Fanconi Syndrome

Updated: Nov 03, 2016
  • Author: Sahar Fathallah-Shaykh, MD; Chief Editor: Craig B Langman, MD  more...
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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.




United States

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.


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.


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.


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.


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.