What is Fanconi syndrome?

What is Fanconi Syndrome?

Fanconi syndrome is a generalized dysfunction of the proximal renal tubule characterized by impaired reabsorption leading to excessive urinary losses of glucose, phosphate, amino acids, bicarbonate, and other solutes, resulting in metabolic acidosis, electrolyte abnormalities, and bone disease. 1, 2

Pathophysiology

The syndrome represents a global transport defect in the proximal tubules, causing renal losses of multiple substances simultaneously 2, 3:

• Glucose wasting occurs despite normal serum glucose levels (glucosuria with normoglycemia) 1, 2
• Phosphate wasting (phosphaturia) leads to hypophosphatemia and subsequent bone disease 1
• Generalized aminoaciduria with excessive excretion of all amino acids is a hallmark feature 1, 2
• Bicarbonate wasting causes type II (proximal) renal tubular acidosis with metabolic acidosis 4, 3
• Additional losses include potassium, sodium, calcium, uric acid, and low-molecular-weight proteins 2, 3

Clinical Manifestations

Metabolic Derangements

• Hypokalemia results from increased urinary potassium losses, often exacerbated by the metabolic acidosis 1
• Hypophosphatemia develops from impaired phosphate reabsorption 1
• Elevated urinary pH occurs despite systemic acidosis 1
• Dehydration and sodium wasting are common, particularly in children 3

Bone Disease

• Rickets in children and osteomalacia in adults result from chronic phosphate wasting 1
• Bone pain accompanies the osteomalacia 1

Systemic Symptoms

• Muscle weakness and fatigue relate to hypokalemia and metabolic acidosis 1
• Growth failure occurs in affected children 1

Etiologies

Inherited Causes (Predominant in Children)

• Cystinosis is the principal cause in children 3
• Tyrosinemia type I is an important inherited metabolic disorder causing Fanconi syndrome 1
• Glycogen storage diseases, including Fanconi-Bickel syndrome 1
• Fanconi anemia (distinct from Fanconi syndrome) can present with proximal tubular dysfunction 1

Acquired Causes (Predominant in Adults)

• Multiple myeloma with light chain deposition is the most common acquired cause in adults 1
• Drug-induced forms are increasingly recognized, with the list of causative agents expanding as new medications are introduced, particularly in oncology 2, 4
• Exogenous toxins and heavy metals can cause acute tubular injury 2, 5

Important Clinical Distinction

Do not confuse Fanconi syndrome (proximal tubular dysfunction) with Fanconi anemia (a rare autosomal recessive disorder of chromosomal instability and cancer susceptibility). 6 Fanconi anemia is characterized by bone marrow failure, increased cancer risk (particularly leukemia and squamous cell carcinomas), and hypersensitivity to DNA cross-linking agents, involving mutations in DNA repair genes (FANCA, B, C, D1/BRCA2, D2, E, F, G, L) 6. While Fanconi anemia patients may develop hematologic manifestations requiring specialized monitoring and cancer surveillance 7, this is an entirely separate genetic syndrome from the renal tubular disorder.

Diagnostic Approach

Essential Laboratory Findings

The cardinal diagnostic triad consists of 1, 2:

• Hyperaminoaciduria (generalized, not selective)
• Glucosuria with normal serum glucose
• Phosphaturia with hypophosphatemia

Additional Testing

• Serum creatinine and eGFR to assess kidney function 1
• Serum electrolytes revealing hypokalemia, hypophosphatemia, and metabolic acidosis 1
• Arterial blood gas demonstrating normal anion-gap metabolic acidosis 4
• Alkaline phosphatase often elevated in rickets/osteomalacia 1
• Serum and urine protein electrophoresis to screen for multiple myeloma in adults 1
• Genetic testing for inherited causes when clinically indicated 1

When to Consider Kidney Biopsy

Biopsy is indicated when Fanconi syndrome presents with 1:

• Hypouricemia
• eGFR <60 mL/min/1.73m² with >2 mL/min/1.73m² per year decline
• Proteinuria with hematuria
• Albumin:creatinine ratio >30 mg/mmol

Management Principles

Treat the Underlying Cause

• For tyrosinemia type I: NTBC (nitisinone) with dietary phenylalanine/tyrosine restriction reverses tubulopathy in nearly all cases within weeks 7
• For cystinosis: Cysteamine therapy initiated immediately upon diagnosis, starting at 1 mg/kg/day and increasing to 2 mg/kg if needed 7
• For drug-induced cases: Discontinue the offending agent 2

Supportive Care and Electrolyte Replacement

• Phosphate supplementation to address hypophosphatemia and prevent bone disease 1
• Potassium supplementation for hypokalemia 1
• Bicarbonate supplementation to correct metabolic acidosis 1
• Fluid replacement at 1.5-2.0 times maintenance rate with 10% dextrose/normal saline to maintain normoglycemia 7

Monitoring

• Regular assessment of electrolytes, renal function, and bone health is crucial 1
• Renal ultrasound to monitor kidney structure 7
• Bone X-rays and densitometry to assess for rachitic changes 7

Critical Pitfall

Early diagnosis and treatment are essential to prevent irreversible complications, particularly growth failure in children and progressive bone disease 1. The wide variability in age of onset, particularly in inherited forms, means that screening at-risk individuals before symptom development is important for optimal outcomes.