Bartter syndrome type 3 (ORPHA:93605)
A form of Bartter syndrome characterized by a later age at onset than the other types of Bartter syndrome, typically presenting beyond the first year of life with failure to thrive, hypokalemic and hypochloremic metabolic alkalosis, increased levels of plasma renin and aldosterone and low to normal blood pressure.
Epidemiology
Exact prevalence is not known.
Clinical description
The disease is characterized by a milder clinical picture with a wide phenotypic heterogeneity when compared to other types of Bartter syndrome. Only one third of the patients present with maternal polyhydramnios which usually does not lead to prematurity. Patients usually present in the first year of life with failure to thrive, poor weight gain or polyuria with polydipsia. Fatigue, muscle weakness, cramps and carpopedal spasms may occur in some patients. Hypokalemia and hypochloremic metabolic alkalosis are common. Urinary calcium excretion is variable, only a few patients develop medullary nephrocalcinosis. In a subset of patients, the clinical picture and the biochemical abnormalities may resemble Gitelman syndrome, another salt losing tubulopathy caused by mutations in the sodium chloride cotransporter, SLC12A3, of the distal convoluted tubule. Indeed, the biochemical hallmarks of hypomagnesmia with hypocalciuria may also be detected in some patients with this type of Bartter syndrome.
Etiology
Mutations in the CLCNKB gene (1p36), encoding the basolateral chloride channel ClC-Kb, have been identified as the underlying molecular defect. ClC-Kb is closely related to ClC-Ka, and both channels are expressed in thick ascending limb of the loop of Henle (TAL), ClC-Ka is exclusively expressed in the loop of Henle, whereas ClC-Kb is also expressed in distal convoluted tubule (DCT), thereby explaining the pronounced DCT features (similar to Gitelman syndrome) in some patients with this type of Bartter syndrome.
Diagnostic methods
Diagnosis is based on the clinical picture, blood gas analysis, plasma and urine electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, calcium), renin and aldosterone levels. Urinary calcium excretion rates variably range from low to normal or slightly increased. Only genetic testing provides the definite diagnosis.
Differential diagnosis
The differential diagnosis includes Gitelman syndrome, pseudo-Bartter syndrome (e.g. in cystic fibrosis), HNF1B-nephropathy, and EAST syndrome. From late adolescence, also diuretic abuse, surreptitious vomiting, and surreptitious laxative use need to be ruled out.
Antenatal diagnosis
Prenatal diagnosis is technically feasible after genetic counseling and may be considered on an individual basis.
Genetic counseling
Transmission is autosomal recessive. Genetic counselling should be offered to any patient with Bartter syndrome and to parents with an affected child. In at-risk couples (both individuals are carriers of a disease-causing mutation) there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment includes oral salt and potassium supplements next to liberal salt and fluid intake. In addition, non-steroidal anti-inflammatory drugs (e.g. indometacin or celecoxib) are helpful in the majority of patients. Potassium-sparing diuretics should only be used with caution. In stressful situations (intercurrent illness, surgical procedures, trauma) blood electrolyte levels may change rapidly, requiring prompt and vigorous treatment.
Prognosis
Reliable long term outcome data are still lacking. Life expectancy may be reduced in severe cases. Quality of life may be compromised. During follow-up, proteinuria may occur, some patients develop chronic renal failure but rarely need renal replacement therapy.

                            Last update: 
                            September 2021


                            - Expert reviewer(s): 
                            Pr Martin KONRAD | ERKNet*


                                * European Reference Network