Congenital Nephrogenic Diabetes Insipidus Secondary to Antenatal Type IVa Bartter Syndrome

Abstract

Bartter syndrome (BS) is a rare autosomal recessive salt-wasting tubulopathy caused by genetic defects in the thick ascending limb of the loop of Henle. Type IVa BS, presents with severe salt wasting, sensorineural hearing loss, and impaired urinary concentrating ability. We report a 6-month-old female infant with antenatal type IVa BS due to a homozygous BSND variant, who developed secondary congenital nephrogenic diabetes insipidus (NDI), complicating her early clinical course. She presented with failure to thrive, recurrent dehydration, severe electrolyte imbalances, and profound polyuria. Diagnostic evaluation, including genetic testing and a water deprivation test with vasopressin challenge, confirmed impaired urinary concentration of renal origin. Management involved correction of electrolyte disturbances, Indomethacin therapy, and supportive care. This case highlights the importance of recognizing secondary congenital NDI in patients with type IVa BS when polyuria and hypernatremia are more pronounced than typically observed, allowing for earlier intervention and optimized clinical outcomes.

Introduction

In 1962, Frederic C. Bartter first identified a syndrome characterized by hypokalemia, metabolic alkalosis, hyperaldosteronism, and hyperplasia of the juxtaglomerular apparatus. ¹ Bartter syndrome (BS) is understood as a rare group of autosomal recessive salt-wasting tubulopathies caused by genetic defects in ion transport within the thick ascending limb of the loop of Henle (TAL). ²

The prevalence of BS is estimated at 1 per 1 000 000 individuals. ³ BS is classified into 5 types based on genetic mutations and clinical presentations, all involving impaired salt reabsorption in the TAL. Type IV BS, caused by mutations in the BSND gene (type IVa) or CLCNKA/CLCNKB genes (type IVb), is associated with sensorineural hearing loss (SNHL), severe salt wasting, polyhydramnios, preterm birth, and reduced urinary concentrating ability. ⁴

Nephrogenic diabetes insipidus (NDI), also known under the updated nomenclature as arginine vasopressin resistance (AVP-R), is characterized by a clinical triad of polyuria, polydipsia, and hypernatremia, result from the kidney’s inability to concentrate urine despite normal or elevated levels of antidiuretic hormone (ADH, also known as arginine vasopressin or AVP). This results in excessive excretion of dilute urine. ⁵

Congenital NDI is primarily caused by genetic defects in the vasopressin signaling pathway, with X-linked mutations accounting for 90% of cases. The remaining 10% are autosomal recessive or dominant mutations.^6,7 In contrast, acquired NDI typically occurs in adults secondary to electrolyte disturbances, renal tubular damage, or medications. ⁸ Notably, congenital NDI is a recognized feature of BS (particularly types 1, 2, and 4a), where TAL dysfunction impairs the medullary osmotic gradient, and Barttin/ClC-K channel defects disrupt collecting duct water reabsorption. This dual defect explains the profound urinary concentration impairment in BSND-mutated patients, as demonstrated in prior cases. ⁹

We present a case of secondary congenital NDI due to antenatal type IVa BS.

Presentation of Case

A 6-month-old female infant presented with a history of recurrent vomiting, failure to thrive (FTT), and dehydration. She was born prematurely at 34 weeks of gestation via cesarean section due to intrauterine growth restriction and severe polyhydramnios. Her birth weight was 1560 g (approximately −1.9 standard deviations (SD)) and a length of 38 cm (approximately −2.3 SD) according to the Fenton growth chart for preterm infants. The prenatal course was otherwise unremarkable, with detailed ultrasonography revealing no significant abnormalities. The mother, in her late thirties, was Para 8 with no history of miscarriage; however, 2 of her offspring had died, one as a stillbirth and another as a premature infant of unknown causes. The parents, who are first-degree relatives, and their surviving children were reported to be healthy. The calculated target height based on parental heights (father: 180 cm, mother: 169 cm) was 168 cm, corresponding to approximately +0.7 SD above the population mean.

The patient’s past medical history was notable for multiple hospital admissions, including treatment for upper respiratory tract infections, urinary tract infections (UTIs), sepsis, moderate to severe gastroesophageal reflux disease (GERD), recurrent vomiting, anemia, hypokalemia, and hypernatremia. These conditions improved with appropriate medical interventions.

