Pediatrics

Bartter and Gitelman syndromes

OVERVIEW: What every practitioner needs to know

Bartter and Gitelman syndromes are both autosomal recessive conditions characterized by renal salt wasting, hypokalemia, and metabolic alkalosis. The two syndromes differ biochemically in that children with Bartter syndrome commonly demonstrate hypercalciuria with normal serum magnesium levels, whereas those with Gitelman syndrome typically show low urinary calcium excretion and low serum magnesium levels.

The different biochemical profiles are the result of genetic defects causing impaired channel activity at different locations within the nephron. The Bartter syndrome phenotype is the result of impaired sodium/chloride reabsorption in the thick ascending limb (TAL), whereas the Gitelman syndrome phenotype is the result of impaired sodium/chloride reabsorption in the distal convoluted tubule (DCT).

Mutations in the SLC12A, KCNJ1, and BSND genes (Bartter syndrome type I, type II, and type IV, respectively) typically result in severe TAL dysfunction and presentation in the neonatal period (neonatal Bartter syndrome). Mutations in the ClCKB gene (Bartter syndrome type III) usually cause milder TAL dysfunction and often present outside the neonatal period. These mutations commonly result in the so-called classic Bartter syndrome.

Gitelman syndrome is usually the result of mutations in the SLC12A3 gene that result in impaired sodium/chloride reabsorption in the DCT. Because ClC-Kb channels are expressed in both the TAL and DCT, mutations in the ClCKB gene may occasionally result in a Gitelman syndrome phenotype.

Are you sure your patient has one of these syndromes? What are the typical findings for this disease?

Neonatal Bartter Syndrome

Neonatal or fetal presentation

Severe polyhydramnios

Prematurity (usually 27-35 weeks)

Severe intravascular volume depletion/dehydration

Polyuria

Growth retardation

Rarely deafness

Classic Bartter Syndrome

Usually presents in children younger than 6 years of age

Salt craving

Polyuria/dehydration

Emesis/constipation

Failure to thrive

Rarely periodic paralysis/rhabdomyolysis

Gitelman Syndrome

May present anytime but usually seen in adolescence or early adulthood

Muscle cramping/weakness/spasms/tetany

Paresthesias

Salt craving

Polydipsia/polyuria/nocturia

Joint pains (chondrocalcinosis)

Rarely palpitations/cardiac arrhythmias

Rarely periodic paralysis/rhabdomyolysis

What are the physical examination features?

Bartter syndrome has been associated with a distinctive appearance: thin with small muscles; triangular facies with a prominent forehead, large eyes, protruding pointed ears, and a pouting expression caused by drooping corners of the mouth. Growth retardation during infancy and childhood can be severe. A delayed adolescent growth spurt has been described, although most children usually attain normal stature.

In Gitelman syndrome it is sometimes possible to elicit a positive Chvostek sign and carpopedal spasms by inflating a blood pressure cuff.

What are the typical laboratory findings?

Bartter Syndrome

Hypokalemia

Metabolic alkalosis

Hypercalciuria (urine calcium:creatine ratio >0.21 in noninfant children)

Normal serum magnesium levels

Normal serum calcium levels

Dilute urine (<300 mOsm/L/kg)

High urinary chloride concentration

High serum plasma renin activity/aldosterone levels (not required for diagnosis)

Gitelman Syndrome

Hypokalemia

Metabolic alkalosis

Hypocalciuria (urine calcium:creatine ratio <0.044 in children >5 years of age)

Low serum magnesium

Normal serum calcium levels

High urinary chloride concentration

Mildly elevated serum plasma renin activity/aldosterone levels (not required for diagnosis)

What are the typical imaging findings?

Bartter Syndrome

Renal ultrasonography: nephrocalcinosis, rarely renal cysts

Gitelman Syndrome

Renal ultrasonography: Normal

What other disease/condition shares some of these symptoms?

