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Fanconi syndrome is a generalized proximal tubule transport disorder.1 The
proximal tubule is responsible for the reabsorption of all filtered
glucose and amino acids, and 80% of the filtered bicarbonate and
phosphate. Patients with Fanconi syndrome have hypophosphatemia,
hypokalemia, and hyperchloremic metabolic acidosis.
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The luminal fluid entering the proximal tubule is an ultrafiltrate
of plasma. Most solutes are transported across the apical membrane
in conjunction with sodium. The driving force for solute transport
is the low intracellular sodium generated by the basolateral Na+-K+-ATPase.
A generalized decrease in proximal tubular transport could result
from a primary injury to the Na+-K+-ATPase
pump or a decrease in intracellular adenosine triphosphate (ATP)
that fuels the pump. Theoretically, an increase in the permeability
of the proximal tubule paracellular pathway could result in Fanconi
syndrome, but this theory has been discounted. Although the cellular
basis for most causes of Fanconi syndrome has not been determined,
most studies have demonstrated that the proximal tubule transport
defect in Fanconi syndrome is the result of a decrease in intracellular
ATP.
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Differential Diagnosis
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The causes for Fanconi syndrome are listed in Table
474-1. Diagnosis of Fanconi syndrome is
usually made due to the presence of symptoms, including failure
to thrive, severe rickets, and sometimes bouts of polydipsia, polyuria,
and dehydration. Laboratory findings include hypophosphatemia, hypokalemia,
and acidosis.2 Evaluation of the urine reveals glucosuria,
generalized aminoaciduria, and hyperphosphaturia, despite the hypophosphatemia,
a stimulus that increases proximal tubule phosphate absorption.
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++
Among the causes of Fanconi syndrome, cystinosis,
an autosomal-recessive disorder, is the most common inherited cause
of Fanconi syndrome in children.3 Further discussion
of this disorder is provided in Chapter 143. Children
with cystinosis are usually well for the first 6 months of life.
Shortly thereafter, they develop polydipsia, polyuria, constipation,
unexplained fevers, and failure to thrive. Patients with cystinosis
have hypophosphatemic rickets due to renal phosphate waisting. These
early signs and symptoms are the result of Fanconi syndrome. Patients
with cystinosis develop a progressive decrease in renal function
and end-stage renal disease by 10 years of age unless treated with
cysteamine.4 Endocrine disorders, including hypothyroidism
and diabetes mellitus, can be seen in older children. Cystine accumulates
in the cornea, leading to photophobia and painful corneal ulcerations.
Older patients with cystinosis who receive a renal transplant can
develop retinopathy, cerebral atrophy, central nervous system dysfunction, myopathy,
and respiratory dysfunction. Gastrointestinal disturbances, including
swallowing difficulties, are also common in older children and adults.
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Two milder forms of cystinosis have been described. In the late
onset form of the disease, patients present in adolescence and have
a slower rate of progression of renal disease. There is also a benign
form of cystinosis, which presents with cystine crystals in the
cornea seen on slit lamp exam, but none of the other manifestations
of cystinosis exist.
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Treatment of Cystinosis
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Cysteamine therapy has proven to be very effective in slowing
or preventing the deterioration in renal function in cystinosis.
Cysteamine also improves the growth in patients with cystinosis. Cysteamine
enters the lysosome, where it forms a mixed disulfide and the cysteine-cysteamine complex
exits across the lysosomal membrane via the lysine carrier. Cysteamine
eye drops effectively dissolve corneal cystine crystals. However,
cysteamine does not prevent or affect the severity of Fanconi syndrome.
Cysteamine also appears to be effective in treating many of the late
manifestations of the disease.
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Treatment of
Fanconi Syndrome
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Treatment of Fanconi syndrome is focused at the treatment of
the primary disease. In patients with hereditary fructose intolerance,
galactosemia, or tyrosinemi, removal of the nonmetabolized sugar
or amino acid from the diet ameliorates the proximal tubular transport
disorder. Patients with a toxin-induced form of the disease should
avoid the offending agent. If Fanconi syndrome is secondary to heavy
metal toxicity or Wilson disease, chelation therapy should be initiated.
If this approach is unsuccessful, therapy consists of replacement
of urinary solute losses. Hypophosphatemia and rickets can be successfully
treated with oral phosphate supplements and 1,25-dihydroxycholecalciferol.
Treatment of the proximal renal tubular acidosis (RTA) is discussed
later in the chapter. The amount of solute replacement is dependent
on the extent of the proximal tubular injury and the filtered load
presented to the proximal tubule. In some patients with severe proximal
tubule injury, reducing the filtered solute load by decreasing the
glomerular filtration rate with indomethacin makes oral replacement
more tolerable.