LEARN Paediatrics EASY

ALLERGIC DISEASES OF EYES & TREATMENT

Gitelman Syndrome :

Gitelman syndrome is a rare autosomal recessive renal tubular disorder caused by defective sodium and chloride reabsorption in the distal convoluted tubule (DCT) due to mutations in the SLC12A3 gene encoding the thiazide-sensitive Na⁺/Cl⁻ cotransporter (NCC).

It mimics the effects of chronic thiazide diuretic use.

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Pathophysiology

Defective NCC transporter in the DCT leads to:

↓ Sodium and chloride reabsorption
→ Mild volume depletion
→ Activation of the renin-angiotensin-aldosterone system (RAAS)

This causes:

* Increased potassium secretion → Hypokalemia
* Increased hydrogen ion secretion → Metabolic alkalosis

The DCT also normally reabsorbs magnesium.

Defective function results in:

* Hypomagnesemia

Reduced intracellular sodium enhances calcium reabsorption, resulting in:

* Hypocalciuria (low urinary calcium)

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Genetics

* Gene: SLC12A3
* Protein affected: Thiazide-sensitive Na⁺/Cl⁻ cotransporter (NCC)
* Inheritance: Autosomal recessive

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Clinical Features

Usually presents in late childhood, adolescence, or adulthood.

Symptoms

* Muscle weakness
* Fatigue
* Muscle cramps
* Salt craving
* Polyuria
* Polydipsia
* Nocturia
* Dizziness
* Constipation
* Paresthesias
* Tetany (due to hypomagnesemia)
* Palpitations

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Signs

* Normal or low blood pressure
* Delayed growth (occasionally)
* Chvostek or Trousseau signs (if severe hypomagnesemia)

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Laboratory Findings

Serum

* ↓ Potassium
* ↓ Magnesium
* ↓ Chloride
* ↑ Bicarbonate (metabolic alkalosis)
* Normal sodium (usually)
* ↑ Renin
* ↑ Aldosterone

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Urine

* Low urinary calcium (hypocalciuria)
* Increased urinary magnesium

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Acid–Base Status

* Metabolic alkalosis

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Blood Pressure

* Normal or low

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ECG Findings

Due to hypokalemia and hypomagnesemia:

* Flattened T waves
* Prominent U waves
* QT prolongation
* Ventricular arrhythmias (rare but serious)

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Diagnosis

Suspect in a patient with:

* Persistent hypokalemia
* Metabolic alkalosis
* Hypomagnesemia
* Hypocalciuria
* Normal/low blood pressure

Confirmation:

* Genetic testing for SLC12A3 mutation

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Differential Diagnosis

Disorder Urinary Calcium Magnesium Age at Presentation
Gitelman syndrome Low Low Adolescence/adulthood
Bartter syndrome High Normal/mildly low Infancy/childhood
Thiazide use Low Low Variable
Vomiting Low urine chloride Variable Variable
Primary hyperaldosteronism Hypertension Normal Adult

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Bartter vs Gitelman Syndrome

Feature Bartter Gitelman
Site Thick ascending limb Distal convoluted tubule
Transporter NKCC2 NCC
Mimics Loop diuretics Thiazide diuretics
Age Neonatal/childhood Adolescence/adulthood
Urinary calcium High Low
Magnesium Normal/mildly low Markedly low
Nephrocalcinosis Common Rare
Polyhydramnios Common (antenatal type) Absent

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Treatment

1. Potassium supplementation

* Lifelong oral potassium replacement

2. Magnesium supplementation

* Essential treatment
* Magnesium oxide, citrate, or other oral preparations

3. Potassium-sparing agents

* Amiloride
* Spironolactone
* Eplerenone

These reduce urinary potassium loss.

4. Liberal salt intake

* May help compensate for salt wasting

5. Adequate hydration

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Complications

* Cardiac arrhythmias
* Severe muscle weakness
* Tetany
* Chondrocalcinosis (due to chronic hypomagnesemia)
* Reduced quality of life from chronic fatigue

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Prognosis

* Generally excellent.
* Most patients have a normal life expectancy.
* Chronic electrolyte replacement is usually required.

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High-Yield MRCPCH/Pediatric Exam Points

* Defect in the distal convoluted tubule.
* Mutation in SLC12A3 (NCC transporter).
* Mimics thiazide diuretic use.
* Hypokalemic, hypochloremic metabolic alkalosis.
* Hypomagnesemia is a hallmark.
* Hypocalciuria distinguishes it from Bartter syndrome.
* Normal or low blood pressure despite elevated renin and aldosterone.
* Treatment centers on magnesium replacement, potassium supplementation, and potassium-sparing agents.

Easy Memory Trick

Syndrome Think of Urinary Calcium
Bartter Before DCT (Loop of Henle), Big calcium loss High
Gitelman Good calcium reabsorption in DCT Low

Bartter Syndrome:

Bartter syndrome is a rare inherited renal tubular disorder characterized by defective sodium, potassium, and chloride reabsorption in the thick ascending limb (TAL) of the loop of Henle.

It causes:

* Renal salt wasting
* Hypokalemia
* Metabolic alkalosis
* Hyperreninemia
* Hyperaldosteronism
* Normal or low blood pressure

It resembles the effects of chronic loop diuretic (e.g., furosemide) use.

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Pathophysiology

Normally, the TAL reabsorbs about 25% of filtered sodium through the Na-K-2Cl cotransporter (NKCC2).