Hypokalemia

Primary renal losses: diuretics, Cushing syndrome, primary hyperaldosteronism (Conn syndrome), secondary hyperaldosteronism (e.g., volume depletion/excessive vomiting, renal artery stenosis), monogenetic causes of hypertension (Liddle syndrome, apparent mineralocorticoid excess, glucocorticoid remedial aldosteronism), Fanconi syndrome, proximal/distal renal tubular acidosis (RTA), Bartter syndrome, Gitelman syndrome

Primary gastrointestinal losses: diarrhea, ileostomy, enteric fistula, nasogastric suction, laxative use/abuse, kayexalate use

Primary skin losses: severe burns (rare)

Dialysis losses

Hypomagnesemia

Reduced intestinal absorption: severe malnutrition, short bowel syndrome, chronic diarrhea, nasogastric suction, enteric fistula, hypomagnesemia with secondary hypocalcemia (TRPM6 gene mutation)

Primary renal losses: diuretics, cisplatin, aminoglycoside administration; calcineurin inhibitors; familial hypomagnesemia with hypercalciuria/nephrocalcinosis ( CLDN-16/Paracellin-1 gene mutation); isolated dominant hypomagnesemia (FXDY2 gene mutation); autosomal dominant hypocalcemia ( CaSR gene mutation resulting in a gain of function of the calcium-sensing receptor); Gitelman syndrome; Bartter syndrome (types III-IV; see ongoing controversies section below)

Redistribution: hungry bone syndrome

Metabolic: hypercalcemia, hypophosphatemia

Miscellaneous: alcoholism, diabetes mellitus

Infantile Nephrocalcinosis

Furosemide exposure, prematurity, hypercalcemia, hypervitaminosis D, distal RTA, familial hypomagnesemia with hypercalciuria/nephrocalcinosis, primary hyperoxaluria, Dent disease, neonatal Bartter syndrome

What caused this disease to develop at this time?

Neonatal Bartter syndrome (Bartter syndrome types I, II, and IV) primarily presents in the fetal or newborn period as a result of profound loop of Henle dysfunction. Mutations in both alleles of the SLC12A1, KCJN1, or BSND gene encoding NKCC2, ROMK, and Barttin, respectively, result in severe dysfunction of the TAL, massive urinary sodium losses, and resulting hypovolemia, hypokalemia, alkalosis, and hypercalciuria. The renin-aldosterone system is activated in an attempt to counteract the volume loss, stimulating excess potassium and hydrogen excretion in the collecting duct. The hypovolemia and hypokalemia further stimulate excessive prostaglandin E2 production within the renal interstitium, which adds to the defect in sodium and water reabsoprtion and amplifies TAL dysfunction.

Classic Bartter syndrome (type III), like its neonatal counterpart, is also the result of dysfunction of the TAL(ClC-Kb mutations); however, this phenotype usually (>80% of the time) presents outside the newborn period and is relatively more mild than the neonatal variant. A likely explanation for this observation is that a homologous ClC-Ka channel is also expressed in the TAL, which continues to function and partially compensate for the defective ClC-Kb channel. This principle is illustrated in rare families in which both copies of ClC-Ka and ClC-Kb genes were either deleted or mutated (Bartter syndrome type V; see below) and the neonatal Bartter phenotype was observed. Urinary prostaglandin E2 levels are usually elevated, but not to the same level as seen in neonatal Bartter syndrome.

Gitelman syndrome occurs as a result of impaired DCT function–associated SLC12A3 mutations (and less commonly with ClC-Kb mutations; see below). Under normal conditions, the DCT is responsible for reabsorbing a much smaller percentage (5%-10%) of urinary sodium/chloride than is the TAL (20%-30%). As a result, these patients usually present as older children and adults with milder symptoms, less profound urinary sodium losses, and hypomagnesemia.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Step 1: Obtain a basic metabolic panel, demonstrating hypokalemia and alkalosis.

Step 2: Assess blood pressure; if normal or low proceed to step 3. If the patient is hypertensive, consider alternative diagnoses (see hypokalemia algorithm below).

Step 3: Assess the potential for gastrointestinal or skin losses. If uncertain check urinary chloride concentration.If no gastrointestinal or skin losses and/or urinary chloride concentration is greater than 20 mEq/L proceed to step 4. If there are obvious extrarenal losses or the urinary chloride concentration is low (<10 mEq/L) consider alternative diagnoses (see hypokalemia algorithm below).

