Fanconi Syndrome

Etiology

Fanconi syndrome can result from a wide range of inherited or acquired causes. Among the inherited forms, several well-established etiologies have been identified, including cystinosis, galactosemia, hereditary fructose intolerance, tyrosinemia, Wilson disease, Lowe syndrome, Dent disease, Alport syndrome, lysinuric protein intolerance, Fanconi-Bickel syndrome, glycogen storage disorders, and mitochondrial cytopathies.[5][6] More recent studies have also identified mutations in the EHHADH and the HNF4A genes as additional genetic causes of Fanconi syndrome. Primary inherited Fanconi syndrome may result from mutations in the proximal tubular sodium-phosphate cotransporter (NaP_i-II).[6]

Acquired causes of Fanconi syndrome are more commonly observed in adults and often result from exposure to medications or toxins. Drugs associated with its development include certain antivirals, such as nucleoside reverse transcriptase inhibitors, chemotherapeutic agents (eg, cisplatin), immunosuppressants (eg, azathioprine), carbonic anhydrase inhibitors (eg, acetazolamide), and antibiotics (eg, gentamicin).[7] More recently, immune checkpoint inhibitors—a newer class of drugs—have been reported to cause acute tubulointerstitial nephritis and Fanconi syndrome, sometimes even months after discontinuation of therapy.[8]

Beyond medications, Fanconi syndrome can develop in the setting of monoclonal gammopathy, heavy metal toxicity (such as lead poisoning), and other environmental toxins. In addition, it has also been reported in more generalized forms of renal injury, including those associated with renal transplantation, nephrotic syndrome, and acute tubular necrosis.[9]

Epidemiology

Fanconi syndrome is a rare disorder with variable incidence depending on its underlying cause. The true prevalence of this condition is difficult to determine due to the heterogeneity of inherited metabolic disorders, acquired toxic or drug-induced causes, and associated systemic diseases encompassed by this syndrome.[10]

Among inherited forms, nephropathic cystinosis is the most common and extensively studied cause. This condition has an estimated global incidence of 1 in 100,000 to 200,000 live births and accounts for up to 5% of pediatric end-stage renal disease (ESRD) in some registries. The condition predominantly affects individuals of European descent, contributing to the higher reported incidence of Fanconi syndrome in Caucasian children.[11]

Other inherited causes, such as Lowe syndrome, Dent disease, and hereditary fructose intolerance, are extremely rare, with reported prevalence rates often cited below 1 in 500,000. Due to their rarity, these conditions are usually diagnosed in specialized metabolic or genetic clinics.[12]

Acquired Fanconi syndrome is more commonly observed in adults and may develop secondary to certain medications, toxins, systemic illnesses, or paraproteinemias. For example:

• Tenofovir disoproxil fumarate: This has been associated with Fanconi syndrome in up to 2% of patients undergoing long-term therapy, particularly in individuals with HIV or preexisting renal disease.[13]

• Ifosfamide-induced Fanconi syndrome: This occurs in 25% to 30% of pediatric oncology patients receiving cumulative doses exceeding 60 g/m².[13]

• Heavy metals and paraproteinemia: Heavy metal poisoning (eg, lead and cadmium) and paraproteinemia (eg, light-chain proximal tubulopathy in multiple myeloma) are uncommon but clinically significant causes of acquired Fanconi syndrome.[2]

Due to underdiagnosis and overlap with other renal tubular disorders, the actual burden of Fanconi syndrome may be underestimated in both pediatric and adult populations.

Pathophysiology

Fanconi syndrome arises from a generalized dysfunction of the proximal convoluted tubule, which is normally responsible for reabsorbing a wide range of filtered solutes, including glucose, amino acids, phosphate, bicarbonate, uric acid, and low-molecular-weight proteins. In this condition, multiple transport mechanisms across the apical (brush border) and basolateral membranes of the tubular epithelium are impaired, resulting in excessive urinary loss of these substances.[14]

Several mechanisms have been proposed to explain the pathogenesis of Fanconi syndrome, many of which remain under investigation.[15] These include:

• Defective uptake of solutes by tubular epithelial cells from the glomerular filtrate.

• Impaired transport of solutes from tubular cells into the peritubular capillaries.

• Increased back-leak of solutes into the tubular lumen due to dysfunctional tight junctions.

• Structural or functional abnormalities in membrane transport proteins.

• Mitochondrial dysfunction leading to ATP depletion, which impairs active transport systems.

In acquired forms, such as those caused by heavy metal toxicity (eg, lead or cadmium) or chemotherapeutic agents (eg, ifosfamide), mitochondrial injury is a common underlying feature. These injuries compromise energy-dependent transport mechanisms, leading to tubular leak.[16]

Importantly, Fanconi syndrome leads to type 2 (proximal) renal tubular acidosis (RTA) due to impaired reabsorption of bicarbonate. However, not all cases of type 2 RTA qualify as Fanconi syndrome, which involves a broader defect affecting the reabsorption of multiple solutes rather than isolated bicarbonate loss.[17] Normally, bicarbonate is almost completely reabsorbed, so the presence of significant bicarbonate in the urine typically indicates a proximal tubular defect.[6] 

The exact pathophysiological mechanism of Fanconi syndrome varies depending on the underlying inherited or acquired cause, and ongoing research continues to clarify the molecular and transport-level defects across different forms of the disease.

