What are the diagnostic investigations for Fanconi syndrome?

Diagnosis of Fanconi Syndrome

Fanconi syndrome is diagnosed through a combination of characteristic laboratory findings demonstrating generalized proximal tubular dysfunction, including glucosuria despite normal serum glucose, hypophosphatemia, metabolic acidosis, and generalized aminoaciduria. 1

Essential Diagnostic Laboratory Tests

Serum Studies

• Metabolic panel: Check serum bicarbonate (typically low due to type II RTA), chloride, phosphate (typically low), and uric acid (typically low/hypouricemia) 2, 1
• Serum glucose: Must be normal to confirm renal glucosuria rather than diabetes 1, 3
• Serum potassium: Often reveals hypokalemia from urinary potassium losses exacerbated by acidosis 1
• Creatinine and eGFR: To assess kidney function, as impaired renal function occurs in many cases 2, 4

Urine Studies

• Urinalysis with dipstick: Demonstrates glucosuria despite normoglycemia 1, 3
• Urine protein electrophoresis: Shows low-molecular-weight proteinuria characteristic of proximal tubular dysfunction 4
• Urine amino acid analysis: Reveals generalized aminoaciduria, a cardinal feature 1, 3, 5
• Urine pH: Typically elevated despite systemic acidosis 1
• Spot urine for phosphate, calcium, and potassium: Demonstrates excessive urinary losses 1
• Albumin:creatinine ratio and protein:creatinine ratio: Quantifies proteinuria 2

Cardinal Diagnostic Triad

The three essential findings that establish the diagnosis are: 3, 5

• Hyperaminoaciduria (generalized, not selective)
• Glucosuria with normal serum glucose levels
• Phosphate wasting (phosphaturia with hypophosphatemia)

Additional Investigations Based on Clinical Context

When Etiology is Unknown

• Genetic testing: For inherited causes including cystinosis (CTNS gene), tyrosinemia type I, Fanconi anemia (multiple genes), and glycogen storage diseases 2, 1, 6
• Medication/toxin review: Comprehensive history of drug exposures, as acquired forms are common in adults 3, 5
• Serum and urine protein electrophoresis: To screen for multiple myeloma with light chain deposition in adults 2, 1

Bone Disease Assessment

• Alkaline phosphatase: Elevated in rickets/osteomalacia from chronic phosphate wasting 2, 1
• Bone radiographs: Look for rachitic changes in children or osteomalacia in adults 1, 6
• Bone densitometry: To assess severity of bone disease 6

Kidney Biopsy Considerations

Kidney biopsy should be performed when: 2

• Fanconi syndrome with hypouricemia is present
• eGFR <60 mL/min/1.73m² with >2 mL/min/1.73m² per year decline
• Proteinuria with hematuria coexists
• Albumin:creatinine ratio >30 mg/mmol

Biopsy typically shows tubulointerstitial changes of varying degrees, with immunofluorescence studies including IgG, IgM, IgA, C1q, C3, and κ and λ light chains to identify monoclonal gammopathy-related causes. 2, 4

Specialized Testing for Specific Etiologies

• Chromosome breakage analysis: For Fanconi anemia diagnosis 2
• Cystine levels: In leukocytes for cystinosis 6
• Succinylacetone in urine: For tyrosinemia type I 6
• Renal ultrasound: To monitor kidney structure 6

Critical Pitfalls to Avoid

• Do not dismiss glucosuria as diabetes: Always verify serum glucose is normal; this distinguishes renal glucosuria from diabetes mellitus 1, 3
• Do not overlook drug-induced causes: Medications and toxins are the most common cause in adults, requiring thorough exposure history 3, 5
• Do not delay genetic testing in children: Inherited causes, particularly cystinosis, require early diagnosis and treatment to prevent irreversible complications 6, 5
• Do not forget to assess bone health: Chronic phosphate wasting leads to rickets in children and osteomalacia in adults, requiring radiographic evaluation 1, 6