Step 4: Check serum magnesium levels and urine calcium to creatinine ratio

Step 5A: If both the serum magnesium and the urine calcium to creatinine ratio are low (<0.044 in children >5 years of age), a presumptive diagnosis of Gitelman syndrome is made. Consider genetic testing of the SLC12A3 gene.

Step 5B: If the serum magnesium level is normal and the urine calcium to creatinine ratio is high (>0.21 in noninfant children), a presumptive diagnosis of Bartter syndrome is made. Consider genetic testing of theSLC12A1, KCNJ1, ClCKB, BSND genes.

Would imaging studies be helpful? If so, which ones?

Renal Ultrasonography

Bartter syndrome: Nephrocalcinosis may be present, rarely renal cysts

Gitelman syndrome: Normal

Confirming the diagnosis

Hypokalemia Algorithm

If hypokalemia what is the acid/base status?

Hypokalemia and acidosis:

Gastrointestinal potassium loss: excessive diarrhea, ileostomy, fistula, laxative abuse Renal potassium loss: proximal RTA, distal RTA, Fanconi syndrome

Hypokalemia and normal serum bicarbonate (transcellular shift):

Thyrotoxic periodic paralysis

Hypokalemic periodic paralysis

Beta agonist exposure

Insulin/glucose administration

Hypokalemia and alkalosis:

Volume contraction with secondary kaliuresis: excessive vomiting/bulimia, cystic fibrosis/severe burns (skin)

Renal potassium loss: hyperaldosteronism, Cushing syndrome, monogenetic causes of hypertension (Liddle syndrome, apparent mineralocorticoid excess, glucocorticoid remedial aldosteronism), renal artery stenosis, diuretic use/abuse, Bartter syndrome, Gitelman syndrome

If hypokalemia and alkalosis what is the blood pressure?

Hypokalemia and alkalosis with hypertension:

Hyperaldosterism

Monogenetic forms of hypertension

Renal artery stenosis

Cushing syndrome

Hypokalemia and alkalosis with normal or low blood pressure:

Volume contraction with secondary kaliuresis: excessive vomiting/bulimia, cystic fibrosis

Diuretic abuse

Bartter syndrome

Gitelman syndrome

If hypokalemia, alkalosis, normotension, what is the urinary chloride concentration?

Low urinary chloride level (<10 mEq/L)

Volume contraction with secondary kaliuresis:

Excessive vomiting/bulimia, cystic fibrosis/severe burns

High urinary chloride level (>20 mEq/L):

Diuretic abuse

Bartter syndrome

Gitelman syndrome

If hypokalemia, alkalosis, normotension, high urinary chloride concentration, what is the serum magnesium level?

Normal serum magnesium level:

Loop diuretic use/abuse

Bartter syndrome

Low serum magnesium level:

Thiazide diuretic use/abuse

Gitelman syndrome

If you are able to confirm that the patient has Bartter or Gitelman syndrome, what treatment should be initiated?

Bartter Syndrome

The main treatment goals are aimed at treating the hypokalemia and minimizing the effects of increased prostaglandin and aldosterone secretion.

Neonatal Bartter Syndrome

In the immediate postnatal period, continuous saline infusions may be required to correct/prevent dehydration.

Indomethacin (starting dosage 1.0-2.5 mg/kg/day administered three times daily) is generally recommended after 6 weeks of age. More recently the use of more selective cyclooxygenase 2 inhibitors such as rofecoxib has been proposed, although data is currently limited.

Oral supplementation with large amounts of potassium chloride (up to 10 mEq/kg/day or 500 mEq in adults) may be required after the neonatal period.

Adjuvant therapies such as potassium-sparing diuretics (spirinolactone, triamterene, amiloride) or angiotensin-converting enzyme inhibitors (captopril, enalapril) may be required in refractory cases but are not generally required in neonatal Bartter syndrome.

Growth hormone may be required if short stature persists

Classic Bartter Syndrome

Oral supplementation with large amounts of potassium chloride (up to 10 mEq/kg/day or 500 mEq in adults) is almost always necessary.

