemical analyses of amniotic fluid in instances of unexplained severe polyhydramnios. Elevated levels of chloride and reductions in those of AFP are considered indicative of fetal Bartter syndrome, thereby facilitating targeted postnatal genetic testing and early confirmation. These abnormalities are assumed to reflect an excessive loss of fetal urinary electrolytes attributable to impaired tubular salt reabsorption. Analyses of amniotic fluid may also aid in differentiating Bartter's syndrome from other causes of polyhydramnios. For example, in esophageal atresia, impaired fetal swallowing results in markedly elevated levels of total protein and γ‐glutamyl transpeptidase (γGTP), along with higher AFP values [6]. Neural tube defects are similar associated with higher levels of AFP and detectable acetylcholinesterase [7]. In contrast, the combination of elevated levels of chloride and relatively low levels of AFP, as observed in the present patients, reflects the distinct pathophysiology of fetal Bartter syndrome.
In both the patients reported herein, prenatal suspicion contributed to influencing the course of management, which necessitated repeated amnioreduction and close monitoring. Awareness of the underlying mechanisms has prompted surveillance for complications related to uterine overdistension, including preterm labor, placental abruption, and umbilical cord compromise. Although no established prenatal treatment exists, the postnatal management of Bartter syndrome differs from that of gastrointestinal obstructive disorders. Early prenatal recognition facilitates appropriate postnatal care and timely decision making.
This study was limited with respect to its small sample size and the fact that amniotic fluid abnormalities are not specific to Bartter syndrome. Nevertheless, when severe polyhydramnios is accompanied by elevated levels of chloride and comparatively low levels of AFP, fetal Bartter syndrome should be considered. In such patients, analysis of amniotic fluid is a practical approach with implications for prenatal counseling, perinatal management, and early diagnostic planning.
Funding
The authors have nothing to report.
Ethics Statement
Ethical approval to report these patients was obtained from the Ethical Review Committee of Yamagata University Faculty of Medicine (approval number: 2021‐S‐93).
Consent
We obtained written informed consent from both patients for the publication of their patients.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Figure S1: Transabdominal ultrasound images obtained in Case 1 (A) and Case 2 (B), for which the maximum vertical pockets were 10.0 and 9.3 cm, respectively, indicating polyhydramnios in both patients.
Acknowledgments
We are grateful to Dr. Kandai Nozu, professor of the Department of Pediatrics, Kobe University Graduate School of Medicine, for helping with genetic analysis.
Data Availability Statement
The data underlying this article cannot be shared publicly due to patient privacy concerns. De‐identified data are available from the corresponding author upon reasonable request.
References
- 1. Bhat Y. R., Vinayaka G., and Sreelakshmi K., “Antenatal Bartter Syndrome: A Review,” International Journal of Pediatrics 2012 (2012): 857136, 10.1155/2012/857136. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Garnier A., Dreux S., Vargas‐Poussou R., et al., “Bartter Syndrome Prenatal Diagnosis Based on Amniotic Fluid Biochemical Analysis,” Pediatric Research 67, no. 3 (2010): 300–303, 10.1203/PDR.0b013e3181ca038d. [DOI] [PubMed] [Google Scholar]
- 3. Kim C. K. and Yang Y. H., “Alpha‐Fetoprotein Values in Maternal Serum and Amniotic Fluid for Prenatal Screening of Genetic Disorders,” Yonsei Medical Journal 28, no. 3 (1987): 218–227, 10.3349/ymj.1987.28.3.218. [DOI] [PubMed] [Google Scholar]
- 4. Vargas‐Poussou R., Feldmann D., Vollmer M., et al., “Novel Molecular Variants of the Na‐K‐2Cl Cotransporter Gene Are Responsible for Antenatal Bartter Syndrome,” American Journal of Human Genetics 62, no. 6 (1998): 1332–1340, 10.1086/301872. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Nozu K., Iijima K., Kawai K., et al., “In Vivo and In Vitro Splicing Assay of SLC12A1 in an Antenatal Salt‐Losing Tubulopathy Patient With an Intronic Mutation,” Human Genetics 126, no. 4 (2009): 533–538, 10.1007/s00439-009-0697-7. [DOI] [PubMed] [Google Scholar]
- 6. Czerkiewicz I., Dreux S., Beckmezian A., et al., “Biochemical Amniotic Fluid Pattern for Prenatal Diagnosis of Esophageal Atresia,” Pediatric Research 70, no. 2 (2011): 199–202, 10.1203/PDR.0b013e318220c08a. [DOI] [PubMed] [Google Scholar]
- 7. Darouich A. A., Liehr T., Weise A., et al., “Alpha‐Fetoprotein and Its Value for Predicting Pregnancy Outcomes—A Re‐Evaluation,” Journal of Prenatal Medicine 9, no. 3–4 (2015): 18–23, 10.11138/jpm/2015.9.3.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: Transabdominal ultrasound images obtained in Case 1 (A) and Case 2 (B), for which the maximum vertical pockets were 10.0 and 9.3 cm, respectively, indicating polyhydramnios in both patients.
Data Availability Statement
The data underlying this article cannot be shared publicly due to patient privacy concerns. De‐identified data are available from the corresponding author upon reasonable request.