At admission at 6 months of chronological age, her weight was 3580 g (below −3 SD) and her length was 47 cm (below −3 SD) compared to WHO growth standards for age, confirming severe FTT. Despite 2 months of hospitalization, her weight gain was negligible, increasing only to 3700 g. On physical examination, she was febrile and showed signs of moderate to severe dehydration. However, no dysmorphic features were observed. Laboratory evaluation revealed hypernatremia (165 mmol/L), hypokalemia (2.7 mmol/L), metabolic alkalosis (pH 7.50, bicarbonate 29 mmol/L), and hyperchloremia (112 mmol/L). Urinary studies showed an elevated fractional excretion of chloride (FECl) greater than 0.5%, consistent with a renal salt-wasting process. These abnormalities were accompanied by elevated lactate (13 mmol/L) and elevated urine pH (7). Serum creatinine and blood urea nitrogen (BUN) were transiently elevated during dehydration but normalized with intravenous rehydration.

The patient developed persistent non-bilious vomiting that was initially controlled with oral Ondansetron but recurred upon withdrawal of the medication. Close monitoring of her serum sodium and potassium levels (Figures 1 and 2) revealed persistent hypokalemia despite oral potassium chloride supplementation. Electrocardiography (ECG) was performed and showed normal results. The patient had a low urine specific gravity (1.005), polyuria, and polydipsia. These findings, combined with her history of severe prenatal polyhydramnios, prompted further investigation for a salt-wasting disorder.

Figure 1.

Na levels day by day from admission, giving that the patient was hypernatremic at the first day. The patient remained almost normonatremic.

Figure 2.

K levels day by day from admission. The patient was admitted with hypokalemia and controlled with oral KCL.

To explore the cause of these findings, a water deprivation test was conducted. The results revealed a urinary concentration defect, characterized by low urine osmolality (106 mOsm/L) and elevated serum osmolality (302.2 mOsm/L). Following this, intravenous vasopressin (DDAVP) was administered, which indicated a renal origin of the concentration defect, as evidenced by a slight increase in urine osmolality (117 mOsm/L). Based on these findings, a diagnosis of NDI was confirmed. Another key finding was an elevated urine calcium-to-creatinine ratio (0.5, normal <0.2) despite normal serum calcium levels. Renal ultrasonography revealed mild bilateral medullary nephrocalcinosis with normal kidney size of both kidneys. Further laboratory testing identified hyperreninemia (220 ng/mL/hour) and hyperaldosteronism (585 pg/mL), also the patient measured an elevated urine output (10 ml/kg/hour). Administration of Indomethacin led to normalization of renin levels.

Given the salt-wasting presentation, recurrent vomiting, and FTT, genetic testing was pursued. Whole exome sequencing (WES) revealed a homozygous variant of uncertain significance (VUS) in the BSND gene (c.635A>G, p.Asn212Ser), which encodes the β-subunit of CLC chloride channels, confirming the diagnosis of type IVa BS. This genetic alteration results in the substitution of asparagine (neutral, polar) with serine (neutral, polar) at codon 212 of the BSND protein. Brainstem auditory evoked response/auditory brainstem response (BAER/ABR) test was conducted, which confirmed the presence of SNHL.

Management included electrolyte correction with intravenous and oral supplementation, maintenance of Indomethacin therapy, and supportive care to address her FTT and associated complications. Indomethacin was continued throughout follow-up. Multidisciplinary care, including nephrology and audiology, was initiated to manage her chronic condition and optimize her developmental outcomes.

Discussion

BS is an autosomal recessive salt-wasting tubulopathy caused by genetic defects in the TAL. These defects result in excessive salt loss, hypokalemic metabolic alkalosis, hyponatremia, relatively low serum chloride levels, hypercalciuria, nephrocalcinosis, polyuria, and hyperreninemic hyperaldosteronism, all occurring in the context of normal blood pressure. ¹⁰ The syndrome carries a risk of increased antenatal and neonatal mortality, as many affected patients have FTT. ¹¹

