Fanconi Syndrome

The renal syndrome that is associated with the Swiss pediatrician Guido Fanconi was actually described in parts and under various names by several investigators who preceded him. The first investigator was Abderhalden; in 1903, he found cystine crystals in the liver and spleen of a 21-month-old infant and called the disease "a familial cystine diathesis." In 1924, Lignac described 3 such children who presented with severe rickets and growth retardation. In 1931, Fanconi described a child who had glucosuria and albuminuria in addition to rickets and dwarfism. Two years later, de Toni added hypophosphatemia to the clinical picture; soon after, Debre et al found large amounts of organic acids in the urine of an 11-year-old girl.

Fanconi's further contribution to the subject came in 1936, when he recognized the similarities between these cases, added 2 new patients to the list, named the disease nephrotic-glucosuric dwarfism with hypophosphatemic rickets, and suggested that the organic acids found in the urine may be amino acids. Fanconi's findings were confirmed in 1943 by McCune et al and in 1947 by Dent, who established that the organic acids originated in the kidneys.

During the years that followed, as the number of reported cases multiplied, the syndrome's association with various conditions characterized by injury of the proximal segment of the renal tubule became clear. Yet, the mechanism underlying these abnormalities remains a matter of debate.

Numerous mechanisms can result in diminished reabsorption of solutes by the proximal tubule. The 3 main categories in which they can be classified are (1) alterations in the function of the carriers that transport substances across the luminal membrane, (2) disturbances in cellular energy metabolism, and (3) changes in permeability characteristics of the tubular membranes.

Numerous symporters and antiporters affect the transport of solutes across the apical membrane of proximal tubule cells. The energy required for the function of these carriers is provided by the sodium-potassium (Na+/K+)–adenosine triphosphatase (ATPase) pump, which is located at the basolateral membrane.

Because of the large number of transport abnormalities observed in Fanconi syndrome, these anomalies are not likely due to alterations in the carriers, which are specific for each of the substances reabsorbed in the proximal tubule. A defect in cellular energy metabolism appears to be a more plausible cause. Under the scenario of a defective cellular energy metabolism, any process that results in a decrease in the level of ATP impairs the performance of secondary active transport mechanisms, such as those of glucose, phosphate, or amino acids. Evidence supporting this hypothesis can be found in various experimental models and clinical forms of Fanconi syndrome.

One of the most extensively studied models of Fanconi syndrome is that induced by maleic acid. Rats and dogs injected with this substance develop glucosuria, phosphaturia, aminoaciduria, bicarbonaturia, and proteinuria, associated with decreases in Na+/K+ -ATPase and ATP levels. Similar changes develop in animals injected with heavy metals, such as cadmium, lead, and mercury.

Cystinosis is one of the most common causes of Fanconi syndrome in children. The disease is caused by the accumulation of cystine in renal tubule cells. An experimental model of Fanconi syndrome was created by injecting rats with cystine dimethylester. Renal tubules exposed to this compound had a high concentration of cystine; low rates of transport; and decreased levels of ATP, oxygen consumption, and mitochondrial respiration. Addition of ATP to the incubation media partially corrected these abnormalities. Some postulate that the decrease in oxidative energy metabolism seen in many forms of Fanconi syndrome is caused by low intracellular phosphate, which results in a depletion of ATP precursors and an increase in adenine nucleotide degradation. Others have found elevated oxidized glutathione in the cystinotic proximal tubular epithelial cell line, suggesting increased oxidative stress that may contribute to tubular dysfunction in cystinosis.

Evidence supporting a role for alterations in tubule membrane permeability in the pathogenesis of Fanconi syndrome is limited. The luminal membrane permeability may increase in the maleic acid model and in animals injected with succinylacetone, the presumed toxin in tyrosinemia and another cause of Fanconi syndrome in humans.

A study sought to determine the genetic cause and underlying defect of Fanconi's syndrome by clinically and genetically characterizing members of a five-generation black family with isolated autosomal dominant Fanconi's syndrome. The study found that the mistargeting of peroxisomal EHHADH disrupts mitochondrial metabolism and leads to renal Fanconi's syndrome. This finding indicates a central role of mitochondria in proximal tubular function.[1]

Whether these findings can be extended to the idiopathic form of Fanconi syndrome is unknown.