Defective transport results in:

↓ Sodium reabsorption
→ Salt wasting
→ Volume depletion

↓

Activation of:

* Renin
* Angiotensin II
* Aldosterone

↓

Increased potassium and hydrogen secretion

↓

* Hypokalemia
* Metabolic alkalosis

Loss of lumen-positive voltage also decreases calcium and magnesium reabsorption.

Result:

* Hypercalciuria
* Nephrocalcinosis (especially neonatal forms)

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Genetics

Autosomal recessive inheritance.

Type I

Gene:
SLC12A1

Defect:
NKCC2 cotransporter

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Type II

Gene:
KCNJ1

Defect:
ROMK potassium channel

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Type III (Most common)

Gene:
CLCNKB

Defect:
Basolateral chloride channel

Usually milder.

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Type IV

Genes:

* BSND
* CLCNKA + CLCNKB

Associated with:

* Sensorineural deafness

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Type V

Gain-of-function mutation:
CASR

Activates calcium-sensing receptor

Results in:

* Salt wasting
* Hypocalcemia
* Hypercalciuria

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Classification

Antenatal (Neonatal) Bartter

Severe disease

Presents before birth.

Features:

* Polyhydramnios
* Prematurity
* Neonatal dehydration
* Severe electrolyte disturbances

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Classical Bartter

Later infancy or childhood.

Less severe.

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Clinical Features

Neonates

* Polyhydramnios
* Prematurity
* Low birth weight
* Polyuria
* Vomiting
* Failure to thrive
* Dehydration
* Fever without infection

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Children

* Growth failure
* Poor weight gain
* Polyuria
* Polydipsia
* Constipation
* Salt craving
* Muscle weakness
* Fatigue
* Delayed puberty

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Severe disease

* Tetany
* Seizures (rare)
* Cardiac arrhythmias
* Nephrocalcinosis
* Chronic kidney disease (occasionally)

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Laboratory Findings

Serum

↓ Potassium

↓

Hypokalemia

↓

↓ Chloride

↓

Metabolic alkalosis

↓

Normal sodium (often)

↓

Low magnesium (sometimes)

↓

High renin

↓

High aldosterone

↓

Normal blood pressure

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Urine

High urinary:

* Sodium
* Potassium
* Chloride

High urinary calcium
(Hypercalciuria)

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Acid–Base

Metabolic alkalosis

High bicarbonate

Low chloride

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Calcium

Bartter:

↑ Urinary calcium

Nephrocalcinosis common

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Magnesium

Usually normal

May be mildly decreased

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Blood Pressure

Normal

or

Low

Despite elevated renin and aldosterone because renal salt wasting prevents hypertension.

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Imaging

Renal ultrasound:

May show

* Nephrocalcinosis
* Medullary calcification

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Diagnosis

Suggestive features

Child with:

* Polyuria
* Failure to thrive
* Hypokalemia
* Metabolic alkalosis
* Normal BP

High urine chloride

High renin

High aldosterone

Diagnosis confirmed by genetic testing.

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Differential Diagnosis

Disorder Urinary Calcium Blood Pressure
Bartter syndrome High Normal/Low
Gitelman syndrome Low Normal
Diuretic abuse High Variable
Vomiting Low urine chloride Normal
Hyperaldosteronism High BP High

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Bartter vs Gitelman Syndrome

Feature Bartter Gitelman
Site Thick ascending limb Distal convoluted tubule
Defect NKCC2 pathway NCC transporter
Age Neonatal/Childhood Adolescence/Adult
Urinary calcium High Low
Magnesium Mildly low/normal Markedly low
Nephrocalcinosis Common Rare
Severity More severe Usually milder

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Treatment

1. Potassium supplementation

Lifelong oral potassium replacement.

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2. NSAIDs

Indomethacin is commonly used because it:

* Reduces prostaglandin production
* Decreases polyuria
* Improves growth
* Reduces salt wasting

Other options:

* Ibuprofen
* Celecoxib (selected patients)

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3. Potassium-sparing agents

* Spironolactone
* Eplerenone
* Amiloride

These reduce potassium loss.

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4. ACE inhibitors / ARBs

Occasionally used in selected patients to reduce RAAS activation, with careful monitoring.

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5. Salt supplementation

Especially in infants with severe salt wasting.

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6. Magnesium

If deficient.

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7. Adequate hydration

Essential, especially during illness.

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Complications

* Growth retardation
* Developmental delay (if untreated)
* Nephrocalcinosis
* Chronic kidney disease
* Arrhythmias
* Recurrent dehydration
* Electrolyte crises

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Prognosis

* Most children survive into adulthood with appropriate treatment.
* Growth improves with early diagnosis and therapy.
* Renal function is usually preserved but may decline in severe or untreated cases.

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Key MRCPCH/Pediatric Exam Points

* Defect in the thick ascending limb of the loop of Henle.
* Mimics loop diuretic (furosemide) use.
* Hypokalemic, hypochloremic metabolic alkalosis.
* High renin and high aldosterone with normal blood pressure.
* Hypercalciuria and nephrocalcinosis are characteristic.
* Antenatal form presents with polyhydramnios and prematurity.
* Indomethacin is a cornerstone of treatment.
* Differentiate from Gitelman syndrome by hypercalciuria (Bartter) versus hypocalciuria and marked hypomagnesemia (Gitelman).

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