Clinical Information

Bartter syndrome (BS) is a rare, hereditary tubulopathy of highly variable severity that can cause renal salt-wasting in infants and young children due to impaired sodium/chloride reabsorption in the thick ascending limb of the nephron.(1)

Characteristic clinical features are hypokalemic, hypochloremic metabolic alkalosis and normal blood pressure despite hyperreninemia and hyperaldosteronism.(1) Children with BS have hypercalciuria and normal serum magnesium levels and may present with symptoms in early childhood or before birth. These symptoms distinguish BS from a more common and milder renal salt-wasting disorder called Gitelman syndrome, which features hypocalciuria and low serum magnesium levels and typically presents after 6 years of age. Autosomal dominant hypocalcemia may resemble Bartter syndrome in patients with a markedly activating gain-of-function variant but is distinguishable from BS by mode of inheritance and the presence of hypocalcemia and hypomagnesemia.

Age of onset and disease severity is highly variable in Bartter syndrome. The most severe form, antenatal Bartter syndrome (also known as hyperprostaglandin E syndrome or neonatal Bartter syndrome), typically results in polyhydramnios, leading to premature birth. Infants often demonstrate failure to thrive and have significant polyuria resulting in risk for life-threatening salt and water loss.

There are four subtypes of Bartter syndrome that typically present antenatally. BS type 1, caused by biallelic alterations in SLC12A1, may also feature fever, vomiting, and nephrocalcinosis in infancy. BS type 2, caused by biallelic variants in KCNJ1, causes symptoms like BS type 1, but patients may demonstrate transient hyperkalemia and acidosis. BS type 4a, caused by biallelic alterations in BSND, and BS type 4b, caused by alterations in CLCNKA and CLCNKB, may be accompanied by sensorineural deafness in addition to renal salt-wasting and related symptoms. Type 4b is also inherited in an autosomal recessive (or biallelic) pattern or can result from digenic inheritance.

Classic Bartter syndrome, also known as type 3, is the second major form of BS and is caused by alterations in CLCNKB. All BS type 3 patients have marked hypochloremia. Age of onset varies in BS type 3 and may correlate with genotype, with individuals with truncating variants presenting earlier in life. Individuals with BS type 3 may present antenatally with polyhydramnios, during infancy with failure to thrive and lethargy, or in adolescence or adulthood with symptoms of chronic hypokalemia, such as constipation, muscle cramps, salt-craving, nocturia, and vomiting. Nephrocalcinosis is uncommon in BS type 3, and patients are usually normocalciuric but may still have severe electrolyte imbalances.

A third from of BS called transient neonatal Bartter syndrome (BS type 5), is associated with severe polyhydramnios and extreme salt wasting at birth that spontaneously resolves in the first few months of life in surviving patients. BS type 5 is caused by variants in MAGED2 inherited in an X-linked recessive pattern.

Although there is some phenotypic overlap between Bartter syndrome, Gitelman syndrome, and autosomal dominant hypocalcemia, they have different genetic causes.

This panel does not include the genes associated with Gitelman syndrome (SLC12A3) or autosomal dominant hypocalcemia (CASR). If simultaneous genetic testing for Bartter syndrome, Gitelman syndrome and/or autosomal dominant hypocalcemic hypercalciuria is desired, order RSCGP / Nephrocalcinosis, Nephrolithiasis, and Renal Electrolyte Imbalance Gene Panel, Varies.