The use of prostaglandin synthase inhibitors such as indomethacin (2-5 mg/kg/day), acetylsalicylic acid (100 mg/kg/day), ibuprofen (30 mg/kg/day), or ketoprofen (20 mg/kg/day) has become routine.

The addition of potassium-sparing diuretics or angiotensin-converting enzyme inhibitors has been effective in some patients.

Growth hormone may be required if catch-up growth is poor.

Gitelman Syndrome

The primary aim of treatment is to correct the hypomagnesemia and hypokalemia.

All patients should be treated with magnesium salts. Magnesium chloride (4-5 mg/kg/day divided into 3-4 doses) is often better tolerated than magnesium sulfate or magnesium oxide.

Additional drugs such as potassium chloride or potassium-sparing diuretics (spironolactone, amiloride, eplerenone) are often required if the hypokalemia is not corrected with the treatment of the hypomagnesemia.

The use of prostaglandin synthase inhibitors has no role in Gitelman syndrome because prostaglandin production is not generally increased.

Systematic cardiac screen for arrhythmias is currently recommended.

What are the adverse effects associated with each treatment option?

Treatment Complications

Indomethacin: Some practitioners recommend not using doses higher than 3mg/kg/day given the risks of intestinal perforation and nephrotoxicity. Indomethacin should not be administered to the mother of a fetus thought to have Bartter syndrome, to premature infants, or within the first 4-6 weeks of neonatal life given the potential effects on the ductus arteriosus and the developing kidney.

Spirinolactone: Antiandrogen effects can occur, including gynecomastia in boys.

Angiotensin-converting enzyme inhibitors: Effective therapy in Bartter syndrome is often limited by hypotension and renal failure resulting from baseline low-normal blood pressure and volume contraction.

Magnesium salts: The doses required to correct the hypomagensemia in Gitelman syndrome often result in abdominal bloating, cramping, and diarrhea.

What are the possible outcomes of Bartter and Gitelman syndromes?

Bartter syndrome: Somatic growth failure is common and usually improves with therapy. Growth hormone deficiency has been rarely reported. The exact risk for the development of chronic kidney disease and/or proteinuria is unknown. One series showed that 25% of patients with neonatal Bartter syndrome had a glomerular filtration rate of less than 90 mL/min/1.73 m 2 at 10-year follow-up.

The most common histologic lesion observed is focal segmental glomerulosclerosis. It has been postulated that chronic activation of the renin-angiotensin system, hypokalemic nephropathy, indomethacin exposure, and nephrocalcinosis all play a role in the renal injury. Cholelithiasis has been occasionally reported in association with neonatal Bartter syndrome and might be related to prematurity.

Gitelman syndrome: The long-term prognosis is generally excellent. Progression to chronic kidney disease or end-stage renal failure is rare. Joint pains and chondrocalcinosis associated with chronic hypomagnesemia have been reported. Although electrocardiographic abnormalities are common, clinically relevant arrhythmias are unusual. Chronic fatigue, weakness, and other quality-of-life measures such as limitations caused by physical health, emotion, level of energy, and general health perception may be more common in Gitelman syndrome.

Rare reports of periodic paralysis, rhabdomyolysis, and serious cardiac arrhythmias have been reported in both Bartter and Gitelman syndromes.

What causes this disease and how frequent is it?

The prevalence of Gitelman syndrome is estimated to range around 25 cases/million population, whereas the prevalence of heterozygous subjects is 1% in the white population.

The worldwide prevalence of Bartter syndrome has not been established but may be as low as 1 case/million population. The incidence of neonatal Bartter syndrome appears to higher in certain small and genetically isolated populations such as Costa Rica (1.2 cases/100,000 live births per year). In general patients with Bartter syndrome are outnumbered by those with Gitelman syndrome and are often the children of consanguineous marriages.

How do these pathogens/genes/exporuses cause the disease?

Please refer to Table I.

Table I.

