Pediatric Bartter Syndrome 

Bartter syndrome, originally described by Bartter and colleagues in 1962, represents a set of closely related autosomal recessive renal tubular disorders characterized by hypokalemia, hypochloremia, metabolic alkalosis, and hyperreninemia with normal blood pressure. The underlying renal abnormality results in excessive urinary losses of sodium, chloride, and potassium. Bartter syndrome has traditionally been classified into 3 main clinical variants: neonatal Bartter syndrome, classic Bartter syndrome, and Gitelman syndrome. Advances in molecular diagnostics have revealed that Bartter syndrome results from mutations in numerous genes that affect the function of ion channels and transporters that normally mediate transepithelial salt reabsorption in the distal nephron segments. Such advances may result in the development of new therapies.^[1] See the image shown below.

A modern, and more clinically relevant, classification of Bartter syndrome takes into account the 3 main anatomic and pathophysiologic disturbances that lead to the salt-losing tubulopathy.

• The first type involves distal convoluted tubule dysfunction that leads to hypokalemia; this is currently known as classic Bartter syndrome or Gitelman syndrome, which can be caused by defects in the NCCT and CLCNKB genes, respectively.
• The second type involves polyuric loop dysfunction that is more severe; this is referred to as antenatal Bartter syndrome or neonatal Bartter syndrome, which is characterized by defects in the NKCC2 and ROMK genes.
• The third type involves the most severe combined loop and distal convoluted tubule dysfunction and is now referred to as antenatal Bartter syndrome with sensorineural deafness; this is caused by defects in the chloride channel genes CLCNKB and CLCNKA or their beta subunit BSND.

The neonatal and classic types of Bartter syndrome are discussed in detail below, and the differentiating features of Gitelman syndrome are highlighted.

Whereas 60% of the filtered sodium chloride is reabsorbed in the proximal tubule, an additional 30% must be reabsorbed by the thick ascending limb of the Henle loop in order to maintain fluid and electrolyte homeostasis. The reabsorption of sodium in the ascending Henle loop primarily occurs by an electroneutral bumetanide-sensitive sodium-chloride potassium-chloride cotransporter (encoded by the gene NKCC2), with a function driven by the low intracellular concentration of sodium. The low sodium concentration in the cell is maintained by the basolateral membrane sodium-potassium pump, which extrudes sodium. Chloride exits the cell through a basolateral channel or a potassium chloride cotransporter; potassium is secreted in the luminal fluid through the apical ATP-regulated potassium channel (encoded by the ROMK gene). See the image below.

Defects in either the sodium-chloride potassium-chloride cotransporter or potassium channel affect the transport of sodium, potassium, and chloride in the thick ascending limb of the loop of Henle. The result is the delivery of large volumes of urine with a high content of these ions to the distal segments of the renal tubule, where only some sodium is reabsorbed and potassium is secreted.

In the subset of patients with neonatal Bartter syndrome, at least 2 genotypes have been identified. Type I results from mutations in the sodium-chloride potassium-chloride cotransporter gene (NKCC2 gene). See the first image below. Type II results from mutations in the ROMK gene. See the second image below.

In the classic form of Bartter syndrome, the defect in sodium reabsorption appears to result from mutations in the chloride-channel (C LCNKB) gene; this constitutes type III. The consequent inability of chloride to exit the cell inhibits the sodium-chloride potassium-chloride cotransporter (see the following image). Increased delivery of sodium chloride to the distal sites of the nephron leads to salt wasting, polyuria, volume contraction, and stimulation of the renin-angiotensin-aldosterone axis. These, combined with biological adaptations of downstream tubular segments, specifically the distal convoluted tubule and the collecting duct, results in hypokalemic metabolic alkalosis.^[2] The hypokalemia, volume contraction, and elevated angiotensin levels increase intrarenal prostaglandin E2 synthesis, which contributes to a vicious cycle by further stimulating the renin-aldosterone axis and inhibiting sodium chloride reabsorption in the thick ascending loop of Henle.

Studies have identified a novel type IV Bartter syndrome.^{[3, 4, 5]} This is a type of neonatal Bartter syndrome associated with sensorineural deafness and has been shown to be caused by mutations in the BSND gene.^{[6, 7, 4]} This gene encodes barttin, an essential beta-subunit that is required for the trafficking of the chloride channel CLC-K (both ClC-Ka and ClC-Kb) to the plasma membrane in both the thick ascending limb and the marginal cells in the scala media of the inner ear that secrete potassium ion-rich endolymph.^[3] Thus, loss-of-function mutations in barttin cause Bartter syndrome with sensorineural deafness. Therefore, in contrast to other Bartter types, the underlying genetic defect in type IV is not directly in an ion-transporting protein but is instead due to indirect interference with the barttin-dependent insertion in the plasma membrane of chloride channel subunits ClC-Ka and ClC-Kb.

Other observations have identified type V Bartter syndrome. This is a type of neonatal Bartter syndrome associated with sensorineural deafness but with no mutations in the BSND gene. Type V Bartter syndrome has been shown to be a digenic disorder due to loss-of-function mutations in the genes that encode the chloride channel subunits ClC-Ka and ClC-Kb.^[8] The specific genetic defect includes both a large deletion in the gene that encodes ClC-Kb (ie, CLCNKB) and a point mutation in the gene that encodes ClC-Ka (CLCNKA).

A summary of currently identified genotype-phenotype correlations is in the table below. For completion, the gene defect in Gitelman syndrome (the thiazide-sensitive sodium-chloride cotransporter, encoded by the gene NCCT) is also appended.

Table. Bartter Syndrome Genotype-Phenotype Correlations (Open Table in a new window)

A more clinically relevant terminology and classification of Bartterlike syndromes has recently been proposed, based on the underlying genetic cause and the anatomic location that leads to the salt-losing tubulopathy.^[9] Using this terminology, 3 major types of salt-losing tubulopathies can be identified (see Background).

Frequency

United States

Bartter syndrome is rare; the precise incidence is unknown.

International

The disease is seen throughout the world.

Mortality/Morbidity

Significant morbidity and mortality occur if Bartter syndrome is untreated. With treatment, the outlook is markedly improved; however, long-term prognosis remains guarded because of the slow progression to chronic renal failure.

Race

No racial predilection is recognized.

Sex

The incidence is similar in both sexes.

Age

The neonatal form of the disease can be suspected before birth or can be diagnosed immediately after birth. In the classic form, symptoms begin in neonates or infants aged 2 years or younger.