Fanconi syndrome

Fanconi syndrome (de Toni-Debré-Fanconi) is considered a “major” tubular dysfunction, characterized by impaired reabsorption of most substances and ions (aminoaciduria, glucosuria, hyperphosphaturia, increased bicarbonate excretion) and systemic metabolic changes.

Fanconi syndrome involves multiple defects in reabsorption in the proximal renal tubules, leading to glucosuria, phosphaturia, generalized aminoaciduria, and decreased bicarbonate concentrations. Symptoms in children include malnutrition, failure to thrive, and rickets; symptoms in adults include osteomalacia and muscle weakness. Diagnosis is based on the presence of glucosuria, phosphaturia, and aminoaciduria. Treatment includes replacement of bicarbonate deficiency and treatment of renal failure.

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Epidemiology

Fanconi syndrome occurs in various regions of the world. The incidence of the disease is, according to current data, 1 in 350,000 newborns. Apparently, not only Fanconi syndrome is taken into account, but also Fanconi syndrome that developed in the neonatal period.

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Causes Fanconi syndrome

Fanconi syndrome is congenital or develops as part of acquired diseases.

The nature of the genetic defect and the primary biochemical product remain poorly understood. It is assumed that the basis is either an anomaly of the renal tubule transport proteins or a gene mutation that ensures the inferiority of enzymes that determine the reabsorption of glucose, amino acids and phosphorus. There is evidence of primary mitochondrial disorders in Fanconi syndrome. The genetic defect determines the severity of the disease. A distinction is made between complete and incomplete Fanconi syndrome, i.e. there may be all 3 main biochemical defects or only 2 of them.

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Risk factors

Fanconi syndrome (de Toni-Debre-Fanconi disease) is more often considered as a syndrome associated with cystinosis, galactosemia, glycogenoses, tyrosinemia, fructose intolerance, Wilson-Konovalov disease, metachromatic leukodystrophy, pyruvate carboxylase deficiency, mitochondrial phosphoenolpyruvate carboxykinase deficiency, exposure to toxic substances (ifosfamide, aminoglycosides, expired tetracyclines, heavy metals) or developing in connection with such acquired diseases as amyloidosis, vitamin D deficiency, etc. However, according to a number of authors, Fanconi syndrome can be an independent disease, related to the most severe rickets-like diseases.

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Pathogenesis

In Russian literature, the term "Fanconi syndrome" or "Debre-de-Tony-Fanconi syndrome" is most often used; the following terms are also common: "glucoamine phosphate diabetes", "glucosamine diabetes", "renal dwarfism with vitamin D-resistant rickets", "idiopathic renal Fanconi syndrome", "hereditary Fanconi syndrome". In foreign literature, the most common terms are: "Renal Fanconi syndrome", "Fanconi syndrome", "primary de-Tbni-Debre-Fanconi syndrome", "Inherited Fanconi syndrome", etc.

Clinical and experimental data confirm the disturbance of transmembrane transport in the proximal convoluted tubules of the nephron. It is still unclear whether a structural or biochemical defect underlies the disease. Rickets-like changes develop either due to the combined effect of acidosis and hypophosphatemia, or only hypophosphatemia. According to some researchers, the pathology is based on a decrease in intracellular ATP reserves.

Hereditary Fanconi syndrome is usually associated with other congenital diseases, especially cystinosis. Fanconi syndrome may also be associated with Wilson disease, hereditary fructose intolerance, galactosemia, glycogen storage diseases, Lowe syndrome, and tyrosinemia. The pattern of inheritance varies depending on the associated disease.

Acquired Fanconi syndrome can be caused by a variety of medications, including some anticancer chemotherapy drugs (eg, ifosfamide, streptozocin), antiretrovirals (eg, didanosine, cidofovir), and expired tetracycline. All of these drugs are nephrotoxic. Fanconi syndrome can also develop with kidney transplantation, multiple myeloma, amyloidosis, heavy metal and other chemical intoxication, or vitamin D deficiency.

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Symptoms Fanconi syndrome

Symptoms of Fanconi syndrome are varied. In children, symptoms often resemble phosphate diabetes. In adults, polyuria, hyposthenuria, muscle weakness, and bone pain are observed. Arterial hypertension is possible, and if left untreated, chronic renal failure may develop.

