Bartter Syndrome - Diagnosis and Differentials

Author Information and Disclosures

Clinical

History: Bartter described 2 patients. The first was a boy aged 4 years 10 months with tetany and dwarfism. He had been hospitalized at age 4 months for vomiting, diarrhea, dehydration, and generalized convulsions. Although otherwise healthy, the boy's growth lagged, and he had polydipsia, which caused him to drink 10-12 glasses of fluid daily. The other patient was a 25-year-old man who presented with a long history of enuresis, slow growth, weakness, and fatigue. He had been hospitalized several times (once in a semicomatose condition) with vomiting, abdominal and leg cramps, and dehydration.

• Because Bartter and Gitelman syndromes result from a mutation in 1 of 5 transporters or subunits, age at onset of symptoms and severity of symptoms vary, depending on the severity of the mutation.

• Patients with antenatal Bartter syndrome often present with polyhydramnios and growth retardation and were delivered prematurely.

• The inability of the kidney tubules to retain salt and water results in urinary fluid loss, so polyuria is common.

• The resulting volume depletion increases thirst, and the normal response is to increase fluid intake.

• If patients cannot receive sufficient salt and water, dehydration and altered mental status can occur.

• In severe cases of Bartter syndrome, vomiting is not uncommon, producing further volume depletion.

• Inability of the kidney tubules to retain potassium, calcium, or magnesium can lead to muscle weakness, spasms, tetany, or palpitations. In Rudin's report of 28 patients, 22 had hypomagnesemia, but most denied any of these symptoms.

• A few patients with severe cases of antenatal Bartter syndrome have also had mental retardation.

Physical:

• Untreated patients tend to be very short.

• Most patients have low or low-to-normal blood pressure. They may show signs of volume depletion.

• Tetany, muscle spasms, and Chvostek Trousseau signs may be observed in patients with hypokalemia, hypocalcemia, and hypomagnesemia. In the older literature, rickets was occasionally reported.

• In 1997, Madrigal and colleagues described a type of this syndrome in Costa Rica in 16 of 20 patients, each with "a peculiar facies distinguished by a triangularly shaped face, large eyes, and protruding ears."

• Strabismus was found in 9 of the patients.

• Another 8 patients had sensorineural hearing loss determined by audiometry. Sensorineural hearing loss is reported in other series.

• This sensorineural loss has now been linked to mutations in the barttin subunit in Bartter syndrome IV.

Causes: Both familial and sporadic forms of Bartter and Gitelman syndromes exist. Bartter and Gitelman syndromes are inherited as autosomal recessive syndromes.

Differentials

Hypomagnesemia

Other Problems to be Considered:

Diuretic abuse
Gitelman syndrome
Hyperprostaglandin E syndrome
Familial hypomagnesemia with hypercalciuria/nephrocalcinosis
Activating mutations of the CaSR calcium sensing receptor

Workup

Lab Studies:

• Consider possible renal tubular disorder if patients, especially dehydrated infants and young children, are found to have hypokalemia and a high serum bicarbonate concentration that do not correct with potassium and chloride replacement treatment.

• Initiate timed urine collection to determine potassium levels.

• In hypokalemia, normal kidneys retain potassium.

• Elevated urinary potassium levels with low blood potassium levels suggest the kidneys are having problems retaining potassium.

• Next, initiate timed urine collection to determine aldosterone levels.

• Aldosterone levels should be low in volume-replete patients.

• If urinary aldosterone levels are high despite volume replacement, there is an abnormal stimulation of aldosterone.

• Patients with primary hyperaldosteronism in a volume-replete state usually have normal-to-high blood pressure.

• Low or low-normal blood pressure with high aldosterone excretion suggests the primary problem is something else, and the aldosterone response is secondary to the undiagnosed primary abnormality.

• Then, initiate a timed urine collection to determine chloride levels.

• Extrarenal volume depletion is a possible reason for low blood pressure, high aldosterone excretion, and potassium loss. In this case, the kidneys retain sodium and chloride, and urinary chloride concentrations should be low.

• High urine chloride levels with low blood pressure, high aldosterone secretion, and high urinary potassium levels are found only with long-term diuretic use and Bartter or Gitelman syndrome.

• If diuretic abuse is suspected, a urine screen for diuretics can be ordered. Otherwise, the diagnosis is Bartter or Gitelman syndrome.

• Mutations in 4 different transporters cause Bartter syndrome. The 4 mutations can be determined in the following ways:

• The older methods require more detailed physiologic investigations, including determination of serum magnesium levels and further urine collections to assess calcium, magnesium, and PGE2 levels.

• In Bartter syndrome, urine calcium excretion is high, leading to nephrocalcinosis, while serum magnesium levels are normal.

• With the transporter mutation that causes Gitelman syndrome, hypomagnesemia is common and is accompanied by hypocalciuria.

• More recently, genetic analysis has become the preferred methodology for determining if a mutation in one of the transporters has occurred. Richard Lifton's laboratory (Yale University) pioneered this approach, which permits the identification of the gene involved and can pinpoint where the mutation occurred.

Imaging Studies:

• Antenatal Bartter syndrome can be diagnosed best by ultrasonography. The fetus may have polyhydramnios and intrauterine growth retardation.

• After birth, especially if the disease is diagnosed in older patients who have hypercalciuria, consider a renal ultrasound or flat plate of the abdomen for nephrocalcinosis.

• Sonographic findings include diffusely increased echogenicity, hyperechoic pyramids, and interstitial calcium deposition.

• Because continued calcium loss may affect bones, dual-energy x-ray absorptiometry (DEXA) scans to determine bone mineral density may be advisable in older patients.

• Nephrocalcinosis can occur and is often associated with hypercalciuria. It can be diagnosed with abdominal radiographs, intravenous pyelograms (IVPs), renal ultrasonograms, or spiral CT scans.

Other Tests:

• Analysis of the genes for the transporters shows multiple problems leading to abnormal gene function, including missense, frame-shift, loss-of-function, and large deletion mutations. For a more detailed review, refer to Simon and colleagues' reports (see Bibliography).

• Hypomagnesemia

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