A number sign (#) is used with this entry because of evidence that transient antenatal Bartter syndrome-5 (BARTS5) is caused by mutation in the MAGED2 gene (300470) on chromosome Xp11.

For a discussion of phenotypic and genetic heterogeneity of Bartter syndrome, see 607364.

Antenatal Bartter syndrome is a potentially life-threatening disease characterized by fetal polyuria, polyhydramnios, prematurity, and postnatal polyuria with persistent renal salt wasting. In transient antenatal Bartter syndrome-5, the onset of polyhydramnios and labor occur several weeks earlier than in other forms of Bartter syndrome. Polyuria lasts from a few days to 6 weeks, ending around 30 to 33 weeks of gestational age. Other features in the neonatal period include hypercalciuria, causing nephrocalcinosis in some cases, as well as hyponatremia, hypokalemia, and elevated renin and aldosterone; these subsequently resolve or normalize, although nephrocalcinosis may persist (Laghmani et al., 2016).

Engels et al. (1991) described 2 male preterm sibs, born at 31 to 33 weeks' gestation, who had peripartum asphyxia due to excessive polyhydramnios. Both infants exhibited polyuria with excessive loss of sodium and potassium, as well as hypercalciuria. In addition, they had hyperreninemia and hyperaldosteronism due to increased renal excretion of prostaglandin E2. In the third week of life, the renal losses decreased, and by the fourth week, fluid and salt replacement was no longer necessary. The brothers showed satisfactory growth, and the older boy had no renal dysfunction at age 4 years. Engels et al. (1991) suggested that this represented a familial transient congenital tubulopathy, noting that polyhydramnios, hypercalciuria, and increased excretion of prostaglandin E2 were consistent with a variant of 'hyperprostaglandin-E2 syndrome' (Bartter syndrome).

Reinalter et al. (1998) reported a 6-year-old Flemish boy who was born after a pregnancy complicated by severe polyhydramnios at a gestational age of 28 weeks. Analysis of the amniotic fluid showed a high chloride content. At birth, the proband displayed extreme polyuria, severe renal sodium and chloride loss, and marked hypercalciuria. He also required intubation and artificial ventilation for 6 days due to slow lung drainage. Five weeks after birth, his sodium chloride loss became renal potassium loss, along with a marked decrease in urine output. Fractional distal chloride reabsorption was 41%, approximately half of the normal range. He was discharged at 11 weeks of age with oral supplements of sodium chloride and potassium gluconate, and with fluid intake of 500 cc/day. At age 3 years, weight and height were at the 50th percentile and his medication was discontinued. He had a fractional distal chloride reabsorption of 44%, but no other features of Bartter syndrome were detected. Upon follow-up at 6 years of age, the boy had no hypokalemic alkalosis, no polyuria, and no hypercalciuria, and growth and development were normal. Renal ultrasound showed normal-sized kidneys with no nephrocalcinosis. Family history revealed that mother's first pregnancy also had been complicated by polyhydramnios, resulting in premature delivery at 25 weeks' gestation of a male infant who died at 7 hours of life.

Laghmani et al. (2016) reported a family in which the mother's first pregnancy was complicated by severe polyhydramnios at 19 weeks' gestation and preterm delivery of a stillborn male at 22 weeks. Two subsequent pregnancies with female fetuses were uneventful. Her fourth pregnancy was again complicated by early-onset severe polyhydramnios, followed by delivery at 27 weeks. The male infant immediately developed progressive polyuria with salt loss requiring intravenous fluid infusion. He also had severe hypercalciuria that caused medullary nephrocalcinosis. Clinical symptoms disappeared at 3 to 4 weeks of life, and he was treated with supplemental electrolytes and indomethacin for 1 year. At 17 years of age, he showed no clinical signs of renal salt loss and had normal urinary concentrating and diluting capacities. The proband's sister developed early-onset severe polyhydramnios during her first pregnancy, and gave birth to a preterm male infant at 31 weeks' gestation. Again neonatal polyuria was observed, which normalized within 1 week. Follow-up at 2 years of age showed that the boy had normal tubular and glomerular function.

In a mother and son from a family with polyhydramnios and transient antenatal Bartter syndrome, Laghmani et al. (2016) performed whole-exome sequencing and identified a nonsense mutation in the MAGED2 gene (Y346X; 300470.0001). The mutation segregated fully with disease in the family. Subsequent sequencing of MAGED2 in 6 additional families with transient antenatal Bartter syndrome revealed mutations in all 6, including a splice site mutation (300470.0002) in the family originally described by Engels et al. (1991) and a 2-bp deletion (300470.0002) in the family previously studied by Reinalter et al. (1998). Because the first son in the family described by Engels et al. (1991) presented with polyhydramnios only, Laghmani et al. (2016) also analyzed the MAGED2 gene in 11 women who had polyhydramnios while pregnant with male fetuses. They identified mutations in 2 more families, including a missense mutation (R446C; 300470.0004) in a fetus who died at 22 weeks' gestation and a splice site mutation in a boy who was born at 29 weeks' gestation and did not develop Bartter syndrome. The fetal genotype was demonstrated to be both necessary and sufficient for the full obstetric and perinatal phenotype by a de novo mutation (K133X; 300470.0005) detected in the affected male infant in 1 family.

Exclusion Studies

In a Flemish boy with transient antenatal Bartter syndrome, Reinalter et al. (1998) stated that no defect in the NKCC2 (SLC12A1; 600839) or ROMK (KCNJ1; 600359) genes had been detected.