Fanconi's Syndrome

Background: The renal syndrome that is identified 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, who, in 1903, 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, and, 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, it became clear that the syndrome is associated with a variety of conditions characterized by injury of the proximal segment of the renal tubule. Yet, the mechanism underlying these abnormalities remains, to this day, a matter of debate.


Pathophysiology: A number of 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. 

The transport of solutes across the apical membrane of proximal tubule cells is affected by a number of symporters and antiporters. 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 adenosine triphosphate (ATP) would impair the performance of secondary active transport mechanisms, such as those of glucose, phosphate, or amino acids. Evidence supporting this hypothesis can be found in a variety of 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 occur 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 due to low intracellular phosphate, which results in a depletion of ATP precursors and an increase in adenine nucleotide degradation. 

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.


Authored by Adrian Spitzer, MD, Professor, Department of Pediatrics, Albert Einstein College of Medicine; Director of NIH Training Program, Children's Hospital at Montefiore Medical Center
eMedicine Journal, September 24 2002, Volume 3, Number 9