Summary

Bartter syndrome is characterised by the association of hypokalemic alkalosis, increased levels of plasma renin and aldosterone, low blood pressure and vascular resistance to angiotensin II. Annual incidence is estimated at 1/830,000. Although five genetic variants have been described, only two forms of the disease can be distinguished according to clinical criteria: an antenatal or infantile Bartter syndrome (most patients with genotypes I, II and IV), characterized by polyhydramnios, premature delivery, polyuria, dehydration, hypercalciuria and nephrocalcinosis; and classical Bartter syndrome (mostly patients with genotype III, but also some type IV patients), manifesting as polyuria-polydipsia in infancy-childhood through to adulthood, dehydration and a variable delay in the height-weight growth curve. Calcium levels in the urine may be normal or slightly increased. Specific signs/symptoms are hearing loss in Bartter syndrome type IV and hypocalcemia in Bartter syndrome type V. Bartter syndrome results from a disorder of sodium, potassium and chloride reabsorption at the level of Henle's loop. Four of the genetic variants of Bartter syndrome are transmitted following an autosomal recessive pattern. They are caused by homozygous or compound heterozygous mutations in four genes encoding proteins involved in chloride reabsorption in the ascending part of Henle's loop: SLC12A1 gene (15q15-21), encoding the sodium-potassium-chloride cotransporter NKCC2 in type I Bartter syndrome; KCNJ1 gene (11q21-25) encoding the potassium channel ROMK in type II; CLCNKB gene (1p36), encoding a basolateral chloride channel, in type III; BSND gene (1p31), encoding barttin, a subunit for the chloride channel, in type IV. A last variant (type V) is transmitted as an autosomal dominant trait, and is associated with heterozygous activating mutations of the CASR gene (3q13.3-q21), encoding the calcium receptor. Diagnosis is based on the clinical picture, plasmaelectrolyte, bicarbonate, magnesium, calcium, renin and aldosterone levels, and urinary electrolyte, calcium and magnesium excretion. Genetic testing provides the definite diagnosis. The differential diagnosis includes pseudo-Bartter syndrome (diuretic abuse, surreptitious vomiting), Gitelman syndrome, cystic fibrosis and celiac sprue (see these terms). Diagnostic testing of amniocytes might be indicated for mothers of affected children, or potential heterozygous carriers (close relatives of affected individuals). Treatment includes oral K supplements, indometacin and possibly potassium-sparing diuretics. In stressful situations (additional diseases, surgical procedures, trauma) blood electrolyte levels may change rapidly, requiring prompt and vigorous intravenous treatment. Life expectancy may be reduced in severe cases; renal failure is rare. Quality of life may be poor, growth rate reduced, and medicalization/hospitalization rate high.

Expert reviewer(s)

• Dr Giacomo COLUSSI