Antenatal Bartter syndrome: a new compound heterozygous mutation in exon 2 of KCNJ1 gene

Abstract

A 30+6/7-week infant was born by vaginal delivery to a 21-year-old primigravida with pregnancy complicated by polyhydramnios. The infant developed polyuria and significant weight loss in the first 2 weeks of life despite appropriate fluid management. He developed hyponatraemia, hypochloraemia, transient hyperkalaemia and prerenal azotaemia with metabolic acidosis. On further evaluation, he had elevated plasma renin and aldosterone levels. Bartter syndrome was considered in the differential diagnosis. Bartter syndrome gene panel revealed a rare compound heterozygous mutation in exon 2 of the KCNJ1 gene (Lys186Glu/Thr71Met), suggesting antenatal Bartter syndrome (type 2). The infant developed late-onset hypokalaemia and metabolic alkalosis by week 4 of life. He regained birth weight by week 3 of life but failed to thrive (10–20 g/kg/day) despite high caloric intake (140 kcal/kg/day). His electrolyte abnormalities gradually improved, and he was discharged home without the need for electrolyte supplements or medications.

Background

We present antenatal Bartter syndrome (ABS) in a preterm infant caused by a rare compound heterozygous mutation in exon 2 of the potassium inwardly rectifying channel subfamily J member 1 (KCNJ1) gene. Ours is the second report in the literature with this mutation. The presence of unexplained polyhydramnios, preterm delivery, polyuria and significant postnatal weight loss pointed to Bartter syndrome in the differential diagnosis. We underline the differences in clinical picture and laboratory values in type 2 ABS caused by mutation of the KCNJ1 gene, also known as renal outer medullary potassium channel 1 (ROMK1) or inward rectifier potassium channel 1.1 (Kir1.1).

Case presentation

Prenatal and birth history

We present a 30+6/7-week gestation male infant conceived in a non-consanguineous marriage and born by spontaneous vaginal delivery to a 21-year-old primigravida with negative prenatal screens for HIV, hepatitis B, syphilis, rubella and group B streptococcus. Polyhydramnios, pruritic urticarial papules and plaques of pregnancy, obesity, and gestational diabetes were noted during pregnancy. Antenatal ultrasound found a single umbilical artery and bilateral pyelectasis in the fetus. Fetal echocardiography was normal. The mother was offered amnioreduction at 30 weeks gestational age but declined due to perceived procedural risk. The infant’s birth weight was 1.56 kg (51st percentile on the Fenton preterm growth chart for boys), and he was appropriate for gestational age for weight, length and head circumference. On physical examination, there were no dysmorphic features such as triangular facies, prominent forehead, pointed ears or large eyes.

Neonatal course

At birth, the infant required invasive mechanical ventilation and exogenous surfactant administration for respiratory distress syndrome (RDS), and his respiratory status gradually improved after that. He was maintained in a neutral thermal environment in an isolette, and gavage feedings were initiated on day of life (DOL) 2 with breast milk. He required parenteral nutritional support briefly, and we advanced it to full enteral feeds gradually, per unit protocol. The infant developed polyuria on DOL 2 (8 mL/kg/hour), which persisted up to DOL 12 (4–5 mL/kg/hour). He had a cumulative weight loss of ~25% despite appropriate fluid management. He developed hyponatraemia, hypochloraemia and transient hyperkalaemia, which peaked on DOL 5 associated with acute kidney injury (table 1). The infant presented with metabolic acidosis, which gradually evolved into metabolic alkalosis by week 4. He had normal serum phosphate and magnesium levels throughout the neonatal intensive care unit stay. The infant gradually improved with supportive care.

Table 1.

