Inherited tubular disorders are genetic diseases affecting specific segments of the renal tubule, causing abnormal transport of electrolytes and solutes. They usually present in infancy or childhood with growth failure, electrolyte imbalance, metabolic disturbances, and polyuria.
Below is a concise but complete paediatric reference for the major inherited tubular disorders: Fanconi syndrome, Bartter syndrome, Gitelman syndrome, and Liddle syndrome.
1. Fanconi Syndrome
Definition
A generalized defect of the proximal renal tubule resulting in impaired reabsorption of multiple substances including glucose, amino acids, phosphate, bicarbonate, and uric acid.
Site of Defect
Proximal convoluted tubule (PCT)
Pathophysiology
Normally the proximal tubule reabsorbs:
- Glucose
- Amino acids
- Phosphate
- Bicarbonate
- Uric acid
In Fanconi syndrome → failure of PCT reabsorption → urinary loss of these substances.
This leads to:
- Metabolic acidosis (loss of bicarbonate)
- Hypophosphatemia → rickets
- Polyuria
- Dehydration
- Growth failure
Causes
Inherited
- Cystinosis (most common cause in children)
- Wilson disease
- Hereditary fructose intolerance
- Tyrosinemia type I
- Galactosemia
- Lowe syndrome
- Dent disease
Acquired
- Drugs (ifosfamide, tenofovir)
- Heavy metals
- Multiple myeloma (rare in children)
Clinical Features
Usually present in infancy or early childhood.
- Failure to thrive
- Polyuria
- Polydipsia
- Dehydration
- Rickets
- Bone pain
- Growth retardation
- Metabolic acidosis
- Hypotonia
Laboratory Findings
Urine:
- Glycosuria (without hyperglycemia)
- Aminoaciduria
- Phosphaturia
- Bicarbonaturia
Blood:
- Hypophosphatemia
- Hypokalemia
- Metabolic acidosis (proximal RTA type 2)
Diagnosis
- Urine amino acid analysis
- Urine glucose with normal blood glucose
- Serum electrolytes
- Genetic testing
- Specific tests for underlying disease (cystine crystals in cystinosis)
Differential Diagnosis
- Distal renal tubular acidosis
- Vitamin D deficiency rickets
- Hypophosphatemic rickets
Management
General treatment
- Fluid and electrolyte correction
- Nutritional support
Specific therapy
- Bicarbonate replacement
* Sodium bicarbonate 5–15 mEq/kg/day
- Phosphate supplementation
* Oral phosphate salts
- Vitamin D therapy
* Calcitriol
- Potassium supplementation
- Treat underlying disorder
* Cysteamine for cystinosis
Prognosis
Depends on cause.
Cystinosis may progress to chronic kidney disease.
2. Bartter Syndrome
Definition
A genetic disorder of the thick ascending limb of the loop of Henle causing defective sodium and chloride reabsorption, mimicking chronic loop diuretic effect.
Site of Defect
Thick ascending limb of loop of Henle
Genes involved:
- NKCC2 transporter
- ROMK potassium channel
- ClC-Kb chloride channel
Pathophysiology
Defect in Na-K-2Cl transporter leads to:
- Increased sodium delivery to distal tubule
- Activation of RAAS
- Increased potassium loss
- Increased hydrogen ion secretion
Results in:
- Hypokalemia
- Metabolic alkalosis
- Normal or low blood pressure
- Hypercalciuria
Types
- Antenatal Bartter syndrome
- Classic Bartter syndrome
- Type I–V genetic variants
Clinical Features
Antenatal
- Polyhydramnios
- Prematurity
Neonatal/childhood
- Polyuria
- Polydipsia
- Failure to thrive
- Dehydration
- Growth retardation
- Muscle weakness
Laboratory Findings
Blood:
- Hypokalemia
- Metabolic alkalosis
- Elevated renin and aldosterone
Urine:
- High urinary potassium
- Hypercalciuria
Diagnosis
- Serum electrolytes
- Urine electrolytes
- High renin and aldosterone
- Genetic testing
Differential Diagnosis
- Gitelman syndrome
- Diuretic abuse
- Renal tubular acidosis
Management
Electrolyte replacement
- Potassium supplementation
Prostaglandin inhibition
Indication: reduce renal salt wasting
Drug: Indomethacin
Mechanism:
- Inhibits prostaglandin synthesis → reduces renal blood flow → decreases electrolyte loss
Dose:
- 1–5 mg/kg/day
Adverse effects:
- Gastritis
- Renal dysfunction
Potassium-sparing agents
- Spironolactone
- Amiloride
ACE inhibitors
May reduce RAAS activation
Prognosis
Variable; growth improves with treatment.
