eMedicine Specialties > Pediatrics: General Medicine > Nephrology
Bartter Syndrome
Updated: Oct 1, 2008
Introduction
Background
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.
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.
Pathophysiology
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 Media file 1.
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 Media file 2. Type II results from mutations in the ROMK gene. See Media file 3.
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 Media file 4). 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, with resultant hypokalemic metabolic alkalosis. 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.7,8,19 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.2,5,8 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.7 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.9 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.
Bartter Syndrome Genotype-Phenotype Correlations
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Table
| Genetic Type | Defective Gene | Clinical Type |
| Bartter type I | NKCC2 | Neonatal |
| Bartter type II | ROMK | Neonatal |
| Bartter type III | CLCNKB | Classic |
| Bartter type IV | BSND | Neonatal with deafness |
| Bartter type V | CLCNKB and CLCNKA | Neonatal with deafness |
| Gitelman syndrome | NCCT | Gitelman syndrome |
| Genetic Type | Defective Gene | Clinical Type |
| Bartter type I | NKCC2 | Neonatal |
| Bartter type II | ROMK | Neonatal |
| Bartter type III | CLCNKB | Classic |
| Bartter type IV | BSND | Neonatal with deafness |
| Bartter type V | CLCNKB and CLCNKA | Neonatal with deafness |
| Gitelman syndrome | NCCT | Gitelman syndrome |
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.15 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.
Clinical
History
The history of patients with Bartter syndrome may include the following:
- Neonatal Bartter syndrome
- Maternal polyhydramnios, secondary to fetal polyuria, is evident by 24-30 weeks' gestation. Delivery often occurs before term. The newborn has massive polyuria (rate as high as 12-50 mL/kg/h).
- The subsequent course is characterized by life-threatening episodes of fluid loss, clinical volume depletion, and failure to thrive.
- A subset of patients with neonatal Bartter syndrome (types IV and V) develop sensorineural deafness.
- Classic Bartter syndrome
- Patients have a history of maternal polyhydramnios and premature delivery.
- Symptoms include polyuria, polydipsia, vomiting, constipation, salt craving, tendency for volume depletion, failure to thrive, and linear growth retardation.
- Other symptoms, which appear during late childhood, include fatigue, muscle weakness, cramps, and recurrent carpopedal spasms.
- Developmental delay and minimal brain dysfunction with nonspecific electroencephalographic changes are also present.
Physical
Findings with Bartter syndrome include the following:
- Neonatal Bartter syndrome
- Patients are thin and have reduced muscle mass and a triangularly shaped face, which is characterized by a prominent forehead, large eyes, protruding ears, and drooping mouth.
- Strabismus is frequently present.
- Blood pressure is within the reference range.
- A subset of patients with Bartter syndrome (types IV and V) develop sensorineural deafness, which is detectable with audiometry.
- Classic Bartter syndrome: The patient's facial appearance may be similar to that encountered in the neonatal type. However, this finding is infrequent.
Causes
Causes of Bartter syndrome include the following:
- Neonatal Bartter syndrome
- An autosomal recessive mode of inheritance is observed in some patients, although many cases are sporadic.
- In type I Bartter syndrome, loss-of-function mutations in the sodium-chloride potassium-chloride cotransporter gene NKCC2 (locus SLC12A1 on chromosome bands 15q15-21) have been detected.
- In type II Bartter syndrome, mutations occur in the ROMK gene (locus KCNJ1 on chromosome bands 11q24-25).
- Newly described genetic defects include type IV (in the BSND gene) and type V (digenic, in both CLCNKB and CLCNKA genes).
- Classic Bartter syndrome
- Some patients have an autosomal recessive mode of inheritance, although many cases are sporadic.
- A subset of patients display mutations in the chloride-channel gene CLCNKB (locus CLCNKB on chromosome band 1p36). These represent type III Bartter syndrome.
More on Bartter Syndrome |
 Overview: Bartter Syndrome |
| Differential Diagnoses & Workup: Bartter Syndrome |
| Treatment & Medication: Bartter Syndrome |
| Follow-up: Bartter Syndrome |
| Multimedia: Bartter Syndrome |
| References |
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References
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Further Reading
Keywords
Bartter syndrome, Bartter's syndrome, Gitelman syndrome, Gitelman's syndrome, Gullner syndrome, Gullner's syndrome, renal tubular disorder, hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia, neonatal Bartter syndrome, classic Bartter syndrome, polyuric loop dysfunction, salt-losing tubulopathy, chronic renal failure, maternal polyhydramnios, failure to thrive, strabismus, hypomagnesemia