As a rule, the first symptoms of the disease manifest themselves in the first year of a child's life. However, in the 10 children with Toni-Debre-Fanconi disease that we observed, the first symptoms appeared after one and a half years of life. At first, polyuria and polydipsia, subfebrile temperature, vomiting, and persistent constipation attract attention. The child begins to lag behind in physical development, bone deformities appear, mainly in the lower limbs of the valgus or varus type. Muscle hypotonia develops, and at 5-6 years of age, children cannot walk independently. With the progression of tubular disorders by 10-12 years of life, chronic renal failure may develop. In addition to the above symptoms, pathological changes are also detected in other organs. Among the 10 children mentioned above who were under our observation, 7 had ophthalmological abnormalities, 6 had CNS pathology, 5 had cardiovascular pathology and anatomical abnormalities of the urinary system, 4 had ENT and gastrointestinal pathology, and in isolated cases, endocrine disorders and immunodeficiency states.

Forms

Idiopathic (primary):

• hereditary (autosomal dominant, autosomal recessive, X-linked);
• sporadic;
• Dent's syndrome.

Secondary:

• In case of congenital disorders of metabolism or transport:
  • cystinosis;
  • tyrosinemia type I;
  • glycogenosis, type XI;
  • galactosemia;
  • congenital fructose intolerance;
  • Wilson-Konovalov disease.
• For acquired diseases:
  • paraproteinemia (multiple myeloma, light chain disease);
  • tubulointerstitial nephropathy;
  • nephrotic syndrome;
  • renal transplant nephropathy;
  • malignant tumors (paraneoplastic syndrome).
• In case of intoxication:
  • heavy metals (mercury, lead, cadmium, uranium);
  • organic substances (toluene, maleic acid, lysol);
  • medicinal products (platinum preparations, expired tetracycline, gentamicin).
• Severe burns.

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Diagnostics Fanconi syndrome

To confirm the diagnosis, radiographic studies of bones and extensive laboratory tests of blood and urine are necessary.

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Laboratory diagnostics of Fanconi syndrome

In the biochemical blood test, the characteristic signs are considered to be a decrease in the content of calcium (<2.1 mmol / l), phosphorus (<0.9 mmol / l), an increase in the activity of alkaline phosphatase, metabolic acidosis (BE = 10-12 mmol / l). Glucosuria, phosphaturia, generalized hyperaminociduria (up to 2-2.5 g / 24 h) are detected. In this case, a loss of glycine, alanine, proline, glutamic acid is noted, that is, a violation of all membrane transport systems in the tubules. Tubular proteinuria is characteristic - the presence of light chains of immunoglobulins, lysozyme, beta ₂ -microglobulins in the urine. A decrease in the concentration of sodium and potassium in the blood, an increase in the clearance of uric acid with a decrease in its content in the blood are noted. Excessive loss of bicarbonates in the urine leads to a pronounced picture of metabolic acidosis. A bioenergetic disorder was revealed in the form of decreased activity of energy metabolism enzymes: a-glycerophosphate dehydrogenase, glutamate dehydrogenase, succinate dehydrogenase. At the same time, almost all patients showed a peroxidation disorder in the form of increased lactic and pyruvic acid levels in the blood.

Laboratory tests

• Generalized aminoaciduria.
• Proximal renal tubular acidosis with bicarbonaturia.
• Phosphaturia, hypophosphatemia, phosphate diabetes.
• Hyposthenuria, polyuria.
• Tubular proteinuria (beta ₂ -microglobulin, immunoglobulin light chains, low molecular weight proteins).
• Hypokalemia.
• Hypocalcemia.
• Hyponatremia.
• Hyperuricosuria.

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Instrumental diagnostics of Fanconi syndrome

X-rays of the skeletal bones are widely used as mandatory instrumental studies in the diagnosis of Fanconi syndrome to detect limb deformation and bone tissue structure disorders - osteoporosis (usually systemic) and a lag in bone tissue growth rates from the child's calendar age. Bone tissue is characterized by a coarse fibrous structure, epiphysiolysis is often detected. In the distal parts of the femur and proximal parts of the tibia, a cellular structure of bone tissue and spur-like formations are detected. Osteoporosis is detected in the late stages of the disease, fractures of tubular bones are possible. X-ray densitometry is used to determine the severity of osteoporosis.

Radioisotope studies reveal accumulation of radioisotope in the patient's bone zones of intensive growth.