3. Gitelman Syndrome
Definition
An autosomal recessive defect of the distal convoluted tubule affecting sodium chloride cotransporter.
Site of Defect
Distal convoluted tubule
Gene:
SLC12A3
Pathophysiology
Impaired Na-Cl reabsorption → mild salt wasting → RAAS activation → potassium loss.
Key feature:
Magnesium wasting and hypocalciuria
Clinical Features
Usually appears in late childhood or adolescence.
- Muscle cramps
- Fatigue
- Tetany
- Growth delay
- Polyuria
- Salt craving
Laboratory Findings
Blood:
- Hypokalemia
- Metabolic alkalosis
- Hypomagnesemia
Urine:
- Hypocalciuria
Diagnosis
- Electrolyte analysis
- Urine calcium
- Genetic testing
Differential Diagnosis
- Bartter syndrome
- Diuretic abuse
Key difference from Bartter
| Feature | Bartter | Gitelman |
| --------- | -------------- | ------------- |
| Site | Loop of Henle | Distal tubule |
| Calcium | Hypercalciuria | Hypocalciuria |
| Magnesium | Normal | Low |
| Age | Infancy | Adolescence |
Management
Electrolyte therapy
- Potassium supplements
- Magnesium supplements
Drugs
- Potassium-sparing diuretics (amiloride, spironolactone)
Diet
- High salt diet
Prognosis
Generally benign with normal life expectancy.
4. Liddle Syndrome
Definition
A rare autosomal dominant disorder causing increased sodium reabsorption in the distal nephron, resulting in severe early hypertension.
Site of Defect
Collecting duct
Gene mutation:
ENaC (epithelial sodium channel)
Pathophysiology
Mutation causes overactive sodium channels.
Consequences:
- Increased Na reabsorption
- Increased K secretion
- Volume expansion
- Hypertension
- Suppressed renin and aldosterone
Clinical Features
- Early severe hypertension
- Hypokalemia
- Metabolic alkalosis
- Muscle weakness
- Polyuria
- Polydipsia
Often diagnosed in childhood or adolescence.
Laboratory Findings
Blood:
- Hypokalemia
- Metabolic alkalosis
- Low renin
- Low aldosterone
Urine:
- Increased potassium excretion
Diagnosis
- Electrolytes
- Renin–aldosterone levels
- Genetic testing
Differential Diagnosis
- Primary hyperaldosteronism
- Apparent mineralocorticoid excess
Management
First-line drugs
Amiloride or triamterene
Mechanism:
Block epithelial sodium channel (ENaC)
Dose:
Amiloride 5–10 mg/day
Important point
Spironolactone is ineffective because aldosterone is already low.
Additional measures
- Low salt diet
Prognosis
Good with early treatment but untreated cases may develop severe hypertension complications.
Quick Comparison Table
| Feature | Fanconi | Bartter | Gitelman | Liddle |
| -------------- | -------------------------------- | ------------------- | ------------------- | ------------------- |
| Tubule site | Proximal | Loop of Henle | Distal tubule | Collecting duct |
| Main defect | Generalized reabsorption failure | NKCC transporter | NaCl cotransporter | ENaC overactivity |
| Potassium | Low | Low | Low | Low |
| Acid-base | Metabolic acidosis | Metabolic alkalosis | Metabolic alkalosis | Metabolic alkalosis |
| Calcium | Normal | High urine Ca | Low urine Ca | Normal |
| Blood pressure | Normal | Normal | Normal | High |
| Renin | Normal | High | High | Low |
| Aldosterone | Normal | High | High | Low |
If you want, I can also provide 30–40 NEET PG / NEXT / USMLE style MCQs from inherited tubular disorders in paediatrics, which are very high-yield for exams.