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, intracranial hypertension,[2]  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.[3]

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.[4]

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 usually reversible with cessation of therapy but can cause permanent or prolonged proximal tubular dysfunction.[5]  Bedridden patients receiving valproic acid are susceptible to hypocarnitinemia, which can cause proximal tubular dysfunction and may lead to Fanconi syndrome. It is suggested that Beta2-microglobulin should be measured regularly in patients receiving valproic acid to assess renal tubular function.[6]

In a study by Wang et al, most patients who developed Fanconi syndrome were receiving an average of two antiepileptic drugs in addition to valproic acid. The authors suggest that combination therapy with valproic acid and other anticonvulsants may increase the risk of Fanconi syndrome.[7]

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.[8]  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.[9]

Adefovir dipivoxil (ADV), a nucleotide analog developed to treat chronic hepatitis B, is associated with reversible acquired Fanconi syndrome.[10, 11] . Even with low dose and long-term use Adefovir may induce Fanconi syndrome.[12]  

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.[13]

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.[14]

Apremilast, a phosphodiesterase 4-inhibitory medication approved for use to treat psoriasis and psoriatic arthritis, has been associated with Fanconi syndrome.[15]

The bisphosphonate zoledronic acid has also been associated with Fanconi syndrome. Portales-Castillo et al reported four cases of new-onset Fanconi syndrome in patients with underlying malignancy who had received zoledronic acid approximately 1 week earlier.[16]  Another case report described a woman with Fanconi syndrome and osteomalacia, who had metastatic breast cancer and had been treated with zoledronate for more than 5 years.[17]

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. Rarely, patients with sarcoidosis can present with Fanconi syndrome which is successfully treated with corticosteroids.[18]  Acute lymphoblastic leukemia can aslo rarely present with Fanconi syndrome.[19]

United States statistics

Fanconi syndrome is due to various causes, some inherited and some acquired. The incidence of each of these conditions is different, although almost all of them are rather rare.

Race-, sex-, and age-related demographics

Race

Cystinosis, the most common form of Fanconi syndrome in children, occurs almost exclusively in whites. No known racial predilections are known for other forms of Fanconi syndrome.

Sex

Most diseases associated with 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.

Oculocerebrorenal syndrome (ie, Lowe syndrome) is transmitted as an X-linked recessive trait, which causes males to be affected more often than females. 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.

Age

The age at onset varies with the etiology. A few of the inherited forms of Fanconi syndrome, such as Lowe syndrome, vitamin D–dependent rickets, and the infantile form of cystinosis, become evident during the first year of life. Other forms, such as the late-onset forms of cystinosis, Wilson disease, galactosemia, and glycogen-storage disease, appear clinically at a later age, usually during childhood. The acquired forms may appear at any age, mostly because of exposure to noxious agents.

Prognosis varies and depends on the cause of the syndrome and the severity of the renal and extrarenal manifestations. As a general rule, the acquired forms of Fanconi syndrome are limited in time and in consequences. The inherited forms are difficult to manage, are usually associated with disturbances in growth, and are involved with specific organs.

• Cystinosis may result in chronic renal failure, visual impairment, hypothyroidism, progressive neurologic disorders, and generalized myopathy. Patients with nephropathic cystinosis who have been well-treated with cysteamine have an excellent clinical outcome, illustrating the critical importance of early diagnosis and treatment. Despite a substantial improvement in prognosis due to cystine-depleting therapy, no cure of the disease is currently available. Kidney Disease: Improving Global Outcome (KDIGO) has recently reviewed cystinosis state-of-the-art knowledge and areas of controversies in pathophysiology, diagnostics, monitoring and treatment in different age groups and most importantly, promising areas of investigation/research that may lead optimal outcome in these patients.[20]

• Galactosemia, even when galactose is eliminated early from the diet, results in developmental delays, speech impairment, and ovarian dysfunction.

• Tyrosinemia leads to chronic liver failure and the development of hepatomas. Liver transplantation has been successfully performed in such cases.

• Wilson disease, when not diagnosed and treated early, may result in neurologic and psychiatric disorders, chronic active hepatitis, and acute hemolytic crises. Liver transplantation has been successfully performed in patients with hepatic failure.

• Congenital cataracts or glaucoma, mental retardation, hypotonia, and kidney abnormalities that can lead to chronic renal failure and end-stage renal disease in adulthood characterize Lowe syndrome.

• Idiopathic Fanconi syndrome may result in chronic renal failure during adolescence or adulthood.

