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Fanconi Syndrome Clinical Presentation

  • Author: Sahar Fathallah-Shaykh, MD; Chief Editor: Craig B Langman, MD  more...
 
Updated: Jun 17, 2015
 

History

The clinical features that cause patients to seek medical care include polyuria, polydipsia, bouts of dehydration (sometimes associated with fever), bone deformities, and impaired growth. Less often, the reasons for investigation are laboratory findings such as proteinuria, hypokalemia, hypophosphatemia, and hyperchloremic metabolic acidosis.

  • Polyuria, polydipsia, and dehydration are interrelated manifestations of the syndrome. They are primarily caused by the loss of excessive amounts of solutes in the urine, accompanied by the loss of water. Despite the dehydration that ensues, the urine is often dilute, which reflects a concentration defect that is partially caused by hypokalemia. The bouts of dehydration may be associated with fever, particularly in infants.
  • Rickets in children or osteomalacia in adults is the result of the excessive urinary losses of calcium and phosphate and of a defect in the hydroxylation of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3.
  • Growth failure, a constant feature of the syndrome, is at least partially caused by the multiple metabolic abnormalities present in this condition. Prominent among these abnormalities are acidosis and disturbances in mineral and vitamin D metabolism. Yet, correction of these abnormalities fails to restore normal growth, particularly in patients with cystinosis.
  • Most patients have proteinuria, although it is often minimal. An obvious exception is the Fanconi syndrome that occurs in the context of nephrotic syndrome. The proteins may be of prerenal origin, as in multiple myeloma; of glomerular origin, as in advanced cases of cystinosis; or of tubular origin, as in all tubulopathies. The latter are the result of impaired reabsorption of small proteins, such as enzymes, peptide hormones, and light chain immunoglobulins. Their molecular weight varies from 5-50 kd.
  • Hypokalemia is the result of urinary losses secondary to increased secretion of potassium, which is stimulated by the delivery of large amounts of sodium and fluid to the distal nephron. Acidosis contributes to this outcome by increasing the filtered load of potassium. Potassium depletion may result in muscle weakness, constipation, and, when severe, sudden death. In addition, hypokalemia contributes to the defect in urine concentration ability seen in these patients.
  • Hypophosphatemia is secondary to the impairment in proximal tubular reabsorption. However, an increase in phosphate excretion can be observed only during the initial phase of the syndrome. Subsequently, a new steady state is reached whereby the amount of phosphate present in the urine closely matches the intake. No defect is apparent in intestinal reabsorption of phosphate in Fanconi syndrome.
  • Acidosis is mainly caused by a defect in the reabsorption of bicarbonate in the proximal tubule. As in all other forms of proximal renal tubular acidosis, the threshold for bicarbonate is low, but distal acidification is normal. Consequently, the urine pH can be lowered appropriately (to a pH of 4.5-5) when the concentration of bicarbonate in plasma is below the threshold. In advanced cases of renal disease, the distal acidifying mechanism is also impaired. Ammoniagenesis appears to be normal.
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Physical

[47, 48] The physical findings characteristic of each form of the syndrome are described above (see History). Some of these findings are pathognomonic, such as the presence of cystine crystals in the cornea in cystinosis; other findings are common for several diseases associated with Fanconi syndrome, such as hepatomegaly, which can be found in glycogenosis, galactosemia, and tyrosinemia. In patients with no pathognomic findings, other signs or laboratory investigations can lead to the identification of the specific abnormality.

The most striking clinical feature of Fanconi syndrome is failure to thrive. Children with Fanconi syndrome usually have a short stature, are frail, have a low muscle tone, and have signs of florid rickets, such as frontal bossing, rosaries, leg bowing, and widening of the wrists, knees, and ankles. Their reflexes may be increased because of hypocalcemia. Needle-shaped refractile bodies in the cornea, detectable by slit-lamp examination, are pathognomonic of cystinosis. They are always found in children older than 2 years but may be observed during the first year of life.

