Abstract
Bartter's disease, an inherited renal tubular disorder is due to a defect in ion transport across the ascending limb of the loop of Henle leading to failure of the ability of kidneys to concentrate urine and hence polyuria. We present three fetuses of mothers with severe polyhydramnios with normal maternal blood sugar profile, routine Toxoplasma, Rubella, Cytomegalovirus, Herpes (TORCH) serology. The ultrasound showed no structural anomaly in the fetus, but consistent overdistended bladder with severe polyhydramnios was observed without any evidence of obstructive uropathy. The biochemical test on amniotic fluid was suggestive of Bartter's disease in case 1 and borderline in case 2, and next-generation sequencing confirmed a mutation of KCNJ1 associated with Bartter's disease Type II in case 1 and a mutation in SLC21A1 in case 2. Amniotic fluid biochemistry was inconclusive in case 3. A consistent full bladder with severe polyhydramnios with onset around 24 to 25 weeks was a novel finding which was observed due to fetal polyuria and can be used as a clue to investigate cases with severe polyhydramnios with no structural anomaly. Antenatal diagnosis will help in the proper management of child and genetic counseling for the next pregnancy.
Keywords: polyhydramnios, overdistended bladder, Bartter's disease, SLC21A1, KCNJ1
Introduction
Bartter's disease, an inherited disorder in the renal tubule is due to defective reabsorption in the thick ascending loop of Henle, leading to salt-wasting hypokalemia and metabolic alkalosis. 1 Mutations of several genes encoding the transporters involved in salt reabsorption in the ascending loop cause different types of Bartter's disease classified into different subtypes such as Type I—NKCC2 ( SLC12A1 ), Type II—ROMK ( KCNJ1 ), Type III—CLC-Kb ( CLCNKB ), Type IVa—barttin ( BSND ), and Type V— CASR , MAGE-D2 —transient antenatal Bartter's disease. Types I to IV are autosomal recessive (AR) disorders, while Type V is an autosomal dominant inherited disorder. MAGE-D2 causes transient X-linked recessive form of Bartter's disease. 2
Maternal polyhydramnios with premature labor is the most common characteristic of Bartter's disease. Polyhydramnios has an incidence of 1 to 3/100 pregnancies. 3 It is defined as the pathological increase of amniotic fluid volume in pregnancy and is measured either as single deepest pocket >8 cm or the amniotic fluid index (AFI) of more than 95% centile for the gestational age. This phenomenon could be due to maternal gestational diabetes (5–26%) or fetal causes. Among the fetal causes are fetal anomalies (8–45%), fetal infections, fetal anemia (1–15%), and multiple pregnancies (8–10%). 1 In cases with severe polyhydramnios, the chances of the fetal anomaly are high.
We present three fetuses of mothers with severe polyhydramnios in which the ultrasound (US) though was normal but aroused the suspicion of polyuria due to overdistended fetal bladder. Amniotic fluid biochemistry was done in all fetuses. Next-generation sequencing for Bartter's disease was done in cases 1 and 2. This confirmed mutations in both fetuses 1 and 2. Fetus 1 had a homozygous mutation in KCNJ1 and thus confirmed Bartter's disease Type II. Fetus 2 had a homozygous mutation in SLC12A1 and thus confirmed Bartter's disease Type I.