Morbidity/mortality

The morbidity of Fanconi syndrome is secondary to the metabolic abnormalities it generates. Most of these abnormalities, such as acidosis, calciuria, and phosphaturia, affect bone accretion and, thus, growth. Some forms of Fanconi syndrome, such as cystinosis, lead to renal failure.

All parents should receive counseling on prevention of lead exposure and avoidance of outdated antibiotics as part of routine well-child care.

• Parents of children with the primary forms of Fanconi syndrome should receive genetic counseling to explain the patterns of inheritance and advise on the risks of recurrence of the syndromes in subsequent pregnancies.

• Parents of children with Fanconi syndrome secondary to galactosemia or tyrosinemia should receive detailed dietary instructions to eliminate the specific untolerated nutrients from the diet.

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.

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.[21, 22]

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.

The diagnosis of Fanconi syndrome is made based on tests that document the excessive loss of substances in the urine (eg, amino acids, glucose, phosphate, bicarbonate) in the absence of high plasma concentrations. More elaborate tests are designed to determine the renal threshold for these substances (ie, the concentration in the blood at which these substances appear in the urine) or their fractional reabsorption (ie, the percentage of the filtered load that is reabsorbed by the renal tubule). The results are compared with normal levels for age. Recently, an increased urinary lactate-to-creatinine ratio has been postulated as a sensitive test for disordered proximal tubular function. Moreover, urinary retinol-binding protein 4 is thought to be a functional biomarker of the proximal tubule and elevated levels appears to be an excellent screening test for Fanconi syndrome.[24]  

The choice of tests designed to determine the cause of the syndrome should be based on information obtained by means of the history or physical examination. When toxic agents such as drugs or heavy metals are suspected, measure their levels in the blood or urine. When cystinosis appears to be the cause, measure the cellular concentrations of cystine in fibroblasts or leucocytes. Enzymatic defects can be ascertained by measuring tissue levels. An international consensus document was published in 2014 that provides expert opinion regarding diagnosis and treatment of nephropathic cystinosis.[25]  

Imaging studies do not play an important role in the diagnosis or follow-up of patients with Fanconi syndrome. Rarely, a patient may come to the attention of the physician because of rickets, a consequence of mineral losses in the urine and disturbances in vitamin D metabolism.

Most patients with Fanconi syndrome have no distinguishing features of renal morphology.

A distortion in the appearance of the proximal tubule, which resembles a swan neck, was described in children with cystinosis and was considered to be the cause of the syndrome. However, this distortion is more likely to be consequence of cellular atrophy secondary to the deposition of cystine.

Nonspecific glomerular and tubular changes are also described in Lowe syndrome.

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.

Monitoring

Closely monitor all patients with Fanconi syndrome, independent of etiology or pathogenesis. Frequency of the patient's visits depends on various factors, including the severity of the syndrome, the ability to maintain fluid and electrolyte balance, the degree of involvement of other organs, and the need for monitoring the effects and side effects of specific medications.

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.

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.

Some of the secondary forms of Fanconi syndrome may be limited by preventing exposure to toxins such as lead and outdated tetracyclines and aminoglycosides. Eliminating lactose from the diet in children with galactosemia and tyrosine/phenylalanine from the diet in children with tyrosinemia helps alleviate the symptoms in some of the primary forms of Fanconi syndrome.

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.

Class Summary

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 effect on the Fanconi syndrome was documented. Cysteamine bitartrate (Procysbi), a delayed-release formula that can be given every 12 hours, is approved by the US Food and Drug Administration (FDA) for management of nephropathic cystinosis in children aged 1 year and older and adults. A randomized controlled crossover trial showed the delayed-release product was safe and effective in reducing WBC cystine levels in patients with cystinosis.[26]  Approval for children as young as 1 year is based on a long-term, prospective, open-label study that enrolled 17 people living with nephropathic cystinosis, including 15 children between the ages of 1 and 5 years old, who had not previously been treated with cysteamine therapy. Children enrolled in the study experienced lowering of white blood cell (WBC) cystine levels from poor controlled to well controlled at 12 and 18 month measurements. Additionally, they experienced measured improvements in growth milestones including weight and height.[27]

Cysteamine bitartrate (Procysbi)

Cysteamine bitartrate is used off-label to reduce cystine levels, potentially delaying kidney and other damage associated with Fanconi syndrome. The delayed-release product is used in the management of nephropathic cystinosis, a rare genetic condition, in adults and children aged 1 year or older. It was granted an orphan product designation.

Class Summary

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.

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.

Class Summary

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.[28]

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.