Key Facts

Fanconi syndrome represents generalised proximal tubular failure. Recognising the pattern of solute losses is key to diagnosis and guides investigation for the underlying cause.

Epidemiology

• Rare overall; most common inherited cause is cystinosis (1 in 100,000-200,000)
• Acquired causes are more common in adults
• Increasing recognition of drug-induced Fanconi (tenofovir)

Aetiology

Inherited (mainly children):

• Cystinosis (most common): AR, CTNS gene → lysosomal cystine accumulation
• Galactosaemia, hereditary fructose intolerance
• Wilson disease, glycogen storage disease type 1
• Lowe syndrome (oculocerebrorenal syndrome)
• Dent disease (X-linked)

Acquired (mainly adults):

• Multiple myeloma/light chain deposition
• Drugs: tenofovir, ifosfamide, cisplatin, aminoglycosides, sodium valproate, expired tetracyclines
• Heavy metal poisoning: lead, cadmium, mercury
• Renal transplant
• Amyloidosis

Pathophysiology

• Proximal tubule is responsible for reabsorption of 60-70% of filtered sodium, almost all glucose, amino acids, phosphate, urate, and bicarbonate
• Generalised proximal tubular injury impairs multiple transport systems simultaneously
• Phosphate wasting → hypophosphataemia → impaired bone mineralisation (rickets/osteomalacia)
• Bicarbonate wasting → type 2 (proximal) RTA → hyperchloraemic metabolic acidosis
• Glycosuria despite normal blood glucose (renal threshold reduced)
• Low-molecular-weight proteinuria (retinol-binding protein, beta-2-microglobulin)

Children (Cystinosis)

• Failure to thrive/growth retardation
• Rickets: bowed legs, widened wrists, rachitic rosary
• Polyuria and polydipsia (concentrating defect)
• Dehydration episodes
• Photophobia (cystine crystals in cornea)
• Blonde hair, fair skin (typical in cystinosis)
• Progressive CKD → ESRD by age 10-12 if untreated

Adults (Acquired)

• Bone pain/fractures (osteomalacia)
• Muscle weakness (hypokalaemia, hypophosphataemia)
• Polyuria (osmotic diuresis from glycosuria)
• Features of underlying cause (myeloma: bone pain, anaemia; tenofovir use)

Red Flags

• Child with rickets + metabolic acidosis + glycosuria → cystinosis until proven otherwise
• Adult on tenofovir with rising creatinine + phosphaturia → drug-induced Fanconi
• Glycosuria with normal blood glucose → always consider Fanconi

Bloods

• U&Es: potassium (low), bicarbonate (low), sodium
• Calcium: normal or low
• Phosphate: low (renal wasting)
• ALP: raised (bone disease)
• Urate: low (renal wasting)
• ABG: normal anion gap metabolic acidosis (type 2 RTA)
• Glucose: normal (glycosuria is renal, not from hyperglycaemia)

Urine

• Glycosuria with normoglycaemia
• Aminoaciduria: generalised (all amino acids)
• Low-molecular-weight proteinuria: retinol-binding protein, beta-2-microglobulin
• Fractional excretion of phosphate: elevated (>20%)
• Urine pH: variable; acidifies once serum HCO3 drops below renal threshold

Special Tests

• White blood cell cystine levels: diagnostic for cystinosis
• Slit-lamp examination: cystine corneal crystals (cystinosis)
• Serum/urine protein electrophoresis: myeloma screen
• Genetic testing: CTNS gene (cystinosis), CLCN5 (Dent disease)
• X-ray: rickets (widened growth plates, cupping/fraying of metaphyses)
• DEXA scan: osteomalacia in adults

Supportive (All Causes)

• Phosphate replacement: Phosphate Sandoz 1-3g/day in divided doses
• Vitamin D: alfacalcidol 0.25-1mcg/day or calcitriol (active vitamin D bypasses renal hydroxylation defect)
• Sodium bicarbonate: 1-3 mmol/kg/day (type 2 RTA – higher doses needed)
• Potassium supplementation: Sando-K or potassium citrate
• Adequate hydration: to prevent dehydration from polyuria

Specific Treatment

Cystinosis:

• Cysteamine (Cystagon/Procysbi): depletes lysosomal cystine; significantly delays ESRD (from age 10 to 20+ years)
• Dose: titrated up to 60-90mg/kg/day in 4 divided doses
• Side effects: GI upset, breath/body odour; Procysbi (delayed-release) better tolerated
• Cysteamine eye drops: for corneal crystals
• Renal transplantation: for ESRD (cystinosis does not recur in transplant)

Acquired:

• Stop offending drug (tenofovir → switch to TAF; stop ifosfamide if possible)
• Treat myeloma: chemotherapy
• Chelation: for heavy metal poisoning

Referral

• All suspected Fanconi syndrome → nephrology
• Cystinosis → specialist paediatric metabolic/nephrology centre
• Bone disease → metabolic bone specialist

• Cystinosis without cysteamine: ESRD by age 10-12 years; with cysteamine: ESRD delayed to age 20+
• Drug-induced Fanconi: usually reversible on drug withdrawal (partial or complete)
• Myeloma-associated: depends on underlying myeloma prognosis
• Post-transplant for cystinosis: excellent graft survival; cystinosis does not recur in graft (but continues in other organs)
• Long-term cystine accumulation causes: thyroid dysfunction, diabetes, myopathy, CNS involvement

Features of Proximal Tubular Dysfunction

Drug-Induced Fanconi Syndrome