Fanconi Syndrome Clinical Presentation

Updated: Mar 16, 2023
  • Author: Sahar Fathallah-Shaykh, MD; Chief Editor: Craig B Langman, MD  more...
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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.


Physical Examination

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.