Histopathology

Histological findings in Fanconi syndrome are often nonspecific. In many cases, light microscopy of renal tissue appears unremarkable. However, mild structural changes may be observed, particularly in chronic or acquired forms of the disease, including distortion of proximal tubular architecture, tubular atrophy, or vacuolization of the tubular epithelial cells. In cases associated with mitochondrial cytopathies or toxin exposure, electron microscopy may reveal mitochondrial swelling, loss of cristae, or cytoplasmic inclusions. However, these findings are often subtle and not pathognomonic.[18]

History and Physical

A thorough patient history is essential when evaluating suspected Fanconi syndrome. The initial step is to determine whether the condition is inherited or acquired. If an inherited form is suspected, clinicians should inquire about known diagnoses such as cystinosis, Wilson disease, hereditary fructose intolerance, or Lowe syndrome. For acquired cases, relevant history may include prior renal transplantation, multiple myeloma, or hematologic malignancies such as acute lymphoblastic leukemia.[5]

A detailed medication history is crucial, as numerous drugs have been implicated in acquired Fanconi syndrome. These include valproic acid, didanosine (ddI), cidofovir, adefovir, tenofovir, ifosfamide, lenalidomide, streptozocin, cisplatin, and ranitidine. A temporal relationship between drug exposure and symptom onset can provide an important diagnostic clue.

Physical examination findings are usually nonspecific but may reflect the consequences of proximal tubule dysfunction. Patients may present with signs of excessive urinary losses of amino acids, phosphate, bicarbonate, glucose, calcium, and uric acid. These losses can lead to complications such as metabolic acidosis, dehydration, polyuria, electrolyte imbalances, and growth failure in children.[19]

Skeletal manifestations are common in Fanconi syndrome. In children, hypophosphatemia can lead to rickets with characteristic bony deformities, while in adults, it may result in osteomalacia. Symptoms of osteomalacia include diffuse bone pain (often in the hips), fatigue, and atraumatic fractures. Severe hypophosphatemia, particularly when serum phosphorus falls below 1 mg/dL, may cause neuromuscular symptoms such as paresthesia, tremor, and proximal muscle weakness. In rare cases, it can impair myocardial contractility or complicate ventilator weaning, although clinically significant heart failure is uncommon. Rhabdomyolysis has also been reported in the context of hypophosphatemia but remains rare.[20]

In cases associated with cystinosis, patients may exhibit signs of systemic cystine accumulation, including corneal deposits visible as crystals, as well as involvement of the bone marrow, liver, and kidneys. A history of cystine kidney stones or staghorn calculi may also be present. Although generalized aminoaciduria is a hallmark of Fanconi syndrome, it is usually clinically insignificant unless accompanied by an underlying metabolic disorder.[11]

Evaluation

The diagnosis of Fanconi syndrome relies on identifying a characteristic pattern of proximal tubular dysfunction through both urine and blood testing.

Urine studies typically reveal the following:

• Glycosuria that is inappropriate with the plasma glucose level and is not caused by diabetes.

• Elevated fractional excretion of uric acid, phosphate, and other solutes.

• Increased urinary levels of β2-microglobulin and N-acetyl-β-D-glucosaminidase, which are markers of proximal tubular injury.

• Generalized aminoaciduria, which is best detected on 24-hour urine collection or specialized amino acid panels.[14]

Additional urine findings may include phosphaturia, bicarbonaturia, and elevated levels of urinary glucose and protein, which indicate the loss of solutes that are normally reabsorbed.

Blood tests frequently demonstrate the following conditions:

• Hypophosphatemia.

• Hypokalemia.

• Hyperchloremic metabolic acidosis (non-anion gap).

• Hypouricemia and low bicarbonate levels can be observed in some cases.[21]

More advanced or confirmatory tests may be used in select cases, as mentioned below.

• Urinary retinol-binding protein 4 and the urinary lactate-to-creatinine ratio can help detect subtle proximal tubular injury.

• Enzyme assays, such as the cystine loading test or leukocyte cystine levels, may support the diagnosis of cystinosis.

• Heavy metal screening and drug level assessments in blood or urine can help identify acquired causes, including toxicity from lead, cadmium, or nephrotoxic medications.[22]

A comprehensive evaluation should also consider underlying systemic diseases or inherited metabolic disorders, taking into account the clinical context, age, and exposure history.

Treatment / Management

Management of Fanconi syndrome focuses on the following key principles:

• Identifying and treating the underlying cause
• Correcting fluid, electrolyte, and acid-base imbalances to mitigate symptoms and prevent complications.

General management measures include:

• Ensuring adequate hydration to prevent volume depletion caused by ongoing urinary losses.

• Replacing lost electrolytes, particularly potassium, phosphate, and bicarbonate, which are commonly depleted.

