A study recently published on April 27, 2016, in the New England Journal of Medicine by Kamel Laghmani and colleagues proposes that identification of MAGE-D2 mutations in pregnant women with polyhydramnios can not only reduce the number of unnecessary diagnostic measures in such women but will also help avoid harmful treatment of preterm babies.

Polyhydramnios is a rare condition that can affect 1%-2% of the women in the second trimester of gestation. Polyhydramnios is a condition characterized by excessive amniotic fluid in the body. This excess of amniotic fluid is usually a result of an imbalance between the fluid’s production and removal. Polyhydramnios can result in perinatal complications such as preterm delivery and congenital disorders such as Antenatal Bartter’s syndrome in babies.

Bartter’s syndrome is a life-threatening condition that is characterized by excessive salt wasting from the body.

A recent study led by Kamel Laghmani attempted to determine the genetic basis of severe polyhydramnios and transient antenatal Bartter’s syndrome in fetuses. The study, spanning from April 2013 to May 2015, comprised obtaining DNA samples from 15 boys from nine families. There was a wide variety of racial and ethnical background in the families chosen for the study i.e., people from Belgian, German, Dutch, Belgian, and Turkish were preferred. All infants were boys and were tested negative for a number of mutations other than MAGE-D2 i.e., BSND (encoding barttin), CNJ1 (encoding ROMK), and SLC12A1 (encoding NKCC2). The medical data for the study were collected retrospectively from the medical charts.

For the sake of adding value to the study, 11 women with unknown (idiopathic) polyhydramnios during pregnancies were also followed.

For the study, the amniotic fluid index was set at >24 cm.


Of all the pregnancies chosen for the study, one was complicated with polyhydramnios and resulted in a preterm delivery of a stillborn male. The same woman experienced two uneventful pregnancies with girls and later went on to deliver a preterm male baby with Bartter’s syndrome, the symptoms of which were surprisingly resolved within three to four weeks of birth. However, the baby was sustained with supplemental electrolytes and anti-inflammatory (ibuprofen) for a year. At the last follow-up, the boy was 17 years of age and had no sign of renal insufficiency. The boy’s sister was diagnosed with polyhydramnios in her first pregnancy. She later birthed a preterm baby boy with neonatal polyuria. At the last follow-up, the boy was two years of age and had normal renal functions. All other pregnancies resulted in preterm babies.

The DNA study of both mother and the male child showed a mutation in MAGE-D2 that encodes melanoma-associated antigen D2 (MAGE-D2). Subsequent sequencing of MAGE-D2 in rest of the families and 11 additional women were done, all of which showed genetic mutations specific to each family. In contrast, none of the genetic mutations were present in 110 people from European descent without a family history of polyhydramnios.

Fetal renal study showed major expression of MAGE-D2 in fetal renal cortex. In MAGED-2 positive tubules, the genetic variation was expressed in the thick ascending loop of Henle.

Study Conclusion

Based upon the evidence obtained from the retrospective and prospective data as well as the study of genetic sequencing, Laghmani and colleagues concluded that MAGE-D2 was critical for maintaining normal pregnancy.

The finding is interesting because up until now mutations in BSND (gene encoding barttin) were considered the cause of Bartter’s syndrome. The current study shows that fetal MAGE-D2-loss resulted in perinatal and after-birth consequences in fetuses. The study also showed a link between the severity of polyhydramnios and the loss of MAGE-D2 in fetuses. Also, the onset of polyhydramnios was seen early in fetuses expressing a loss of MAGE-D2 than those expressing a loss of BSND i.e., 19 vs 12 weeks of gestation.

Up until now, studies and trial involving MAGE-D2 revolved primarily around tumor biology and proliferation. In contrast, the current study is unique in its content and findings and deserves further investigation into the rare disorder and its genetic linkage.

Because little has been known about the function of MAGE-D2, the researchers further delved into the study to identify its precise mechanism. MAGE-D2 binds with cytoplasmic proteins called Hsp40 and Gs-alpha and regulates biosynthesis of NCC in the endoplasmic reticulum. MAGE-D2 plays a role in the normal development of renal functions in the fetuses.

The study was wrapped up with the conclusion that the loss-of-function mutations in MAGE-D2 accounted for transient renal salt-wasting which promoted the early development of severe polyhydramnios in fetuses. Its identification in pregnant women with male fetuses can help avoid unnecessary diagnostic measures in such women and harmful treatment in the preterm babies.

Polyhydramnios Facts

  • Polyhydramnios is a rare disorder with an incidence of 1 in 500,000 pregnancies.
  • The exact cause of polyhydramnios is not known in as many as 30-60% of the cases.
  • Polyhydramnios is also commonly called ‘hydramnios’.