Fetus 1
A 23-year-old G2 P1L0 was referred at 28 weeks of pregnancy with polyhydramnios. This was a spontaneous conception with no history of consanguinity. The patient did not complain of breathlessness or abdominal pain and was on tablet indomethacin (25 mg) orally twice daily. The investigation reports suggested: a negative indirect Coombs test, the blood sugar screening test (Diabetes In Pregnancy Study group India) was 149 mg/dL, although there was a routine blood sugar profile and glycosylated hemoglobin of 4.6%. Venereal disease research laboratory test was nonreactive and immunoglobulin M serology for toxoplasma, cytomegalovirus, and rubella was negative. The US results showed a single live fetus of 28 weeks with an AFI of 34 cm. No structural defect was identified in the fetus. However, the bladder of the fetus was consistently overdistended ( Fig. 1 ). Amniocentesis for karyotype and biochemical testing for electrolytes were done. Amniocentesis for biochemical analysis showed that the chloride level was 121 mEq/L which is higher than normal (median value 108 mEq/L). 4 The karyotype was normal. The patient was counseled for a possibility of Bartter's disease in the neonate, and the prognosis was guarded. The patient developed respiratory discomfort at 32 weeks due to overdistended abdomen ( Fig. 2 ). Amniotic fluid drainage was done which yielded 3.5 L of fluid. Indomethacin was stopped at 32 weeks due to possibility of premature duct closure. She underwent amniotic fluid drainage three times at regular intervals until 36 weeks when she went into spontaneous labor. Controlled artificial rupture of membranes was done, and a stillborn female neonate weighing 2.06 kg was delivered. The neonate appeared dehydrated and had growth restriction (birth weight 1 centile for 36 weeks). The cord blood electrolytes showed severe hypokalemia, hyponatremia, and hypochloremia. Cord blood was sent for next-generation sequencing. The report showed a homozygous mutation of KCNJ1 gene. The patient was counseled that the neonate had Bartter's disease type II, which has antenatal presentation and is the severe form of Bartter's disease and also about a 25% risk of recurrence in next pregnancy as it is an AR disorder. Prenatal diagnosis can be made in the next pregnancy at 11 to 13 weeks by chorionic villous sampling and molecular testing for the previously identified KCNJ1 mutation.
Fig. 1.
( A ) Case 1 and ( B ) case 3: USG showing severe polyhydramnios and overdistended bladder.
Fig. 2.
Maternal overdistended abdomen—case 1.
Fetus 2
Primigravida at 25 weeks was referred for polyhydramnios with AFI of 262. Parents were consanguineous (first cousins) ( Fig. 3 ). Maternal blood sugar was normal. There was no associated anomaly on the US. However, the urinary bladder was overdistended. There was no evidence of obstructive uropathy on the scan. Records suggested normal AFI until 20 weeks. She was started on indomethacin 25 mg, twice daily. Follow-up ultrasonography at 30 weeks suggested alpha feto protein (AFI) of 419. Amniotic fluid drainage was done, and fluorescence in situ hybridization for five common aneuploidy suggested normal results. Electrolyte analysis was also done on amniotic fluid: Na + 145 mEq/L, K + 3.7 mEq/L, and Cl − 115 mEq/L ( Table 1 ). The patient developed a leaking following procedure which settled in 2 days. She delivered a female neonate at 32 weeks (had polyuria postnatally) with a birth weight of 1.76 kg (29 centiles for gestation), and there was no history of delayed cry. She started head control at 6 months; speech was reported at 1.5 years, sitting at 1 year, and started walking at 3 years of age. Currently, she is 4 years old and is on Potklor and indomethacin and going to school. She has failure to thrive and is advised to carry her water bottle every time to avoid dehydration.
Fig. 3.
Three-generation pedigree—case 2.
Table 1. Amniotic fluid electrolytes and genes in fetuses.
| Case | Gestational age at diagnosis | AFP | Na + in mEq/L | K + in mEq/L | Cl − in mEq/L | Gene | Outcome |
|---|---|---|---|---|---|---|---|
| 1 | 28 wk | – | 146 | 3.2 | 121 | KCNJ11 | Intrapartum stillbirth |
| 2 | 30 wk | Normal | 145 | 3.7 | 115 | SLC12A1 | Infant alive, 4 y old and on treatment |
| 3 | 26 wk | Normal | 132 | 3.64 | 107.2 | – | Neonatal death |
Abbreviation: AFP, Alpha feto protein.
Next-generation sequencing was done and identified a homozygous nonsense mutation c.2798_2799insA in SLC12A1 which causes Bartter's disease Type I. This gene codes for NKCC2 protein.
Fetus 3
A 25-year-old G2P + 0L0A0 at 24 to 25 weeks of gestation was referred because of severe polyhydramnios. US suggested AFI of 34; the stomach was appropriately seen. There was no other malformation. The urinary bladder was overdistended ( Fig. 1b ). Amniocentesis was done for karyotype and amniotic fluid electrolytes.
