Bartter Syndrome and Gitelman Syndrome

Bartter syndrome and the more common Gitelman syndrome result from

In Bartter syndrome, the defect is in the ascending thick limb of the loop of Henle. In Gitelman syndrome, the defect is in the distal tubule.

In both syndromes, the impairment of sodium chloride reabsorption causes mild volume depletion, which leads to increases in renin and aldosterone release, resulting in potassium and hydrogen losses. In Bartter syndrome, there is increased prostaglandin secretion as well as a urinary concentrating defect due to impaired generation of the medullary concentration gradient. In Gitelman syndrome, hypomagnesemia and a low urinary calcium excretion are common. In both disorders, sodium wasting contributes to a chronic mild plasma volume contraction reflected by a normal to low blood pressure despite high renin and angiotensin levels.

The features at clinical presentation vary ( see Table: Some Differences Between Bartter Syndrome and Gitelman Syndrome Some Differences Between Bartter Syndrome and Gitelman Syndrome ).

Both syndromes are usually autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more , although sporadic cases and other types of familial patterns can occur. Of note, there is an X-linked mutation in the MAGED2 gene, which can cause severe antenatal Bartter syndrome that is transient and resolves by 1 to 2 years of life.

There are several genotypes of both syndromes (see table Subtypes of Bartter Syndrome Subtypes of Bartter Syndrome* ); different genotypes can have different manifestations (1 Etiology reference Bartter syndrome and Gitelman syndrome are autosomal recessive renal disorders characterized by fluid, electrolyte, urinary, and hormonal abnormalities, including renal potassium, sodium, chloride... read more ).

Bartter syndrome tends to manifest prenatally or during infancy or early childhood. Gitelman syndrome tends to manifest during late childhood to adulthood.

Of note, some patients, especially those with Gitelman syndrome, are asymptomatic and diagnosed incidentally after blood tests are done.

Bartter syndrome can manifest prenatally with intrauterine growth restriction and polyhydramnios. Different forms of Bartter syndrome can have specific manifestations, including hearing loss, hypocalcemia Hypocalcemia Hypocalcemia is a total serum calcium concentration < 8.8 mg/dL (< 2.20 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized calcium concentration < 4... read more , and nephrocalcinosis, depending on the underlying genetic defect. Children with Bartter syndrome, more so than those with Gitelman syndrome, may be born prematurely and may have poor growth and development postnatally, and some children have intellectual disability.

Inability to retain potassium, calcium, or magnesium can lead to muscle weakness, cramping, spasms, tetany, or fatigue. This is especially apparent in Gitelman syndrome. Polydipsia, polyuria, salt cravings, and vomiting may be present in both syndromes.

Most patients with Bartter syndrome or Gitelman syndrome have low or low-normal blood pressure and may have signs of volume depletion.

In general, neither Bartter syndrome nor Gitelman syndrome typically leads to chronic renal insufficiency.

Bartter syndrome and Gitelman syndrome should be suspected in children with characteristic symptoms or incidentally noted laboratory abnormalities, such as metabolic alkalosis Metabolic Alkalosis Metabolic alkalosis is primary increase in bicarbonate (HCO3⁻) with or without compensatory increase in carbon dioxide partial pressure (Pco2); pH may be high or nearly normal. Common... read more and hypokalemia Hypokalemia Hypokalemia is serum potassium concentration < 3.5 mEq/L (< 3.5 mmol/L) caused by a deficit in total body potassium stores or abnormal movement of potassium into cells. The most common... read more . Measurement of urine electrolytes shows high levels of sodium, potassium, and chloride that are inappropriate for the euvolemic or hypovolemic state of the patient.

Diagnosis is by exclusion of other disorders:

A 24-hour measurement of urinary calcium or the urine calcium/creatinine ratio may help distinguish the two syndromes; the levels are typically normal to increased in Bartter syndrome and low in Gitelman syndrome.

Definitive diagnosis, including identification of disease subtypes, is through genetic testing, which is now becoming more widely available.

Children of carriers have a 25% chance of being affected by a recessive form, so asymptomatic siblings should be screened for electrolyte derangements, primarily hypokalemia and metabolic alkalosis, as well as hypomagnesemia. Parents of an affected child can consider consulting a genetic counselor regarding prenatal and preimplantation genetic screening for subsequent pregnancies.

Because renal prostaglandin E2 secretion contributes to the pathogenesis in Bartter syndrome, NSAIDs (eg, oral indomethacin 0.33 to 1.33 mg/kg 3 times a day or 0.25 to 1 mg/kg 4 times a day, ibuprofen 5 to 10 mg/kg 3 times a day) (1 Treatment references Bartter syndrome and Gitelman syndrome are autosomal recessive renal disorders characterized by fluid, electrolyte, urinary, and hormonal abnormalities, including renal potassium, sodium, chloride... read more , 2 Treatment references Bartter syndrome and Gitelman syndrome are autosomal recessive renal disorders characterized by fluid, electrolyte, urinary, and hormonal abnormalities, including renal potassium, sodium, chloride... read more ). Selective cyclooxygenase (COX)-2 inhibitors (eg, celecoxib) also may be used in patients with Bartter syndrome. If COX-2 inhibitors are used, patients should be given drugs to suppress gastric acid (1 Treatment references Bartter syndrome and Gitelman syndrome are autosomal recessive renal disorders characterized by fluid, electrolyte, urinary, and hormonal abnormalities, including renal potassium, sodium, chloride... read more , 2 Treatment references Bartter syndrome and Gitelman syndrome are autosomal recessive renal disorders characterized by fluid, electrolyte, urinary, and hormonal abnormalities, including renal potassium, sodium, chloride... read more ).

Electrolyte supplementation is the mainstay of management. Regimens usually include sodium chloride, usually 5 to 10 mEq/kg/day. Additionally, potassium chloride supplementation should be given, initially about 1 to 3 mEq/kg/day. Patients with magnesium wasting should be given magnesium salts , but this therapy may be limited by the development of diarrhea. Some magnesium salts, such as aspartate, citrate, or lactate, have better bioavailability. A high solute load, such as that resulting from sodium supplementation, should be avoided in patients who have a urinary concentrating defect, secondary nephrogenic diabetes insipidus Nephrogenic Diabetes Insipidus Nephrogenic diabetes insipidus (NDI) is an inability to concentrate urine due to impaired renal tubule response to vasopressin (ADH), which leads to excretion of large amounts of dilute urine... read more , or both because it exacerbates polyuria and polydipsia resulting from obligate water loss and could precipitate significant hypernatremia. In general, electrolyte supplementation should try to maintain adequate serum levels with minimal fluctuation, thus, dosing should be spread out as long as it does not significantly increase the risk of nonadherence.

Although potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers have been used in some patients, current consensus is that these therapies are largely unproved (1 Treatment references Bartter syndrome and Gitelman syndrome are autosomal recessive renal disorders characterized by fluid, electrolyte, urinary, and hormonal abnormalities, including renal potassium, sodium, chloride... read more , 2 Treatment references Bartter syndrome and Gitelman syndrome are autosomal recessive renal disorders characterized by fluid, electrolyte, urinary, and hormonal abnormalities, including renal potassium, sodium, chloride... read more ).

Thiazide diuretics for management of hypercalciuria are generally not recommended, but this may complicate sodium supplementation, which can worsen the risk of nephrolithiasis and nephrocalcinosis.

Nutritional optimization is important, especially for infants and young children.

Exogenous growth hormone can be considered to treat short stature.