Bartter syndrome (ORPHA:112)
Bartter syndrome is a group of rare renal tubular disease characterized by impaired salt reabsorption in the thick ascending limb of Henle's loop and clinically by the association of hypokalemic alkalosis, hypercalciuria/nephrocalcinosis, increased levels of plasma renin and aldosterone, low blood pressure and vascular resistance to angiotensin II.
Epidemiology
Annual incidence is estimated at 1/1000,000 in Europe.
Clinical description
Five distinct genotypes have been described, with four distinct clinical variants: an antenatal/infantile Bartter syndrome (most patients with genotypes I and II; see this term), characterized by polyhydramnios, premature delivery, polyuria, dehydration, hypercalciuria and nephrocalcinosis; an infantile Bartter syndrome with deafness (genotype IV, see this term), with congenital sensorineural deafness; classic Bartter syndrome (mostly patients with genotype III, but also some patients with genotype I and II; see this term), manifesting as polyuria-polydipsia in infancy-childhood through adulthood, dehydration and a variable delay in the height-weight growth curve; and autosomal dominant hypocalcemia with Bartter syndrome (patients with genotype V, see this term), associating chronic hypocalcemia and tubular salt wasting, hypokalemia and alkalosis.
Etiology
Bartter syndrome results from a defect in sodium, potassium and chloride reabsorption at the level of Henle's loop. They are caused by homozygous or compound heterozygous mutations in four genes encoding proteins involved in tubular fluid reabsorption in the thick ascending part of Henle's loop: SLC12A1 gene (15q15-21), encoding the sodium-potassium-chloride cotransporter NKCC2 in type I Bartter syndrome; KCNJ1 gene (11q24) encoding the potassium channel ROMK in type II; CLCNKB gene (1p36), encoding a basolateral chloride channel, in type III; and BSND gene (1p32.3), encoding barttin, the beta-subunit for the basolateral chloride channels, CLCNKA and CLCNKB in type IV. A final variant (type V) is associated with heterozygous activating mutations of the CASR gene (3q21.1), encoding the calcium sensing receptor.
Diagnostic methods
Diagnosis is based on the clinical picture, as well as in plasma and urine electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, calcium), renin and aldosterone levels. Calcium levels in the urine may be normal to markedly increased. Hypocalcemia is observed in Bartter syndrome type V. Genetic testing provides the definite diagnosis.
Differential diagnosis
The differential diagnosis includes pseudo-Bartter syndrome (diuretic abuse, surreptitious vomiting), Gitelman syndrome, cystic fibrosis and celiac disease (see these terms).
Antenatal diagnosis
Diagnostic testing of amniocytes might be indicated for mothers of affected children, or potential heterozygous carriers (close relatives of affected individuals).
Genetic counseling
Four of the genetic variants (types I,II,III,IV) of Bartter syndrome are transmitted following an autosomal recessive pattern whereas variant (type V) is transmitted as an autosomal dominant trait.
Management and treatment
Treatment includes oral potassium supplements, non-steroidal anti-inflammatory drugs (e.g. indomethacin) and possibly potassium-sparing diuretics. In stressful situations (intecurrent diseases, surgical procedures, trauma) blood electrolyte levels may change rapidly, requiring prompt and vigorous intravenous treatment.
Prognosis
Life expectancy may be reduced in severe cases but renal failure is rare. Quality of life may be poor, growth rate reduced, and hospitalization rate high.

                            Last update: 
                            September 2014


                            - Expert reviewer(s): 
                            Dr Giacomo COLUSSI