Amniotic fluid electrolytes at 25 weeks showed Na + 132 mEq/L, K + 3.64 mEq/L, and Cl − 107 mEq/L ( Table 1 ). Tablet indomethacin was started. Amniotic fluid drainage was done at 27 and 29 weeks and delivered a male neonate of 1.7 kg at 30 weeks. The neonate had polyuria after birth and died on days 6 to 7 of life.
Discussion
In all fetuses, the US showed no structural anomaly in the fetus or placenta, but consistent fetal full bladder was observed. We suspected polyuria and did testing on amniotic fluid to confirm the clinical suspicion. The biochemical test of amniotic fluid showing high chloride levels was suggestive of Bartter's disease in fetus 1. The next-generation sequencing confirmed the mutation of KCNJ1 associated with Bartter's disease Type II in fetus 1. In fetus 2, amniotic fluid chloride levels were found to be borderline. Clinical exome sequencing detected a nonsense mutation in SLC12A1 in fetus 2, thus confirmed the clinical suspicion. This gene codes for NKCC2 protein. Majority of these are missense or nonsense mutations. Each of the known mutations prevents the NKCC2 protein from transporting ions into kidney cells. As a result, the kidneys cannot reabsorb salt normally and excess salt is lost through the urine (salt wasting). The abnormal salt loss disrupts the normal balance of sodium, potassium, and other ions in the body. These imbalances underlie the major features of Bartter's disease. The frameshift mutation changes the protein sequence, structure, and might alter the function of protein, thus resulting in the underlying changes in the phenotype as seen in the patient.
In fetus 3, the biochemical testing on amniotic fluid electrolytes was inconclusive.
Differential diagnosis of overdistended bladder along with polyhydramnios will include fetal causes leading to polyuria such as obstructive uropathy. However, in these cases, there will be apparent features of urinary tract obstruction detected on the US. Congenital chloride diarrhea also causes polyhydramnios and raises amniotic fluid chloride levels; however, in these cases, the urinary bladder is normally seen on US, but bowel loops are distended with fluid. 5 Diabetes insipidus also causes polyuria, but usually, there is no antenatal polyhydramnios.
Bartter's disease was initially described by Bartter et al in 1962. 1 The incidence is said to be 1:50,000 to 1:100,000. 6 It is a renal tubular disease characterized by impaired salt reabsorption in the thick ascending limb of Henle's loop, resulting in excessive urinary losses of sodium, chloride, and potassium. There are three clinical variants, namely, neonatal, classic, and Gitelman's disease. Bartter's disease results from the mutations in numerous genes and has mainly AR inheritance. 7 In the neonates, it presents as prematurity, polyuria, and severe salt wasting and failure to thrive. The quality of life is poor, growth rate is reduced, and hospitalization rate is high.
We did amniotic fluid biochemistry and measured electrolytes and noted amniotic fluid chloride levels raised in fetus 1 and borderline in fetus 2 and normal chloride in fetus 3. Prenatal analysis of Bartter's disease is vital for appropriate management of the disease. However, as reported in the literature, studies using biochemical electrolyte analysis remains controversial. 8 High chlorides in amniotic fluid are most promising, while other electrolyte imbalance is not seen. One previous study showed that amniotic fluid chloride concentration ranged from 114 to 123 mEq/L in antenatal Bartter's disease patients, which is high compared with average amniotic fluid chloride concentration (around 107–109 mEq/L between gestational age of 25 and 37 weeks). 9 10 Another marker for Bartter's disease is a measure of amniotic fluid level protein. A study reported significant differences ( p < 0.0001) for protein amniotic fluid levels when compared with the two control groups (1.55, 3.9, and 5.2 g/L, respectively) and low Bartter index (0.16, 0.82, and 1.0, respectively). They further concluded that Bartter's disease could be prenatally suspected on amniotic fluid biochemistry (sensitivity 93% and specificity 100%). 11 Aldosterone which has been extensively studied in the amniotic fluid also has limited diagnostic potential as the previous studies trying to establish its utility in diagnosis remained inconsistent.