A careful family history may disclose the existence of an inherited disease such as cystinosis. Most diseases associated with a Fanconi syndrome are inherited in an autosomal recessive pattern. Consequently, the child of 2 heterozygous parents, whether male or female, has a 25% chance of being homozygous. The children of an affected individual (homozygous) are all heterozygous and can be affected only if the other parent is heterozygous, a very rare event. An exception to this mode of inheritance is oculocerebrorenal syndrome, which is transmitted as an X-linked recessive trait. In oculocerebrorenal syndrome, each daughter has a 50% chance of being a carrier, whereas each son has a 50% chance of inheriting the mutant gene and having the disease. Therefore, in each pregnancy, the female carrier has a 25% chance of having an affected son.

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Causes

Fanconi syndrome can be primary (inherited) or secondary (acquired). The only exception to this rule is the idiopathic form of the syndrome. Short descriptions of the various causes of Fanconi syndrome are as follows:

The idiopathic Fanconi syndrome occurs in the absence of any identifiable cause, and most cases are sporadic. Some cases are inherited, but the mode of inheritance appears to vary (autosomal dominant, autosomal recessive, X-linked). Not all manifestations of the syndrome are present at onset. Recurrent episodes of dehydration, rickets, and failure to thrive are the most common. Prognosis varies. Some patients develop renal failure in late childhood or early adulthood.

Several inborn errors of amino acid or carbohydrate metabolism are associated with Fanconi syndrome. All are inherited in an autosomal recessive pattern.

Cystinosis is caused by the accumulation of cystine in lysosomes, probably as a result of a defect in efflux. The gene for cystinosis (CTNS) was mapped to band 17p13. The gene encodes for cystinosin, a 7-transmembrane-domain protein made up of 367 amino acids. The phenotype severity in cystinosis appears to vary with the mutations in the CTNS gene.

Benign, or adult, cystinosis is characterized by the deposition of relatively low amounts of cystine in the cornea and bone marrow. The kidneys are spared, and the renal manifestations are absent.

Infantile or nephropathic cystinosis is characterized by the presence of large amounts of cystine in all cells, including the kidneys. Incidence is approximately 1 case per 200,000 live births. Children with cystinosis usually have a fair complexion and blond hair, although the syndrome is also described in African Americans.

The first signs are polyuria and polydipsia, followed by episodes of dehydration, anorexia, and failure to thrive. The metabolic and renal features are detectable after the first few months of life. Nephrocalcinosis becomes evident shortly thereafter. Photophobia, which is caused by the deposition of cystine crystals in the cornea, usually appears in children aged 3-6 years. Retinopathy is a later finding. In the absence of treatment, the disease leads to chronic renal failure by the end of the first decade of life. Dialysis and transplantation can be successfully performed in these children.

Following transplantation, cystine continues to accumulate in all organs, including the kidney interstitium, but it spares the proximal tubule cells. The increased longevity of these patients has resulted in the development of complications other than renal. Among these complications are hypothyroidism, decreased visual acuity, diabetes mellitus, neurologic disturbances, muscle weakness, and arrhythmias.

Adolescent cystinosis is an intermediate form, both in terms of the age of onset and the severity of symptoms. Nevertheless, it can lead to end-stage renal disease.

Galactosemia is caused by a deficiency in the activity of galactose-1-phosphate uridyltransferase. This enzyme catalyzes the reaction between galactose-1-phosphate and uridine-diphosphate-glucose to create uridine-diphosphate-galactose and glucose-1-phosphate. Deficiency of galactose-1-phosphate uridyltransferase leads to the accumulation of galactose-1-phosphate in various organs, including the liver, kidneys, brain, and ovaries, as well as the lenses of the eye. This accumulation only occurs when children with galactose-1-phosphate uridyltransferase deficiency receive milk, which is high in lactose, a major source of galactose.

Affected infants develop vomiting, diarrhea, and failure to thrive. Many of them become jaundiced because of increased levels of unconjugated bilirubin. The clinical picture is complicated by cataracts, splenomegaly, and hepatomegaly, leading to cirrhosis. Hyperaminoaciduria, albuminuria, and galactosuria (but not glucosuria) appear early in the course of the disease.

The pathogenesis of the disease is unclear. Experimental evidence points to cellular disturbances in carbohydrate metabolism and in the galactosylation of proteins. Accumulation of galactose-1-phosphate may deplete the cells of phosphate and compromise energy metabolism. Generation of galactitol from galactose may contribute to the development of cataracts.

