eMedicine Specialties > Pediatrics: General Medicine > Nephrology
Fanconi Syndrome: Treatment & Medication
Updated: Jun 30, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
The treatment of a child with Fanconi syndrome mainly consists of the replacement of substances lost in the urine. Prominent among these substances are fluids and electrolytes.- Dehydration due to polyuria must be prevented by allowing free access to water; treat dehydration with either oral or parenteral solutions.
- Metabolic acidosis due to the loss of bicarbonate is corrected by the administration of alkali, usually 3-10 mg/kg/d of sodium bicarbonate in divided doses.
- Addition of a diuretic, such as 1-3 mg/kg/d of hydrochlorothiazide, may be necessary to avoid volume expansion, which magnifies the excretion of bicarbonate by lowering the renal threshold. Unfortunately, the diuretic increases potassium wasting and thus the need to augment potassium supplementation in the form of potassium bicarbonate, citrate, or acetate.
- Correction of metabolic acidosis is beneficial but is not sufficient for the treatment of bone disease. Phosphate and vitamin D supplementation are also necessary.
- Normalization of serum phosphate levels may be achieved by administering 1-3 g/d of supplemental phosphate. Administration should start at the lower level and be slowly increased over several weeks to minimize GI symptoms.
- Vitamin D, administered as 1,25-dihydroxyvitamin D3 or 1a-hydroxyvitamin D3, is preferred because liver and/or renal hydroxylation may be impaired in patients with Fanconi syndrome.
- The losses of glucose, amino acids, and uric acid are not usually symptomatic and do not require replacement. Recently, carnitine supplementation has been tried in an attempt to increase muscle strength; however, results have been mixed.
Surgical Care
Liver transplantation has been successfully used in patients with liver failure due to Wilson disease or tyrosinemia. Liver transplantation leads to the rapid disappearance of the renal tubular abnormalities.
Kidney transplantation has been performed in many patients with renal failure due to cystinosis. Cystine accumulates in the monocytes and interstitial cells of the transplanted kidney but not in proximal tubule cells. Consequently, the tubular transport abnormalities do not recur.
Consultations
A slit-lamp eye examination should be requested whenever the diagnosis of cystinosis is suspected. Detection of needle-shaped refractile bodies in the cornea is pathognomonic. In patients with Wilson disease, a slit-lamp examination can be used to detect the pathognomonic Kayser-Fleischer rings. An ophthalmology consultation is also warranted in patients with galactosemia and Lowe syndrome because ocular manifestations can be present.
Diet
Several forms of Fanconi syndrome are caused by deficiencies in enzymes involved in the metabolism of nutrients, such as galactose, fructose, tyrosine, and phenylalanine. Elimination of these substances from the diet results in the disappearance of the renal manifestations of the syndrome. However, some of the systemic abnormalities, such as developmental delay, growth retardation, speech impairment, and ovarian dysfunction in galactosemia or hepatic cirrhosis in tyrosinemia, do not appear to be affected. Patients with Wilson disease benefit from a low-copper diet and therapy with D-penicillamine.
Activity
None of the conditions associated with Fanconi syndrome mandate restrictions in activities. However, some of these conditions can result in failure of organs, such as the liver or kidneys, or in diminution of muscle strength, which, in turn, may limit the ability of children to engage in physically demanding activities.
Medication
The medications required to correct abnormalities due to the renal loss of various substances are listed in Medical Care. In this section, the use of drugs designed to correct the causes of the syndrome are addressed. These drugs are confined to only 2 of the conditions associated with Fanconi syndrome, cystinosis, and Wilson disease.
Cystine-lowering agents
Numerous compounds have been found to decrease the levels of cystine in cultured cells, but only a few were proven effective in clinical trials. Prominent among the effective drugs is cysteamine, which has been shown to decrease the tissue levels of cystine, delay the progression of renal disease, and improve linear growth, particularly when treatment is started in children younger than 2 years. However, no affect on the Fanconi syndrome was documented.
Cysteamine (Cystaphos, Cystagon)
Cystinosis is caused by a defect in the transporter that mediates the egress of cystine from the cell lysosome into the cytosol. Cysteamine hydrochloride enters the lysosome and combines with cystine, forming cysteine and cysteamine-cysteine; both compounds can exit the lysosome via a transporter different from that for cystine. Phosphocysteamine (Cystaphos) is devoid of the foul odor and taste but is substantially more expensive than cysteamine. A recent formulation, cysteamine bitartrate (Cystagon), appears to be well tolerated and results in cellular levels of cystine lower than those observed with the other compounds.
Adult
Start at low dose and increase over 4-6 wk to 2 g/d PO divided q6h; measure leukocyte cystine levels q3mo; achieve and maintain cystine level of <1 nmol 0.5 cystine/mg protein
Pediatric
<6 years: Sprinkle cysteamine capsule contents over food
<12 years: 1.3 g/m2/d PO (about 60 mg/kg/d) maintenance dose, divided qid
>12 years and >50 kg: Administer as in adults
Administer one fourth to one sixth of maintenance dose initially; then increase gradually over 4-6 wk to avoid intolerance
Note: Strict dosing regimen is required to prevent nocturnal cystine accumulation.
None reported
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Can cause occasional reversible leukopenia and abnormal liver function studies; monitor blood counts and obtain liver function studies; because of adverse GI effects, therapy may have to be interrupted and the dose adjusted; may cause CNS symptoms (eg, seizures, lethargy, somnolence, depression, encephalopathy)
Chelating agents
These agents inhibit a toxin by reacting with it to form less active or inactive complex.