Trend of basic metabolic panel in the first 2 weeks of the infant’s life

Laboratory parameter (reference range)	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Day 8	Day 9	Day 10	Day 11	Day 12
Blood urea nitrogen (2–17 mg/dL)	19			56	76.5 (70–79)	59.6 (56–64)	57.6 (57–66)	61 (57–66)	75.5 (74–77)	89	68	55
Serum creatinine (0.3–0.7 mg/dL)	0.75			0.94	1.10 (0.94–1.21)	0.83 (0.81–0.84)	0.83 (0.78–0.88)	0.78 (0.77–0.81)	0.79 (0.77–0.80)	0.83	0.70	0.63
Serum sodium (130–145 mmol/L)	136.3 (134–139)	141	140	134	125.3 (120–128)	132.8 (130–135)	134.3 (133–135)	140.7 (139–142)	141	140	141	140
Serum potassium (4.5–5.6 mmol/L)	6.2	5.3			6.6 (6.3–7.1)	5.8 (5.5–6.3)	5.2 (4.5–6)	5.6 (5.3–5.9)	6			6
Serum chloride (96–110 mmol/L)	105.6 (105–106)	105	101	97	88.1 (82–91)	95 (94–96)	92.3 (91–94)	102 (98–106)	106.5 (105–108)	106	106	102
Serum bicarbonate (17–24 mmol/L)	23.5 (23–24)	23	24	20	17.5 (15–19)	19.5 (17–21)	21.3 (18–24)	20.3 (19–21)	19 (17–21)	19	22	23
Serum calcium (8.7–11.3 mg/dL)	9.3 (9–9.5)	9.5	9.8	10.9	10.4 (11.4–9.5)	10 (9.5–10.5)	10.6 (10.4–10.7)	11 (10.9–11.4)	11.3 (11.2–11.3)	11	10.5	9.8

Investigation

Urine electrolytes revealed sodium (48 mmol/L) and chloride (28 mmol/L) loss with elevated urinary calcium creatinine ratio (1.25 mg/mg). Urinary potassium was normal (18 mmol/L). Renin and aldosterone levels on DOL 5 showed hyperreninaemia (339 ng/mL/hour; normal 2–37 ng/mL/hour) and hyperaldosteronism (1000 ng/dL; normal <23 ng/dL). We performed a renal sonogram to follow up on the pyelectasis noted on the prenatal sonogram. The renal sonogram showed mild bilateral hydronephrosis classified as P1 or low risk by urinary tract dilatation classification system.¹ Voiding cystourethrogram ruled out any structural abnormality or vesicoureteral reflux. A screening head sonogram performed for prematurity showed ischaemic changes (left > right). Brain MRI was performed to further characterise the ultrasound finding and revealed multifocal punctate ischaemic injury of the periventricular white matter. To confirm the clinical suspicion of Bartter syndrome, we sent a genetic panel for Bartter syndrome to Connective Tissue Gene Tests (Allentown, Pennsylvania, USA). The panel used a next-generation sequencing technique for nine genes: BSND, CASR, CLCNKA, CLCNKB, GNA11, KCNJ1, MAGED2, SLC12A1 and SLC12A3. The DNA sequencing revealed c.556A>G (p. Lys186Glu)/c.212C>T (p. Thr71Met) transition in exon 2 of the KCNJ1 gene, which confirmed a rare biallelic mutation causing ABS.

Differential diagnosis

We considered nephrogenic diabetes insipidus in the differential diagnosis of a neonate with polyuria. However, the presence of hyponatraemia ruled out this diagnosis. Moreover, urine (297 mOsm/kg) and serum (307 mOsm/kg) osmolality were almost equal. Idiopathic hyperaldosteronism was also in the differential since it can present in the newborn period with hyponatraemia, hypokalaemia, hypertension and polyuria secondary to hypokalaemia-induced renal dysfunction. Hypertension was characteristically absent in our patient, and the presence of elevated serum aldosterone with elevated plasma renin activity ruled out this possibility. We entertained the possibility of physiological partial aldosterone resistance or functional pseudohypoaldosteronism of newborns as the cause of our infant’s biochemical presentation of hyponatraemia, hyperkalaemia and hyperreninaemic hyperaldosteronism. The hyperkalaemia in our patient was transient. Persistent polyuria and failure to thrive despite parenteral nutrition did not fit this diagnosis. The absence of diarrhoea, emesis, pancreatic insufficiency or meconium ileus ruled out conditions causing pseudo-Bartter syndrome-like congenital chloride diarrhoea, idiopathic hypertrophic pyloric stenosis and cystic fibrosis. Next, salt-losing tubulopathies were considered based on the clinical picture and work-up initiated for Bartter syndrome.