As seen in the present case series, the severe polyhydramnios and overdistended urinary bladder were noted in all three fetuses, and this appears the most sensitive noninvasive indicator of Bartter's disease. The polyhydramnios appears after 20 weeks of gestation and usually around 24 to 25 weeks and is severe (AFI around 30 and progressive) in manifestation and is associated with a full bladder.
A consistent full bladder with polyhydramnios was a novel finding and, to the best of our knowledge, has never been reported before in antenatal Bartter's disease. It was observed due to fetal polyuria.
Conclusion
These three fetuses bring into focus Bartter's disease as a rare cause of unexplained severe polyhydramnios. Correct etiological diagnosis is essential for delineating the prognosis and proper management of newborns after birth. This study will help in counseling regarding recurrence in a future pregnancy. Looking for overdistended bladder on antenatal US is a simple and cost-effective observation.
Funding Statement
Funding None.
Conflict of Interest None declared.
Informed Consent
Consent was taken for procedures during pregnancy.
Authors' Contribution
S.T. observed fetuses 2 and 3 and examined the novel finding of overdistended bladder. M.K. observed fetus 1 and suspected antenatal barter syndrome. S.M took active part in managing fetus 2. G.S. performed radiology for fetus 2. V.T. performed radiology for fetus 3. P.P. contributed in writing the manuscript.
References
- 1.Bartter F C, Pronove P, Gill J R, Jr, MacCardle R C. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. 1962. J Am Soc Nephrol. 1998;9(03):516–528. doi: 10.1681/ASN.V93516. [DOI] [PubMed] [Google Scholar]
- 2.Cunha T DS, Heilberg I P. Bartter syndrome: causes, diagnosis, and treatment. Int J Nephrol Renovasc Dis. 2018;11:291–301. doi: 10.2147/IJNRD.S155397. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hamza A, Herr D, Solomayer E F, Meyberg-Solomayer G. Polyhydramnios: causes, diagnosis and therapy. Geburtshilfe Frauenheilkd. 2013;73(12):1241–1246. doi: 10.1055/s-0033-1360163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Benzie R J, Doran T A, Harkins J L, Owen V M, Porter C J. Composition of the amniotic fluid and maternal serum in pregnancy. Am J Obstet Gynecol. 1974;119(06):798–810. doi: 10.1016/0002-9378(74)90093-3. [DOI] [PubMed] [Google Scholar]
- 5.Emmett M. Waltham, MA: 2014. Bartter and Gitelman syndromes. [Google Scholar]
- 6.Breinbjerg A, Siggaard Rittig C, Gregersen N, Rittig S, Hvarregaard Christensen J. A novel variant in the SLC12A1 gene in two families with antenatal Bartter syndrome. Acta Paediatr. 2017;106(01):161–167. doi: 10.1111/apa.13635. [DOI] [PubMed] [Google Scholar]
- 7.Kleta R, Bockenhauer D. Bartter syndromes and other salt-losing tubulopathies. Nephron, Physiol. 2006;104(02):73–80. doi: 10.1159/000094001. [DOI] [PubMed] [Google Scholar]
- 8.Dane B, Yayla M, Dane C, Cetin A. Prenatal diagnosis of Bartter syndrome with biochemical examination of amniotic fluid: case report. Fetal Diagn Ther. 2007;22(03):206–208. doi: 10.1159/000098719. [DOI] [PubMed] [Google Scholar]
- 9.Proesmans W, Massa G, Vandenberghe K, Van Assche A.Prenatal diagnosis of Bartter syndrome Lancet 19871(8529):394. [DOI] [PubMed] [Google Scholar]
- 10.Proesmans W. Bartter syndrome and its neonatal variant. Eur J Pediatr. 1997;156(09):669–679. doi: 10.1007/s004310050688. [DOI] [PubMed] [Google Scholar]
- 11.Garnier A, Dreux S, Vargas-Poussou R et al. Bartter syndrome prenatal diagnosis based on amniotic fluid biochemical analysis. Pediatr Res. 2010;67(03):300–303. doi: 10.1203/PDR.0b013e3181ca038d. [DOI] [PubMed] [Google Scholar]