French cohort of transient antenatal Bartter syndrome with MAGED2 mutations

Abstract

Background MAGED2 was recently identified in an X-linked severe and transient form of antenatal Bartter's syndrome associated with polyhydramnios and prematurity but also in idiopathic polyhydramnios in the male offspring. An inappropriate expression of the sodium-chloride transporters NKCC2 and NCC is disclosed. Methods MAGED2 was screened by Sanger Sequencing in a series of 35 cases with transient or antenatal Bartter's syndrome and no pathogenic variant in SLC12A1, KCNJ1, CLCNKB and BSND genes. Results We found 15 cases from 14 families harboring MAGED2 variants including four nonsense, three miss sense, two frame shift and two splice-site variants; two small in frame deletions and one complete deletion of MAGED2 gene. Only one variant was previously reported, p.Arg446Cys. Severe polyhydramnios occurred in all pregnancies, at 18 to 25 weeks of gestation requiring serial amniocentesis (one to ten, when data available). In four cases, polyhydramnios was present in previous or later pregnancies. One pregnancy resulted in medical termination of pregnancy. All the infants (14) were born pre-term with gestational age at delivery between 26 and 36 weeks. All presented a Bartter's syndrome with severe polyuria (median diuresis was 13 mL/kg/h). Surprisingly, two cases were females. The severity of their phenotype and the course of the disease were comparable to those for male. The medical follow-up of 12 patients revealed that the salt and water losses resolved between 2 and 18 months with the end of indomethacin treatment or water and salts supplements. Two cases, with associated neurological disorders died at 1 and 12 months. Conclusion We confirmed with our French series of 15 MAGED2 cases the phenotypic presentation of this transient antenatal Bartter's syndrome. This new syndrome has to be considered in the differential diagnosis of Bartter's syndrome with the screening of MAGED2 as part of the molecular diagnosis.