Genetics of the Bartter and Gitelman syndromes
Syndrome Gene Affected Gene Product Location of Transporter Clinical Presentation
Bartter syndrome type I SLC12A1 NKCC2 Thick ascending limb Neonatal Bartter syndrome
Bartter syndrome type II KCJN1 ROMK Thick ascending limb Neonatal Bartter syndrome
Bartter syndrome type III ClCKB ClC-Kb Thick ascending limb/distal convoluted tubule Classic Bartter syndrome/ Gitelman syndrome (<20%)
Bartter syndrome type IV BSND Barttin Thick ascending limb/stria vascularis (inner ear) Neonatal Bartter syndrome with deafness
Gitelman syndrome SLC12A3 NCCT Distal convoluted tubule Gitelman syndrome

Other clinical manifestations that might help with diagnosis and management

One variant of neonatal Bartter syndrome (type IV) occurs as a result of a mutation in the BSND gene, which is expressed in both the TAL of the nephron and the stria vascularis of the inner ear. Barttin is an essential beta-subunit of the ClC-K channels, which are essential for endolymph production in the inner ear and maintaining the driving force for sodium/chloride reabsorption in the TAL. If a patient with suspected Bartter syndrome presents in the newborn period or if deafness is suspected, formal auditory brainstem response testing for sensorineural deafness is indicated .

Neonatal Bartter syndrome may rarely present with profound hyponatremia, hyperkalemia, and metabolic acidosis in the newborn period. This paradox occurs because the immature distal nephron (distal to the TAL) is overwhelmed by excess sodium/chloride delivery and cannot appropriately compensate for the massive naturesis. By 6 weeks of age, the distal nephron is more efficiently able to reabsorb the sodium/chloride and secrete potassium/hydrogen, and the classic hypokalemic metabolic alkalosis predominates.

Are additional laboratory studies available; even some that are not widely available?

Amniotic fluid chloride concentration: Although rarely evaluated, a high chloride concentration has been noted (>2 standard deviations above the mean) in the amniotic fluid of expecting mothers.

Urinary prostaglandin E2 levels: Elevated in Bartter syndrome, although not required to confirm the diagnosis; normal in Gitelman syndrome.

How can these Bartter and Gitelman syndromes be prevented?

Bartter and Gitelman syndromes cannot be prevented unless a prenatal diagnosis is made and the pregnancy is terminated. In view of the good prognosis of Gitleman syndrome, antenatal diagnosis is not advised.

Both Gitelman and Bartter syndromes are inherited in an autosomal recessive fashion and the risk of transmitting the disease from two asymptomatic heterozygous parents to their offspring is 25%.

Physicians must bear in mind that a child of a patient with Gitelman syndrome may be apparently free of symptoms in infancy, but the clinical syndrome can appear later at an adult age. DNA analysis is recommended in siblings of a child affected by Gitleman syndrome.

What is the evidence?

Seyberth, HW. "An improved terminology and classification of Bartter-like syndromes". Nat Clin Pract Nephrol. vol. 4. 2008. pp. 560-7.

Knoers, NV, Levtchenko, EN. "Gitelman syndrome". Orphanet J Rare Dis. vol. 3. 2008. pp. 22.

Rodríguez-Soriano, J. "Bartter and related syndromes: the puzzle is almost solved". Pediatr Nephrol. vol. 12. 1998. pp. 315-27.

Schurman, SJ, Shoemaker, LR. "Bartter and Gitelman syndromes". Adv Pediatr. vol. 47. 2000. pp. 223-48.

Shaer, AJ. "Inherited primary renal tubular hypokalemic alkalosis: a review of Gitelman and Bartter syndromes". Am J Med Sci. vol. 322. 2001. pp. 316-32.

Simopoulos, AP. "Growth characteristics in patients with Bartter's syndrome". Nephron. vol. 23. 1979. pp. 130-5.

Bianchetti, MG, Edefonti, A, Bettinelli, A. "The biochemical diagnosis of Gitelman disease and the definition of "hypocalciuria."". Pediatr Nephrol. vol. 18. 2003. pp. 409-11.

Graziani, G, Fedeli, C, Moroni, L. "Gitelman syndrome: pathophysiological and clinical aspects". QJM. vol. 103. 2010. pp. 741-8.