Morphological examination of bone tissue biopsies reveals that the structure of the bone beams is disrupted, revealing lacunae and weak bone mineralization.

Nephrobiopsy reveals a peculiar picture of the proximal tubules (they resemble a "swan neck" in shape), epithelial atrophy, and interstitial fibrosis. The glomeruli are involved in the process at the very final stages of the disease. Electron microscopic examination reveals a large number of mitochondria in the epithelium.

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Examples of diagnosis formulation

Fanconi syndrome. OMIM-134 600. Chronic renal failure, terminal stage. Secondary hyperparathyroidism. Systemic osteoporosis. Varus deformity of the limbs.

Glycogenosis type I. Fanconi syndrome. Chronic renal failure stage I.

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Differential diagnosis

Differential diagnostics are carried out with all diseases in which Fanconi syndrome develops. These include the following hereditary diseases:

• galactosemia;
• glycogenosis type I;
• tyrosinemia;
• cystinosis;
• osteogenesis imperfecta;
• Konovalov-Wilson disease;
• thalassemia;
• congenital nephrotic syndrome;
• renal tubular acidosis.

In addition to hereditary diseases, differential diagnosis is carried out with acquired pathological conditions:

• poisoning with heavy metals, chemicals and drugs, especially those with expired expiration dates;
• secondary hyperparathyroidism;
• severe burns;
• multiple myeloma;
• diabetes mellitus.

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Treatment Fanconi syndrome

Treatment of Fanconi syndrome is aimed at correcting hypokalemia, proximal renal tubular acidosis, and other electrolyte disturbances. Phosphate diabetes therapy is carried out according to general rules. Patients with Fanconi syndrome should be advised to drink plenty of fluids.

In secondary Fanconi syndrome, its symptoms decrease or disappear completely with successful treatment of the underlying disease.

Treatment goals

Non-drug and drug treatment of patients with Fanconi disease are very close in essence, as they involve correction of electrolyte disorders (elimination of potassium and bicarbonate deficiency), shifts in acid-base balance. Symptomatic therapy is also necessary.

Diet therapy

Since it is necessary to limit the excretion of sulfur-containing amino acids, potato and cabbage foods are suitable as dietary means. It is advisable to carry out treatment with active vitamin D preparations with a diet that limits salt, including products that have an alkalizing effect: milk, fruit juices. It is necessary to widely use preparations containing potassium, you should eat prunes, dried apricots, raisins. With a pronounced potassium deficiency, it is advisable to add panangin or asparkam. If acidosis is pronounced, then one diet is not enough, sodium bicarbonate, citrate mixtures should be used.

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Drug treatment of Fanconi syndrome

Active vitamin D preparations are widely used to eliminate phosphorus-calcium metabolism disorders: l,25(OH)D3 _or l(OH)D3 _. Initial doses of vitamin D3 _are 10,000-15,000 IU per day, then the dose is gradually increased to the maximum - 100,000 IU per day. The dose of vitamin D3 is increased _under the control of calcium and phosphorus levels in the blood and is stopped when these indicators are normalized. Prescription of calcium and phytin preparations is mandatory. Treatment is carried out in repeated courses to prevent relapse. With the normalization of phosphorus-calcium metabolism and the disappearance of signs of acidosis, massage and salt-pine baths are indicated.

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Surgical treatment of Fanconi syndrome

In case of severe bone deformities, surgical correction is indicated, which is carried out with stable clinical and laboratory remission lasting at least 1.5 years.

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Indications for consultation with other specialists

In case of pronounced changes in the kidneys: high proteinuria, hypertension, anatomical anomalies - consultations with a nephrologist and urologist are indicated. In case of hyperparathyroidism, consultation with an endocrinologist is mandatory. In cases of ophthalmological disorders - an ophthalmologist.

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Indications for hospitalization

Indications for hospitalization: severe metabolic disorders and skeletal deformation.

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Prevention

Prevention of primary hereditary tubulopathy - Fanconi syndrome - timely medical and genetic counseling in the presence of such a disease in the family. The genetic risk for siblings is 25%.

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Forecast

The prognosis of the disease is usually associated with severe changes in the renal parenchyma: pyelonephritis, tubulointerstitial nephritis, chronic renal failure. The development of chronic renal failure requires replacement therapy.

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