What are the diagnostic criteria and treatment options for a child or adolescent with a history of hypokalemia, hypomagnesemia, and metabolic alkalosis, suspected of having Gitelman syndrome?

Gitelman Syndrome Diagnosis

Diagnose Gitelman syndrome in a child or adolescent presenting with hypokalemia, hypomagnesemia, and metabolic alkalosis by confirming hypocalciuria (the key distinguishing feature), elevated fractional chloride excretion (>0.5%), and ultimately genetic testing for SLC12A3 mutations, while first excluding diuretic abuse and distinguishing it from Bartter syndrome based on later age of presentation and low urinary calcium. 1, 2

Clinical Presentation

Gitelman syndrome typically presents during adolescence or adulthood (usually after age 6 years), distinguishing it from Bartter syndrome which presents prenatally or in early infancy. 1, 2 Key clinical features include:

• Transient muscle weakness and tetany (sometimes with abdominal pain, vomiting) 2, 3
• Paresthesias, especially facial 2
• Hypocalcemic tetany can occur despite normal serum calcium due to severe hypomagnesemia impairing PTH secretion 4, 3
• Blood pressure lower than general population 2
• Many patients are completely asymptomatic until adulthood 2

Diagnostic Criteria

Essential Laboratory Findings

The diagnostic triad consists of:

1. Hypokalemia (typically <3.5 mmol/L) with metabolic alkalosis 5, 2, 6
2. Hypomagnesemia (often <0.9 mEq/L) 5, 3, 6
3. Hypocalciuria - this is the critical distinguishing feature from Bartter syndrome 5, 2, 3

Confirmatory Testing

• Fractional excretion of chloride >0.5% indicates renal salt wasting 1, 4
• Increased urinary sodium and chloride excretion despite hypokalemia 5
• Hypochloremic metabolic alkalosis 1, 5, 2
• Normal renal function (distinguishes from chronic kidney disease) 5

Genetic Confirmation

Genetic testing for SLC12A3 mutations (encoding the thiazide-sensitive NaCl cotransporter) confirms the diagnosis in the majority of cases, with over 140 different mutations identified. 2 A small minority have CLCNKB gene mutations. 2 Analytical sensitivity is 90-100% in children but only 12.5% in adults due to broader differential diagnosis. 1

Critical Differential Diagnosis

Distinguishing from Bartter Syndrome

The key differences are:

• Age of onset: Gitelman presents in adolescence/adulthood; Bartter presents prenatally or in infancy 1, 2
• Urinary calcium: Hypocalciuria in Gitelman vs. hypercalciuria in Bartter (Types 1,2,4) 1, 4
• Severity: Gitelman is milder without polyhydramnios or severe neonatal presentation 1, 7
• Magnesium: More prominent hypomagnesemia in Gitelman 1, 2

Exclude Secondary Causes

Must exclude diuretic abuse (thiazides mimic Gitelman syndrome) and laxative abuse before confirming hereditary tubulopathy. 1 This is particularly important in adults where diuretic abuse accounts for the lower diagnostic yield of genetic testing. 1

Treatment Approach

Asymptomatic Patients

Most asymptomatic patients remain untreated with annual ambulatory monitoring by nephrology. 2 The long-term prognosis is excellent. 5, 2

Symptomatic Management

1. Lifelong magnesium supplementation (magnesium oxide or magnesium sulfate) is the cornerstone of therapy 2, 6

   • Magnesium replacement is critical as hypomagnesemia impairs calcium homeostasis and prevents potassium repletion 4

2. Potassium chloride supplementation (not potassium citrate, which worsens alkalosis) 4, 5

   • Target serum potassium 4.5-5.0 mEq/L 4

3. Potassium-sparing diuretics (amiloride 2.5-5 mg daily or spironolactone 25-100 mg daily) help maintain potassium levels 4, 6, 7

4. NSAIDs (indomethacin) for symptomatic patients to inhibit prostaglandin-mediated effects, with gastric acid suppression 4, 6

5. High-sodium and high-potassium diet encouraged for all patients 2

Acute Presentations

For hypocalcemic tetany: urgent IV calcium gluconate, but monitor ECG as hypocalcemia may paradoxically protect against arrhythmias from severe hypokalemia. 4, 3 Address underlying hypomagnesemia simultaneously. 4, 3

Critical Pitfalls

• Do not use potassium citrate or other non-chloride potassium salts - these worsen metabolic alkalosis and perpetuate potassium wasting 4
• Do not overlook magnesium replacement - hypocalcemia and hypokalemia will not correct without addressing hypomagnesemia 4, 3
• Cardiac screening should be offered to assess arrhythmia risk, as sudden cardiac arrest has been reported occasionally 2
• Genetic counseling is important given autosomal recessive inheritance with ~1% carrier frequency in Caucasians 2