Elimination of galactose from the diet results in reversal of symptoms, including the cataracts. Yet, children with this disease fail to thrive, have developmental delays, and exhibit ovarian dysfunction.

Hereditary fructose intolerance is caused by a deficiency in fructose-1-phosphate aldolase activity. This enzyme cleaves fructose-1-phosphate into D-glyceraldehyde and dihydroxyacetone phosphate, which, in turn, is converted into glucose or carbon dioxide and water.

Incidence is approximately 1 case per 20,000 live births. The disease becomes apparent when foods that contain fructose, sucrose, or sorbitol are introduced in the diet. Ingestion of such foods causes vomiting, severe dehydration, hemorrhagic diathesis, and acute liver and kidney failure. A full Fanconi syndrome is also present and can persist long after fructose has been excluded from the diet.

Continuous exposure to fructose results in hepatic insufficiency, nephrocalcinosis, and failure to thrive. Animal and human evaluations reveal that fructose loading leads to intracellular phosphate depletion and decreased ATP. This effect occurs in individuals with or without enzyme deficiencies but is more severe in the former group. Treatment of hereditary fructose intolerance consists of strict avoidance of fructose-containing foods.

Tyrosinemia (type I) is the result of a deficiency in fumarylacetoacetate hydrolase activity. The gene is located on chromosome 15. Mutations in this gene result in disturbances of tyrosine metabolism that affect the liver, kidneys, and peripheral nerves. The liver is the organ primarily affected in this disease. Manifestations of hepatic dysfunction can become evident during the first few months of life. Cirrhosis of the liver is the ultimate outcome, sometimes complicated by hepatic carcinoma. Disturbances in renal tubule transport are almost always present, and severe rickets is commonly observed as a result of phosphate losses. Some patients develop nephrocalcinosis and renal insufficiency. Peripheral neuropathy is associated with pain and sometimes paralysis.

Elevations in plasma levels of tyrosine and methionine translate into a specific cabbagelike odor that may lead to the diagnosis. The substance at the origin of Fanconi syndrome is succinylacetone, a compound that is structurally similar to maleic acid. Succinylacetone is derived from maleylacetoacetate and fumarylacetoacetate that accumulate in the tissues of patients with tyrosinemia. Succinylacetone may also account for the peripheral neuropathy through its inhibitory effect on d -aminolevulinic acid dehydratase and the subsequent accumulation of d -aminolevulinic acid, which is neurotoxic.

Treatment with a low tyrosine, low phenylalanine diet results in a prompt and substantial diminution of the renal abnormalities. Its effect on the liver disease is less certain.

2-(2-Nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) has been shown to block p -hydroxyphenylpyruvate dioxygenase (pHPPD) and thus the formation of maleylacetoacetate (MAA) and fumarylacetoacetate (FAA); these compounds are thought to cause harm by reducing the intracellular levels of glutathione and acting as alkylating agents. In patients treated with NTBC, the excretion of succinylacetone and d -aminolevulinic acid is diminished, and renal and hepatic function is improved.

Glycogen-storage diseases comprise a group of conditions that have inherited defects in glycogen metabolism as a common denominator. The most frequently affected tissues are the liver and the muscles. A Fanconi syndrome ensues only in those forms of the syndrome in which the deposition of glycogen in the renal tubules interferes with the generation of ATP.

The typical example is Fanconi-Bickel syndrome, characterized by impaired galactose use and the deposition of glycogen in liver and proximal tubule cells. The syndrome is caused by homozygosity or compound heterozygosity for mutations of the facilitated glucose transporter 2 gene (GLUT2). The patient presents in infancy with failure to thrive, hepatosplenomegaly, and rickets. Neonatal presentation with hyperglycemia and polyuria has been reported.

Fanconi-Bickel syndrome can be confused with type I glycogen storage disease, which is caused by a deficiency in glucose-6-phosphatase activity. This latter group of patients present in the newborn period, or shortly thereafter, with severe hypoglycemia and lactic acidosis. Renal disease is usually a late complication. The treatment of children with Fanconi-Bickel syndrome is symptomatic.

Wilson disease is caused by a disturbance in the metabolism of copper. Incidence is estimated to be 1 case per 50,000 live births. The genetic defect resides on band 13q14.

