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Fanconi syndrome

Diagnosis and management of Fanconi syndrome in pediatric patients

Hereditary and acquired causes of Fanconi syndrome

Inherited Acquired
Arthrogryposis, renal dysfunction, cholestasis (ARC) syndrome Acute tubulointerstitial nephritis and uveitis (TINU) syndrome
Cystinosis Anorexia nervosa
Dent disease Autoimmune interstitial nephritis and membranous nephropathy
Distal renal tubular acidosis (dRTA), if untreated
Fanconi-Bickel syndrome Exogenous substances: drugs*, chemical compounds, heavy metals
Galactosemia Kidney transplantation
Glycogen storage disease type 1 (von Gierke disease) Myeloma
Hereditary fructose intolerance Nephrotic syndrome
Lowe syndrome Severe vitamin D deficiency
Lysinuric protein intolerance Sjögren syndrome
Maturity-onset diabetes of the young (MODY)
Microvillus inclusion disease
Mitochondrial diseases
NaPi2a deficiency
Tyrosinemia type I
Wilson disease
  • *Drugs include chemotherapeutic agents (cisplatin, ifosfamide), valproic acid, aminoglycosides (e.g., gentamicin), tenofovir, salicylates

Signs and symptoms

  • Failure to thrive
  • Polyuria/polydipsia
    • Can result in chronic volume depletion
  • Rickets
  • Muscle weakness
  • Constipation
    • May be a manifestation of dehydration or electrolyte abnormalities

Lab findings

  • Aminoaciduria is the earliest manifestation
    • Progresses to glycosuria, phosphaturia,
  • Persistent normal anion gap (nongap) metabolic acidosis (NAGMA)
  • Glucosuria
  • Hypophosphatemia
  • Hypokalemia
  • Hyperuricosuria
  • Proteinuria
  • Low serum 1,25-dihydroxyvitamin D


  • Progresses to full Fanconi syndrome by 12 months of age


  • Classic galactosemia is the most severe form of galactosemia and is caused by complete deficiency of galactose-1-phosphate uridyltransferase (GALT)
  • Patients with galactosemia have liver dysfunction, Fanconi syndrome, frequent infections, failure to thrive and cataracts
  • Absence of GALT activity in red blood cells is the diagnostic test for galactosemia.

Lowe syndrome

  • Inheritance: X-linked recessive
    • OCRL1 on chromosome Xq25-26 encoding the Lowe oculocerebral syndrome 1 (OCRL-1) protein
  • Pathogenesis: OCRL-1 is an inositol polyphosphate 5-phosphatase expressed in all cells except hematopoietic cells
    • Phosphoinositides regulate many cellular processes including membrane trafficking and actin cytoskeleton remodeling
    • OCRL-1 has important roles in endosomal trafficking
      • Impaired megalin-cubilin receptor-mediated endocytosis in the proximal tubule leads to LMW proteinuria
        • Normally, LMW proteins bind to megalin on the apical surface of proximal tubular cells and undergo endocytosis, then acidification causes dissociation of the megalin-LMW protein complex and LMW proteins are released to be degraded in lysosomes and megalin is recycled back to the cell surface
        • In Lowe syndrome, megalin recycling is impaired
  • Phenotype:
    • Ocular manifestations
      • Bilateral congenital cataracts in nearly all
        • Cataracts develop in utero and can be seen on prenatal ultrasound
      • Infantile glaucoma in ~50%
      • All have impaired visual acuity
    • Neurological manifestations:
      • Central generalized hypotonia
        • Diminished or absent deep tendon reflexes (DTRs)
      • Delayed motor milestones
      • Intellectual disability in almost all, most of which are in the severe-profound range
      • Behavioral abnormalities including aggression, tantrums, repetitive movements, self-injurious behaviors
    • Severe growth impairment
      • Independent of kidney manifestations
    • Musculoskeletal features:
      • Joint hypermobility
      • Scoliosis
      • Osteopenia
      • Up to half of adults get debilitating arthropathy with palmar/plantar fibrosis, subcutaneous nodules, nontender joint swelling, flexion contractures, and bony erosions
    • Kidney manifestations:
      • Proximal tubular dysfunction
        • Low molecular weight (LMW) proteinuria
        • Aminoaciduria
        • Metabolic acidosis
        • Hypophosphatemia
          • Rickets
        • Polyuria
        • Hypercalciuria
          • Can cause nephrocalcinosis and/or nephrolithiasis
      • Over time, may develop tubulointerstitial fibrosis and glomerulosclerosis leading to progressive CKD and progression to ESKD in adulthood

Dent disease

  • Inheritance: X-linked recessive
    • CLCN5 in most patients (~60%)
    • OCRL1 in ~20% of patients, termed Dent disease 2 (DD2)
    • ~20% of cases of Dent disease remain genetically unresolved
  • Pathogenesis
    • CLCN5 encodes CLC5, a chloride-proton antiporter primarily in the subapical endosomes of the proximal tubule, which is required for maintaining acidification in the endosome
      • Acidification is required for LMW proteins to dissociate from the receptors and undergo degradation
    • Mechanisms of hypercalciuria and hyperphosphaturia are not completely understood, but may be due to high urinary PTH levels
  • Phenotypes
    • Dent disease 2 (DD2) due to OCRL1 mutation
      • Depending on where the mutation falls and the type of mutation, OCRL1 mutations also can cause Lowe syndrome, which has extrarenal manifestations [GeneReviews]
      • DD2 is generally considered a milder form of Lowe syndrome without neurologic or ocular manifestations and typically less severe kidney disease
        • They usually do not develop acidosis and they have normal or near normal facial appearance, intelligence, muscle tone, and ocular findings
      • Typically have elevated LDH and CK (CPK)
  • Treatment
    • No specific treatments
    • Hypercalciuria can be managed with sodium restriction, thiazide diuretics
    • Hypophosphatemia and rickets may require phosphate, vitamin D supplementation
      • Vitamin D can worsen hypercalciuria
    • Limited data on the use of ACEi
      • ACEi for LMW proteinuria has not been shown to contribute to CKD progression