Treatment

The infant received supportive care. Fluid and electrolyte supplements were provided based on the requirement in the first 2 weeks through parenteral nutrition. The infant reached full enteral feeds by DOL 11. We started enteral sodium supplements (oral sodium chloride solution 4 mEq/mL) on DOL 13. On DOL 24 the infant developed hypokalaemia requiring enteral potassium supplements (oral potassium chloride solution 20 mEq/15 mL). However, by DOL 28, the infant had weaned off both the supplements. He regained birth weight on DOL 25 but failed to thrive (10–20 g/kg/day weight gain) despite high caloric intake (140kcal/kg/day) until discharge.

Outcome and follow-up

The infant continues to be followed at the neurodevelopmental high-risk and paediatric nephrology clinics after discharge. There were no concerns regarding his developmental milestones at 5 months of age. He is on formula feeds (alimentum) and some table foods, but continues to have failure to thrive with weight for age, length for age and head circumference all at the first percentile. His renal function is normal (blood urea nitrogen 11 mg/dL and serum creatinine 0.23 mg/dL) with mild metabolic alkalosis (serum bicarbonate 28.8 mmol/L). He is maintaining his serum electrolytes in the low normal range without supplements. His serum calcium (11.6 mg/dL) and phosphorus (5.1 mg/dL) levels showed mild elevation. The infant is not on any medications and is closely monitored by the nephrology team.

Discussion

ABS is a rare autosomal recessive salt-losing tubulopathy caused by mutations in one of the five genes that encode channel proteins in the thick ascending limb of Henle’s (TALH): SLC12A1 (type I), KCNJ1 (type II), BSND (type IVa), CLCNKA/CLCNKB (type IVb) and MAGED2 (transient form).^2–5 Although not perfect, the genotype of the disease correlates with the phenotype. Mutations in the KCNJ1 gene causing ABS described in the past were limited to affect exon 4 or 5.^{6 7} Our patient had a compound heterozygous mutation in exon 2 of the KCNJ1 gene. In the current literature, two other patients with Bartter syndrome presenting beyond the newborn period had missense mutations involving exon 2.^{8 9} The specific biallelic mutation seen in our patient has not been reported previously to the best of our knowledge. The differences in the clinical and biochemical phenotype of our patient could be related to this new mutation.

The disease caused by the KCNJ1 gene mutation in chromosome 11q24 affects an ATP-sensitive ROMK/Kir1.1 in the TALH. The disease characteristically presents in the second trimester (median gestational age 25 weeks) as unexplained polyhydramnios secondary to fetal polyuria.¹⁰ Infants are born preterm at a median gestational age of 33 weeks with a male preponderance.^{7 11} Polyuria, dehydration and failure to thrive are the most common presenting clinical features. The characteristic biochemical abnormality noted in this subtype is transient hyperkalaemia in the early neonatal period, which later evolves into hypokalaemia due to the postnatal maturation of alternate potassium channels.¹² Impaired sodium chloride reabsorption leads to secondary hyperreninaemic hyperaldosteronism with normal blood pressure. Newborn infants present universally with hypercalciuria with a median calcium creatinine ratio of 2.81 mmol/mmol (0.99 mg/mg) and late-onset nephrocalcinosis (median age of presentation 2.5 years).⁷

