Fanconi Syndrome: Definition, Causes, Diagnosis, and Management
What is Fanconi Syndrome?
Fanconi syndrome is a generalized dysfunction of the proximal renal tubule resulting in excessive urinary losses of phosphate, glucose, amino acids, bicarbonate, and other solutes, leading to hypophosphatemia, hypokalemia, metabolic acidosis, and glucosuria despite normal serum glucose. 1, 2, 3
The syndrome represents a global transport defect in the proximal tubule that overwhelms the capacity of more distal nephron segments to reclaim these substances. 1
Clinical Presentation
Cardinal Laboratory Features
The diagnosis requires identifying the characteristic pattern of proximal tubular losses:
- Hypophosphatemia from impaired phosphate reabsorption, leading to osteomalacia in adults and rickets in children with frontal bossing 4, 5, 6
- Hypokalemia from increased urinary potassium losses, exacerbated by metabolic acidosis 4, 5
- Glucosuria despite normal serum glucose levels—a pathognomonic finding 4, 5, 6
- Generalized aminoaciduria with excessive amino acid excretion 4, 5
- Metabolic acidosis (normal anion gap) from bicarbonate wasting and defective hydrogen ion excretion 1, 7
- Elevated urinary pH (often >5.5) despite systemic acidosis 5
Clinical Manifestations
- Bone disease: Rickets in children, osteomalacia in adults from chronic phosphate wasting 4
- Muscle weakness and fatigue related to hypokalemia and metabolic acidosis 4
- Growth failure in children 4
- Polyuria and polydipsia from fluid losses associated with proximal tubulopathy 6
- Bone pain from osteomalacia 5
Etiologies
Inherited Causes (More Common in Children)
- Cystinosis (CTNS gene)—the most common inherited cause in children 4, 3
- Tyrosinemia type I 4
- Glycogen storage diseases, particularly Fanconi-Bickel syndrome (GLUT2 deficiency) 4, 6
- Fanconi anemia (multiple genes involved in DNA damage repair) 8, 4
- Dent disease (CLCN5, OCRL genes) 8
- Primary inherited forms from mutations in sodium-phosphate cotransporter (NaPi-II) 1
- Hereditary fructose intolerance, galactosemia 7
Acquired Causes (More Common in Adults)
- Multiple myeloma with light chain deposition—the most common acquired cause in adults 4
- Drug-induced (increasingly recognized):
- Tenofovir disoproxil fumarate: Proximal tubule toxicity with concentration-dependent accumulation, especially when combined with ritonavir-boosted protease inhibitors (lopinavir, atazanavir, saquinavir) that block MRP-2 transporter and increase tenofovir exposure by 32% 8, 7
- Adefovir, cidofovir (acyclic nucleoside phosphonates) 8
- Ifosfamide, cisplatin (chemotherapy agents) 2
- Valproic acid, aminoglycosides 2
- Lymphoma, particularly HTLV1-associated acute T-cell leukemia/lymphoma (ATLL) with intense proximal tubule infiltration 9
- Heavy metals and toxins (lead, cadmium, mercury) 2, 3
- Sjögren's syndrome 7
Diagnostic Work-Up
Essential Initial Laboratory Tests
Serum studies:
- Electrolytes: sodium, potassium, chloride, bicarbonate 4
- Phosphate, calcium, creatinine, eGFR 4
- Glucose 4
- Uric acid 1
- Alkaline phosphatase (elevated in rickets/osteomalacia) 4
Urine studies:
- Urinalysis with glucose measurement (glucosuria with normal serum glucose) 4, 6
- Urine amino acids (generalized aminoaciduria) 8, 4
- Urine phosphate, calcium, and low-molecular-weight proteins 8, 4
- Urine pH (elevated despite acidosis) 5
- Albumin:creatinine ratio and protein:creatinine ratio 4
Exclude Key Differential Diagnoses
Measure serum bicarbonate to confirm metabolic acidosis and distinguish from isolated phosphate wasting disorders like X-linked hypophosphatemia (XLH). 8 In XLH, FGF23 levels are non-suppressed with isolated renal phosphate wasting but without metabolic acidosis, hypercalciuria, or generalized proximal tubular dysfunction. 8
Identify Underlying Cause
- Comprehensive medication review: Specifically assess for tenofovir, antiretrovirals, chemotherapy agents 8, 4, 7
- Serum and urine protein electrophoresis in adults to screen for multiple myeloma 4
- Genetic testing for inherited causes when indicated: CTNS (cystinosis), FANC genes (Fanconi anemia), SLC2A2 (Fanconi-Bickel), CLCN5/OCRL (Dent disease) 4, 6
Kidney Biopsy Indications
Consider biopsy when: 4
- eGFR <60 mL/min/1.73m² with >2 mL/min/1.73m² per year decline
- Proteinuria with hematuria
- Albumin:creatinine ratio >30 mg/mmol
- Suspected lymphomatous infiltration 9
Management
Treat the Underlying Cause
Discontinue offending medications immediately when drug-induced Fanconi syndrome is identified. 8, 7 Most cases of tenofovir-induced Fanconi syndrome resolve or improve with drug discontinuation. 8, 7
For tenofovir-associated cases, switch to alternative antiretroviral therapy and avoid ritonavir-boosted regimens that increase tenofovir exposure. 8
Supportive Care and Electrolyte Replacement
Replace lost electrolytes aggressively: 4, 5, 6
- Phosphate supplementation for hypophosphatemia (oral phosphate salts) 4, 6
- Potassium supplementation for hypokalemia 4, 5
- Bicarbonate supplementation (sodium bicarbonate or citrate) to correct metabolic acidosis 4, 5, 6
- Fluid replacement for volume depletion from polyuria 3
- Vitamin D supplementation to treat and prevent rickets/osteomalacia 6
Monitoring
Regular monitoring is essential: 4
- Electrolytes and renal function
- Bone health assessment (alkaline phosphatase, bone density)
- Growth parameters in children 4, 6
Special Populations
Fanconi anemia patients require additional surveillance: 8, 4
- Monitor for bone marrow failure (complete blood counts)
- Screen for malignancies (80% cumulative incidence of leukemia by age 10 in FANCD1/BRCA2 mutations) 8
- Proactive bone marrow monitoring for progressive failure, myelodysplastic syndrome, or clonal evolution 8
Critical Pitfalls to Avoid
- Do not miss drug-induced causes: Always review medications, particularly tenofovir and ritonavir combinations in HIV patients 8, 7
- Do not confuse with isolated phosphate wasting disorders: Fanconi syndrome has generalized proximal tubular dysfunction (aminoaciduria, glucosuria, acidosis), not just phosphate wasting 8
- Do not delay electrolyte replacement: Severe hypokalemia and acidosis can be life-threatening 5
- Do not overlook multiple myeloma in adults: Always perform protein electrophoresis 4
- Do not forget genetic testing in children: Early diagnosis of cystinosis or other inherited causes allows targeted therapy 4, 3