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Page 76 Xu et al. J Transl Genet Genom 2023;7:87-93 https://dx.doi.org/10.20517/jtgg.2023.10

[1-3]
associated with increased morbidity and mortality . It was reported that 12 percent of these cases were
[4]
diagnosed as severe polyhydramnios . The most common mechanisms for polyhydramnios are decreased
[5]
fetal swallowing and fetal polyuria , which may be idiopathic or caused by a variety of diseases.
[6]
Approximately 40% of polyhydramnios is idiopathic . However, 25 percent of infants with a prenatal
diagnosis of idiopathic polyhydramnios are diagnosed with an abnormality after birth, such as Bartter
[7]
syndrome (BS) . Antenatal BS typically presents with severe polyhydramnios, premature delivery,
hypokalemic alkalosis, and secondary hyperaldosteronism. Most antenatal BS patients require lifelong
treatment with mineral supplementation and nonsteroidal anti-inflammatory drugs, and some may have
severe chronic kidney disease progression . In 2016, Kömhoff et al. reported that pathogenic variants in the
[8]
MAGED2 (melanoma-associated antigen D2) gene result in mislocalization of both NKCC2 (sodium-
potassium-2-chloride cotransporter) and NCC (sodium chloride cotransporter) . The mutant MAGED2
[9]
proteins cause a severe but transient X-linked antenatal BS (BS type 5), which mainly affects male infants .
[10]
Up to now, fewer than 50 cases with BS type 5 have been reported all over the world. Although some
patients died in utero or shortly after birth [10,11] , most of them had a normal estimated glomerular filtration
rate at last follow-up [10-18] . Individual cases of BS type 5 with positive outcomes after serial amniocentesis
therapy have been reported [11,15,17,18] , and one fetus has spontaneous remission of polyhydramnios after two
amnioreductions . Prenatal indomethacin therapy has been reported to decrease amniotic fluid in some
[18]
fetuses with antenatal BS [19-21] , whereas its effects on fetuses with BS type 5 are still uncertain. To date, only a
[13]
male infant with BS type 5 treated with prenatal indomethacin has been reported . He had severe
progressive polyhydramnios since 21 weeks of gestation (WG); despite several courses of indomethacin,
amnioreductions on five separate occasions were required, and he was born at 29 WG after premature
rupture of membranes. However, the dose of indomethacin and the genotype have not been described.
Although antenatal BS is quite rare, it should be considered in the differential diagnosis of polyhydramnios
if a structural abnormality and maternal diabetes are excluded. Accurate prenatal diagnosis may help to
provide appropriate prenatal consultation and postnatal management.

CASE REPORT
A previously healthy 33-year-old G2P1 female was referred at 29 WG due to polyhydramnios detected by
ultrasound imaging since 25 WG. Ultrasonography at 28 WG indicated severe polyhydramnios, with
amniotic fluid index (AFI) of 43 cm (normal AFI: 5-24 cm) . There were no structural abnormalities in the
[22]
fetus. Screening for Down’s syndrome was negative. The result of 75 g oral glucose tolerance test (OGTT)
was normal. She gave birth to a healthy full-term girl in 2018. There was no family history of severe
polyhydramnios or hereditary diseases. Ultrasonography at 29 WG in our hospital also indicated
polyhydramnios, with the single deepest pocket (SDP) of 15.2 cm (normal SDP: 2-8 cm), and cervical
shortening (13.3 mm). Owing to premature rupture of membranes at 30 WG, the woman received a short
course of magnesium sulfate infusion and oral indomethacin (a dose of 25 mg six times daily for the first
week and four times daily for the second week) for tocolysis and its amniotic fluid-reducing effects. A
course of dexamethasone was also administered to reduce the possibility rate of neonatal respiratory distress
syndrome. An amnioreduction was performed under continuous US guidance at 30 + 2 WG, and the
volume drained was 2,200 mL. Amniotic fluid leakage ceased within a week after the amnioreduction. The
SDP at 32 WG+, 33 WG+ and 34 WG+ were 13 cm, 9.4 cm and 8.7 cm, respectively [Figure 1]. After
obtaining the couple’s informed consent for the genetic analysis, genomic DNA of the fetus was extracted
from amniotic fluid, and the couple’s DNAs were extracted from peripheral white blood cells. No
chromosomal abnormalities were detected using Karyotype analysis and chromosomal microarray. Whole-
exome sequencing (WES) followed by Sanger sequencing analysis showed the fetus carried MAGED2
(NM_177433.1) hemizygous nonsense variant c.967C>T [p. (Asp323*)] inherited from the mother
[Figure 2]. This variant has been reported previously , and was classified as pathogenic (PVS1, PM2, PP4)
[11]
according to the American College of Medical Genetics and Genomics guidelines .
[23]