• Administering alkali therapy (eg, oral sodium bicarbonate or potassium citrate) to correct the associated proximal (type 2) RTA. This is particularly important in children to prevent growth retardation.[5][6] 

Amino acid supplementation is generally not necessary but may be considered in select pediatric cases with significant nutritional deficiencies. Carnitine supplementation has shown inconsistent benefits and is not routinely recommended for use.

The cornerstone of effective treatment is addressing the underlying etiology:

• In drug-induced Fanconi syndrome (eg, from tenofovir, ifosfamide, or cisplatin), discontinuation or substitution of the offending agent is essential.

• In cases of heavy metal poisoning, chelation therapy and elimination of the source of exposure are indicated.

• For inherited disorders such as cystinosis, disease-specific therapies (eg, cysteamine for cystinosis) can slow disease progression and improve clinical outcomes.[21]

Although supportive therapy can alleviate symptoms and improve quality of life, it does not reverse the underlying tubular defect. Therefore, long-term outcomes primarily depend on early recognition and effective management of the underlying cause.

Differential Diagnosis

Fanconi syndrome presents with nonspecific features such as polyuria, polydipsia, growth failure, electrolyte disturbances, and bone abnormalities, which can mimic several other conditions.[23] A careful differential diagnosis is crucial to prevent misdiagnosis and ensure an accurate evaluation.

Key conditions to consider in the differential diagnoses are listed below.

• Diabetes mellitus: This condition may present with glycosuria, polyuria, and polydipsia. In contrast, glycosuria in Fanconi syndrome occurs despite normal blood glucose levels.

• Diabetes insipidus: This condition also causes polyuria and polydipsia, but typically does not involve electrolyte disturbances or glycosuria.

• Proximal renal tubular acidosis (type 2 RTA): This condition may occur as an isolated entity or as part of Fanconi syndrome. In isolated type 2 RTA, bicarbonate wasting occurs without generalized solute loss.

• Chronic kidney disease: This condition may present with similar laboratory findings, but it is typically associated with a reduced glomerular filtration rate (GFR) and may not exhibit the selective solute wasting characteristic of Fanconi syndrome.

• Vitamin D deficiency: This can lead to rickets or osteomalacia. However, in Fanconi syndrome, these bone disorders arise due to phosphate wasting rather than isolated vitamin D deficiency.

• Hypophosphatemic rickets: This shares similar skeletal findings with inherited Fanconi syndrome, but typically does not involve glycosuria or generalized aminoaciduria.

• Bartter and Gitelman syndromes: These salt-wasting tubulopathies may present with hypokalemia and metabolic alkalosis, which contrasts with the acidosis characteristic of Fanconi syndrome.

• Multiple myeloma: This condition can cause proximal tubule dysfunction due to light chain deposition (light chain proximal tubulopathy), which may mimic or cause Fanconi syndrome, especially in older adults.

Prognosis

The prognosis of Fanconi syndrome varies widely and is primarily determined by the underlying cause, the timing of diagnosis, and the effectiveness of treatment.

In acquired cases, such as those caused by medications or toxins, Fanconi syndrome may improve or even resolve completely with the prompt removal of the offending agent and appropriate supportive care. However, chronic exposure or delayed diagnosis can result in irreversible tubular damage and progressive kidney dysfunction.[24]

In inherited forms, particularly cystinosis or Lowe syndrome, Fanconi syndrome is typically progressive and requires long-term management. Without appropriate treatment, affected individuals may experience complications such as growth failure, bone deformities, nephrocalcinosis, and progression to chronic kidney disease (CKD) or ESRD. Advances in disease-specific therapies, such as cysteamine for cystinosis, have significantly improved outcomes and delayed the onset of renal failure in children with the condition.[4]

Overall, early recognition and targeted management of both the tubular dysfunction and the underlying cause are essential for improving long-term outcomes and minimizing the risk of renal and systemic complications.

Complications

Fanconi syndrome can lead to various complications, primarily resulting from chronic urinary losses of essential solutes and inadequate correction of the underlying defect. These include the following complications:

• Growth failure in children due to chronic acidosis, phosphate wasting, and nutritional deficiencies.

• Rickets (in children) and osteomalacia (in adults), resulting from deficiencies in phosphate and vitamin D, lead to bone pain, deformities, and an increased risk of fractures.

• Electrolyte abnormalities, including:

  • Hypophosphatemia, which may cause muscle weakness, paresthesia, and, in severe cases, respiratory failure or arrhythmias.

  • Hypokalemia, which can lead to fatigue, muscle cramps, and cardiac arrhythmias.

  • Metabolic acidosis (type 2 RTA), which may worsen bone disease and contribute to growth impairment.[4]

• Nephrocalcinosis and nephrolithiasis, especially in cases of cystinosis or prolonged phosphate loss.

• CKD or progression to ESRD, particularly in untreated or inherited forms.

• Dehydration and volume depletion, due to persistent polyuria and impaired sodium reabsorption.[19]

• Secondary complications of underlying conditions, such as visual impairment in Lowe syndrome or systemic crystal deposition in cystinosis.

• A rare variant associated with the Acadian population (primarily in Nova Scotia) has been associated with interstitial lung disease.[25]