Wilson disease is characterized by reductions in the hepatic rate of copper incorporation into ceruloplasmin and in the biliary excretion of copper. The result is progressive accumulation of copper in the liver, subsequent overflow into the blood, and deposition in other tissues. The impairment in biliary copper excretion may be due to a defect in a P-type copper-transporting ATPase. The most common presentation, which usually occurs in children older than 6 years, is with chronic active hepatitis or cirrhosis. Greenish brown rings, termed Kayser-Fleischer rings, at the limbus of the cornea are pathognomonic.

Neurologic symptoms, such as behavioral disturbances, dysarthria, and malcoordination of voluntary movements are often present. Other symptoms include hemolytic anemia, renal stones, renal tubular acidosis, cardiomyopathy, and hypoparathyroidism. Generalized hyperaminoaciduria rarely becomes evident during childhood. Several agents have been found to be effective in the treatment of children with Wilson disease. Prominent among the treatments is D-penicillamine. Prognosis mainly depends on the extent of damage incurred prior to the onset of therapy.

Bilateral congenital cataracts, glaucoma, general hypotonia, hyporeflexia, severe mental retardation, and Fanconi syndrome characterize oculocerebrorenal syndrome (Lowe syndrome).

The defect was mapped to band Xq25-26. The gene OCRL-1 was identified by positional cloning and found to have strong homology to the gene on chromosome 1 for human inositol polyphosphate-5-phosphatase found in the Golgi apparatus. This enzyme removes the 5-phosphate from 1,4,5-inositol triphosphate, which may inactivate the phosphatidyl-inositol pathway. The relationship between this presumed effect and undersulfation of glycosaminoglycans found in patients with Lowe syndrome is unclear.

Unlike the cataracts, which are always present at birth, abnormalities in renal function may become apparent only after a few weeks or a few months of extrauterine life. Aminoaciduria, with relative sparing of branch-chain amino acids, is a constant feature of the syndrome. Glucosuria is not always present and its severity varies. Phosphate and potassium reabsorption follow a pattern similar to that of glucose. Acidosis, which is caused by a defect in the proximal reabsorption of bicarbonate, is almost always present. Cognitive, behavioral, and neuromuscular abnormalities vary in frequency and severity. Seizures occur in about 50% of patients. The renal disease advances with age, leading to chronic renal failure in adulthood. The treatment is symptomatic.

Mitochondrial cytopathies include a group of diseases characterized by myopathy, ataxia, seizures, and various other manifestations, including the Fanconi syndrome, determined by the specific tissue or tissues affected. The common denominator appears to be impaired oxidative phosphorylation due to alterations in mitochondrial DNA. Most patients present within the first months of life; few survive past age 1 year. Treatment, designed to emulate electron transport or to minimize free-radical damage, has met with little success.

Paroxysmal nocturnal hemoglobinuria has been rarely associated with Fanconi syndrome and is likely due to hemosiderin deposition in the proximal tubules.[2]

Microvillus inclusion disease, a rare congenital enteropathy associated with brush border atrophy with mutations in the MYO5B gene, has also been associated with Fanconi syndrome.[3]

A multitude of toxic and immunologic factors can impair proximal tubule function, resulting in a Fanconi syndrome. Prominent among these factors is exposure to heavy metals, such as cadmium, lead, mercury, platinum, and uranium. Rarely, Chinese herbs have been reported to cause Fanconi syndrome. Lead intoxication is the only heavy metal exposure that is encountered in children. However, in children, the tubular dysfunction is usually eclipsed by manifestations related to the central nervous system, such as apathy, somnolence, irritability, aggressiveness, and poor coordination. A history of pica can usually be elicited from the parents. An accurate, early diagnosis depends on laboratory determinations of lead levels. Treatment with chelating agents is usually effective in reversing the neurologic and renal abnormalities.

Fanconi syndrome has also been reported to occur as a result of drug ingestion. Well-recognized ingestions include those with outdated tetracycline and aminoglycoside antibiotics, such as gentamicin.

Tetracycline toxicity is probably caused by anhydro-4-epitetracycline, a degradation product that is formed when the drug is stored for long periods or kept in a moist environment. The metabolite decreases oxidative metabolism and energy production.