Type IV BS is unique among BS subtypes for its association with SNHL and is further divided into type IVa and IVb based on the underlying genetic mutation. In type IVa, mutations in the BSND gene disrupt Barttin, a β-subunit essential for the proper insertion of chloride channels into the plasma membrane. This impairment leads to defective salt reabsorption in the kidneys and potassium secretion in the stria vascularis and vestibular labyrinth of the inner ear, resulting in severe salt wasting and SNHL. In type IVb, digenic mutations in 2 genes directly affect the chloride channels’ function. ⁴ Type IVa and IVb BS are associated with severe clinical phenotypes, including poor response to non-steroidal anti-inflammatory drugs therapy, growth retardation, and early progression to end-stage renal disease. ¹⁰ Phenotypic variability in type IVa BS is well-documented. Mutations such as G47R result in milder disease or later onset, while mutations like the one identified in this patient are associated with severe neonatal phenotypes, SNHL, and significant morbidity.

The BSND gene encodes barttin, a β-subunit essential for ClC-Ka/Kb channel function in both the TAL and collecting duct. ¹² In type IVa BS, barttin dysfunction causes congenital NDI via 2 mechanisms: (1) impaired countercurrent multiplication (TAL defect) and (2) reduced aquaporin-2 trafficking (collecting duct defect), as reported in BSND-associated cases. ⁹ Our patient’s homozygous BSND variant exemplifies this dual pathology, with severe polyuria and hypernatremia disproportionate to classic BS.

A literature review confirms that cases of secondary congenital NDI due to antenatal type IVa BS are exceedingly rare. Severe polyhydramnios, a hallmark of BS due to excessive fetal polyuria, is rarely associated with other inherited tubular disorders, including NDI and proximal tubulopathies. ¹³ In congenital NDI, urinary osmolality can markedly decrease below 100 mOsm/kg, whereas in BS, it typically remains above this threshold. ⁹ In our case, although urinary osmolality was low, primary congenital NDI was ruled out via WES. While congenital chloride diarrhea (CCD) can mimic BS with some features, it is typically accompanied by postnatal watery diarrhea, which was absent in this case. ¹⁴ Pseudo-BS, occasionally seen in Cystic Fibrosis (CF) patients due to salt loss in sweat, was excluded based on the absence of respiratory or pancreatic involvement, and CFTR mutations were not identified on WES. ¹⁵ Gitelman syndrome (GS) often presents later in life with hypocalciuria and hypomagnesemia, making it less likely in neonatal or early infant presentations like the one reported here. Rare causes of hypokalemia with metabolic alkalosis, such as hepatocyte nuclear factor 1β nephropathy or distal renal tubular acidosis (dRTA), were also considered. ¹⁶ However, these conditions often involve additional distinguishing features, such as acidemia in dRTA or associated renal cysts and diabetes in HNF1β nephropathy. These considerations highlight the importance of integrating clinical features with laboratory findings to achieve an accurate diagnosis.

Management of type IVa BS and associated NDI requires a multidisciplinary approach, as there are no specific guidelines for this rare overlap condition. General BS management involves correction of electrolyte imbalances and addressing associated complications such as nephrocalcinosis. Secondary congenital NDI adds complexity, necessitating careful fluid management to prevent severe dehydration while maintaining adequate growth. ¹⁰ Experimental therapies for type IVa BS, such as Hsp90 inhibitors (eg, 17-AAG), show promise in enhancing chloride channel function and improving symptoms. ¹⁷ While not yet clinically available, such approaches highlight future therapeutic directions.

This article reports a secondary congenital NDI due to BS, showing the need for clinical suspicion when urinary concentrating defects are more severe than expected for typical BS. Clinicians should recognize that persistent hypernatremia, profound polyuria, and extremely low urine osmolality in BS patients may signal an additional secondary congenital NDI component, even in the absence of congenital NDI mutations. By showing that secondary congenital NDI can complicate the course of type IVa BS early in infancy, this case expands the phenotypic spectrum of BSND mutations. Early identification of this overlap permits more tailored fluid and electrolyte management strategies, potentially mitigating growth failure, renal damage, and neurodevelopmental delays.

Conclusion

This article highlights a rare case of a female infant with congenital NDI secondary to type IVa BS, complicating early infancy with profound salt wasting, severe polyuria, and FTT. It highlights the importance of considering an additional urinary concentrating defect when polyuria and hypernatremia are disproportionate in BS.