Our patient had hyperkalaemia which lasted until the second week of life as expected from ROMK channel defect, which gradually evolved into hypokalaemia requiring potassium supplements by week 4 of life. However, distinctively both the hyponatraemia and hypokalaemia were mild, which gradually improved within the next 2 weeks and enabled us to stop the electrolyte supplements. Follow-up showed the infant continued to maintain serum electrolytes at normal levels without any supplements or need for non-steroidal anti-inflammatory drugs (NSAIDs)/ACE inhibitor therapy. Milder forms of ABS have been described in CLCNKB and MAGED2 mutations.^{13 14} Adult-onset Bartter syndrome caused by both homozygous and compound heterozygous mutations in the KCNJ1 gene has been described in the literature.^{8 15} However, a milder form of ABS with a neonatal onset due to KCNJ1 mutation has not been described before. ABS, especially type 1 and 2, is considered a severe type with risk of nephrocalcinosis; however, our patient had a relatively mild course. Functional heterogeneity of the ROMK channel based on the genotype could explain the differences in the presentation in our patient with a novel mutation.¹⁶

There is no known relationship between brain ischaemia and Bartter syndrome. We believe that our patient’s findings of brain ischaemia are related to prematurity and severe RDS requiring mechanical ventilation on day 1 of life. A Canadian Neonatal Network study including infants born at a gestational age of 30–32 weeks between 2011 and 2016 reported that the rate of severe neurological injury was 3.1% among screened infants.¹⁷ In this large cohort study, mechanical ventilation on day 1 has been identified as one of the critical risk factors for neurological injury in infants born between 30 and 32 weeks.

The management of ABS includes fluid and electrolyte supplementation in the form of sodium chloride and potassium chloride. If there is associated hypomagnesaemia, it needs to be supplemented as well. Optimising nutrition to facilitate adequate growth is essential. NSAIDs are recommended for symptomatic patients, and the early institution of these drugs has shown favourable growth velocity return.¹⁸ Routine use of potassium-sparing diuretics, ACE inhibitors or angiotensin receptor blockers should be avoided. Routine use of thiazides to control hypercalciuria should be avoided as well.¹⁹ Recent recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders have suggested long-term follow-up of patients with ABS in specialised centres with expertise in this rare disorder. Infants should be monitored for adequate metabolic control, growth and psychomotor development every 3–6 months initially and 6–12 months after ensuring stable control of their condition beyond infancy. Children should have their serum electrolytes, blood urea nitrogen, serum creatinine, parathyroid hormone and urine calcium creatinine ratio checked during follow-up. Clinicians should suspect and evaluate for secondary nephrogenic diabetes insipidus in children with persistent or worsening polyuria. Annual renal ultrasound should be performed to monitor for nephrocalcinosis. Children with persistent growth retardation despite optimal metabolic control should be evaluated for growth hormone deficiency.^{20 21} Long-term follow-up of children with ABS should include watching for late-onset proteinuria and chronic kidney disease.^{22 23} Incorporating quality of life assessment using age-appropriate scales in the follow-up is vital in older school-aged children with ABS.²⁴

Learning points.

• Antenatal Bartter syndrome is a rare autosomal recessive salt-losing tubulopathy presenting in the fetus and newborn with significant genetic heterogeneity.

• Early postnatal transient hyperkalaemia with a history of polyhydramnios, prematurity and polyuria should raise suspicion for antenatal Bartter syndrome due to KCNJ1 mutation.

• The clinical and biochemical phenotypic spectrum correlates with the genotype.

• Bartter syndrome gene panel aids in the characterisation of the genotype.

• Differential diagnoses include nephrogenic diabetes insipidus, idiopathic hyperaldosteronism, pseudohypoaldosteronism type 1, pseudo-Bartter syndrome-like congenital chloride diarrhoea, cystic fibrosis and pyloric stenosis.

Ethics statements

Patient consent for publication

Parental/guardian consent obtained.