Aminoglycosides accumulate in proximal tubule cells, but the mechanism of action has not been identified.

Cisplatin, ifosfamide, and 6-mercaptopurine are chemotherapy agents that can cause Fanconi syndrome.

Valproic acid, commonly used as an antiepileptic drug, may rarely induce severe Fanconi syndrome. However, valproic acid may be especially important in young patients and in those with severe disabilities after long-term therapy. The disease is reversible with cessation of therapy.

Tenofovir, a nucleotide reverse transcriptase inhibitor used in the treatment of human immunodeficiency virus (HIV) infection, has been reported to cause Fanconi syndrome and acute kidney failure.[4] Increased values of urinary beta-2 microglobulin and retinol-binding protein, observed in up to 70% of patients, have been associated to tenofovir-associated mitochondrial dysfunction.[5]

Adefovir dipivoxil (ADV), a nucloeotide analog developed to treat chronic hepatitis B, is associated with reversible acquired Fanconi syndrome.[6, 7] . Even with low dose and long-term use Adevovir may induce Fanconi syndrome. 

Rifampin therapy has been observed to cause Fanconi syndrome, but it usually resolves with cessation of therapy. Thus, markers of proximal tubular injury should be carefully monitored in patients receiving rifampin.[8]

Deferasirox, a widely used oral iron chelator for the treatment of patients with iron overload due to chronic transfusion therapy for diseases such as β-thalassemia and sickle cell disease, has been reported to cause reversible Fanconi syndrome.[9]

Dysproteinemias, such as multiple myeloma, amyloidosis, light-chain nephropathy, and benign monoclonal gammopathy, are causes of Fanconi syndrome in adults.

Immunologic injury of the proximal tubules can be observed in interstitial nephritis, renal transplantation, and various malignancies. Sarcoidosis, can rarely present with fanconi syndrome that is successfully treated with corticosteroid[46]

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Contributor Information and Disclosures
Author

Sahar Fathallah-Shaykh, MD Associate Professor of Pediatric Nephrology, University of Alabama at Birmingham School of Medicine; Consulting Staff, Division of Pediatric Nephrology, Medical Director of Pediatric Dialysis Unit, Children's of Alabama

Sahar Fathallah-Shaykh, MD is a member of the following medical societies: American Society of Nephrology, American Society of Pediatric Nephrology

Disclosure: Nothing to disclose.

Coauthor(s)

Adrian Spitzer, MD Clinical Professor Emeritus, Department of Pediatrics, Albert Einstein College of Medicine

Adrian Spitzer, MD is a member of the following medical societies: American Academy of Pediatrics, American Federation for Medical Research, American Pediatric Society, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Frederick J Kaskel, MD, PhD Director of the Division and Training Program in Pediatric Nephrology, Vice Chair, Department of Pediatrics, Montefiore Medical Center and Albert Einstein School of Medicine

Frederick J Kaskel, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, Eastern Society for Pediatric Research, Renal Physicians Association, American Academy of Pediatrics, American Pediatric Society, American Physiological Society, American Society of Nephrology, American Society of Pediatric Nephrology, American Society of Transplantation, Federation of American Societies for Experimental Biology, International Society of Nephrology, National Kidney Foundation, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD The Isaac A Abt, MD, Professor of Kidney Diseases, Northwestern University, The Feinberg School of Medicine; Division Head of Kidney Diseases, The Ann and Robert H Lurie Children's Hospital of Chicago

Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, International Society of Nephrology

Disclosure: Received income in an amount equal to or greater than $250 from: Alexion Pharmaceuticals; Raptor Pharmaceuticals; Eli Lilly and Company; Dicerna<br/>Received grant/research funds from NIH for none; Received grant/research funds from Raptor Pharmaceuticals, Inc for none; Received grant/research funds from Alexion Pharmaceuticals, Inc. for none; Received consulting fee from DiCerna Pharmaceutical Inc. for none.

Additional Contributors

Deogracias Pena, MD Medical Director of Dialysis, Medical Director of Pediatric Nephrology and Transplantation, Cook Children's Medical Center; Clinical Associate Professor, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Medical Director of Pediatric Nephrology, Florida Hospital for Children

Deogracias Pena, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Pediatric Nephrology

Disclosure: Nothing to disclose.

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