Akil, I, Ozen, S, Kandiloglu, AR, Ersoy, B. "A patient with Bartter syndrome accompanying severe growth hormone deficiency and focal segmental glomerulosclerosis". Clin Exp Nephrol. vol. 14. 2010. pp. 278-82.

Puricelli, E, Bettinelli, A, Borsa, N. "Long-term follow-up of patients with Bartter syndrome type I and II". Nephrol Dial Transplant. vol. 25. 2010. pp. 2976-81.

Cortesi, C, Lava, SA, Bettinelli, A. "Cardiac arrhythmias and rhabdomyolysis in Bartter-Gitelman patients". Pediatr Nephrol. vol. 25. 2010. pp. 2005-8.

Janssen, AG, Scholl, U, Domeyer, C. "Disease-causing dysfunctions of barttin in Bartter syndrome type IV". J Am Soc Nephrol. vol. 20. 2009. pp. 145-53.

Finer, G, Shalev, H, Birk, OS. "Transient neonatal hyperkalemia in the antenatal (ROMK defective) Bartter syndrome". J Pediatr. vol. 142. 2003. pp. 318-23.

Proesmans, W. "Bartter syndrome and its neonatal variant". Eur J Pediatr. vol. 156. 1997. pp. 669-79.

Colussi, G, Rombolà, G, De Ferrari, ME. "Correction of hypokalemia with antialdosterone therapy in Gitelman's syndrome". Am J Nephrol. vol. 14. 1994. pp. 127-35.

(Given the rarity of these diseases there are no randomized controlled trials. One study of six adults with Gitelman syndrome found that spironolactone was more effective than amiloride in partially correcting the hypokalemia.)

Vezzoli, G, Arcidiacono, T, Paloschi, V. "Autosomal dominant hypocalcemia with mild type 5 Bartter syndrome". J Nephrol. vol. 19. 2006. pp. 525-8.

Bogdanovic, R, Draaken, M, Toromanovic, A. "A novel CLCN5 mutation in a boy with Bartter-like syndrome and partial growth hormone deficiency". Pediatr Nephrol. vol. 25. 2010. pp. 2363-8.

Ongoing controversies regarding etiology, diagnosis, treatment

There have been at least two distinct entities referred to as type V Bartter syndrome in the literature:

1. Autosomal dominant hypocalcemia with mild salt-losing effect: autosomal dominant hypocalcemia results from a gain of function mutation in the calcium-sensing receptor (CaSR). The condition classically results in hypocalcemia, hypercalciuria, and inappropriately suppressed parathyroid hormone levels. The CaSR also has both direct and indirect effects on sodium/chloride reabsorption in the TAL. As a result, gain of function mutations in the CaSR rarely result in mild TAL salt wasting with resultant hypokalemia, alkalosis and a Bartter-like phenotype.

2. Digenic inheritance from double mutations in both alleles of the ClC-Ka and ClC-Kb genes: At least two families have been described in which both copies of ClC-Ka and ClC-Kb genes were either deleted or mutated. These infants presented with a phenotype nearly identical to that of type IV Bartter syndrome with profound neonatal salt wasting, hypokalemia, alkalosis, and sensorineural hearing loss.

Variability in urinary calcium and magnesium excretion in Bartter syndrome:

As described above, Bartter syndrome results from decreased sodium/chloride reabsorption in the TAL and patients classically demonstrate hypercalciuria with normal serum magnesium levels. Conversely, the decreased sodium/chloride reabsorption from the DCT results in hypocalciuria and hypomagnesemia seen in classic Gitelman syndrome. However, several of these ion channels which are predominantly expressed in the TAL and have been classically assoicated with Bartter syndrome (ClC-Ka, ClC-Kb, and Barttin) also demonstrate expression and activity in the DCT. As a result, patients with Bartter syndrome types III-IV may have variable degrees of urinary magnesium and calcium excretion and may not fall easily into the classic definitions of either Bartter or Gitelman syndromes.

Association between Dent disease and Bartter phenotype:

Recently two separate reports described children with genetically proven Dent disease type I and features of Bartter syndrome. At this time the pathophysiologic characteristics of these two seemingly distinct entities are unclear.

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