D-penicillamine (Cuprimine, Depen)
Recommended for removal of excess copper in patients with Wilson disease. In vitro, 1 atom of copper combines with 2 molecules of penicillamine; 1 g of penicillamine is expected to cause excretion of approximately 200 mg of copper. In practice, however, only about 1% of this amount excreted. Determine dosage by measurements of urinary copper excretion and free copper in the serum.
Adult
0.75-1.5 g PO qd, resulting in excretion of >2 mg copper; by 3 mo, serum concentration of free copper (total copper minus ceruloplasmin-copper) <10 mg/dL; tailor maintenance therapy to maintain level free copper serum level <10 mg/dL
Pediatric
Administer as in adults
Increases effects of immunosuppressants, phenylbutazone, and antimalarials; decreases digoxin effects; bioavailability may decrease with coadministration of zinc salts, antacids, and iron
Documented hypersensitivity; renal insufficiency; previous penicillamine-related aplastic anemia
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Allergic manifestations include rashes, pruritus, pemphigus accompanied by fever, arthralgia, and lymphadenopathy; GI manifestations include anorexia, epigastric pain, nausea, vomiting, and occasional diarrhea; may cause severe bone marrow depression, hematuria, and proteinuria severe enough to produce a nephrotic syndrome; may cause CNS toxicity (eg, tinnitus, peripheral neuritis, myasthenia gravis); examine patients frequently and obtain weekly urine analyses and blood cell counts; administer on empty stomach (ie, 1 h before meals or 2 h after meals)
Trientine hydrochloride (Syprine)
Use in patients who are intolerant to penicillamine. Clinical experience limited. Unlike penicillamine, does not contain a sulfhydryl group, making it unable to chelate cystine; therefore, use only to treat Wilson disease. Administer on empty stomach and swallow capsules whole with water.
Adult
750-1250 mg/d PO divided bid/qid initially; may increase to 2000 mg/d if serum copper is persistently >20 mg/dL; determine optimal long-term maintenance dosage q6-12mo
Pediatric
500-750 mg/d PO divided bid/qid initially; may increase to 1200 mg/d in children <12 y and 2000 mg/d in children >12 y if serum copper is persistently >20 mg/dL; determine optimal long-term maintenance dosage q6-12mo
Effects decrease with iron or other mineral supplements
Documented hypersensitivity; biliary cirrhosis; rheumatoid arthritis; cystinuria
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Controlled studies of the safety and efficacy in children not conducted; teratogenic in rats at dosages similar to those used in humans; may cause anorexia, nausea, abdominal pains, heartburns, melena, muscle pains, and rhabdomyolysis; may cause iron deficiency or SLE; administer on empty stomach (ie, 1 h before meals or 2 h after meals)
Can cause bone marrow suppression and proteinuria; weekly CBC counts at initiation of therapy should be obtained
Tyrosine Degradation Inhibitor
In addition to dietary treatment, some advise the use of NTBC, which is a highly potent inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase. NTBC prevents formation of fumarylacetoacetate from tyrosine. Results from an international study initiated in 1992 resulted in US Food and Drug Administration (FDA) approval in January 2002.
An open-label study of 207 patients (aged from birth to 21.7 y, median age 9 mo) revealed an improved overall survival rate compared with historical control subjects (29% vs 88% survival probabilities at 4 y) when patients who were younger than 2 months presented with hereditary tyrosinemia type I and were treated with nitisinone and dietary restriction.2
Nitisinone (Orfadin)
Used adjunctively to dietary restrictions to treat hereditary tyrosinemia type-1. Highly potent reversible inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase. Prevents formation of fumarylacetoacetate from tyrosine.
Adult
Limited data exist: 1 mg/kg/d PO divided bid initially administered at least 1 h before meals; adjust dose to individual patient requirements; not to exceed 2 mg/kg/d
Pediatric
1 mg/kg/d PO divided bid initially administered at least 1 h before meals; adjust dose to individual patient requirements
May increase to 1.5 mg/kg/d after 1 mo if biochemical parameters are not normalized; not to exceed 2 mg/kg/d
None reported
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Must be used in conjunction with dietary restriction of tyrosine and phenylalanine to prevent toxicity caused by elevated plasma tyrosine; may cause transient thrombocytopenia and leukopenia; obtain baseline and periodic eye examinations to monitor for tyrosine toxicity; regularly monitor hepatic function by imaging and laboratory tests
More on Fanconi Syndrome |
| Overview: Fanconi Syndrome |
| Differential Diagnoses & Workup: Fanconi Syndrome |
 Treatment & Medication: Fanconi Syndrome |
| Follow-up: Fanconi Syndrome |
| References |
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Further Reading
Keywords
Fanconi syndrome, Fanconi's syndrome, primary Fanconi syndrome, inherited Fanconi syndrome, secondary Fanconi syndrome, acquired Fanconi syndrome, idiopathic Fanconi syndrome, nephrotic-glucosuric dwarfism with hypophosphatemic rickets, oculocerebrorenal syndrome, oculocerebrorenal syndrome of Lowe, Lowe syndrome, Lowe's syndrome, Lowe-Terrey-MacLachlan syndrome, vitamin D–dependent rickets, cystinosis, cystine storage disease, De Toni–Fanconi syndrome, Lignac-Fanconi syndrome, Wilson disease, Wilson's disease, galactosemia, glycogen-storage disease, hypophosphatemia, renal failure
