Fanconi Syndrome

Fanconi syndrome (de Tony-Debreux-Fanconi) is considered as a “large” canalicular dysfunction characterized by impaired reabsorption of most substances and ions (aminoaciduria, glucosuria, hyperphosphaturia, an increase in bicarbonate excretion) and systemic metabolic changes.

Fanconi syndrome includes multiple defects of reabsorption in the proximal renal tubules, which leads to glycosuria, phosphaturia, generalized aminoaciduria, and a decrease in the concentration of bicarbonates. Symptoms in children include hypotrophy, physical retardation and rickets, symptoms in adults - osteomalacia and muscle weakness. The diagnosis is based on the detection of glucosuria, phosphaturia and aminoaciduria. Treatment includes recovery of bicarbonate deficiency, as well as treatment of renal failure.

[1],

Epidemiology

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

[2], [3], [4], [5], [6], [7],

Causes of the fanconi syndrome

Fanconi syndrome - congenital or develops in the framework of acquired diseases.

The nature of the genetic defect and the primary biochemical product remains poorly understood. It is believed that the basis is either an abnormality of renal tubular 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. A genetic defect determines the severity of the disease. Distinguish between complete and incomplete Fanconi syndrome, that is, there may be all 3 major biochemical defects or only 2 of them.

[8], [9], [10], [11], [12]

Risk factors

Fancón Syndrome, aminoglycosides, expired tetracyclines, heavy metals) or developing in connection with such acquired diseases as amyloidosis, deficiency um and vitamin D et al. However, according to several authors, Fanconi syndrome may be an independent disease, related to the most severe rahitopodobnyh diseases.

[13], [14], [15]

Pathogenesis

The term “Fanconi syndrome” or “Debre-de-Tony-Fanconi syndrome” is more commonly used in the domestic literature; the terms “glucoaminophosphate diabetes”, “glucophosphamine diabetes”, “renal nanism with vitamin D-resistant rickets”, “idiopathic renal syndrome” are also common. Fanconi "," Fanconi's hereditary 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 transmembrane transport impairment in the proximal convoluted nephron tubule. It is still not clear whether a structural or biochemical defect underlies the disease. Rachitus-like changes develop either due to the combined effect of acidosis and hypophosphatemia, or only hypophosphatemia. According to a number of researchers, the basis of pathology is a decrease in intracellular stocks of ATP.

Hereditary Fanconi syndrome usually accompanies other congenital diseases, especially cystinosis. Fanconi syndrome can also be combined with Wilson's disease, hereditary fructose intolerance, galactosemia, diseases of glycogen accumulation, Low syndrome and tyrosinemia. The type of inheritance varies depending on the associated disease.

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

[16], [17], [18], [19], [20]

Symptoms of the fanconi syndrome

The symptoms of Fanconi syndrome are varied. In children, symptoms more often resemble phosphate diabetes. In adults, polyuria, hypostenuria, muscular weakness, pain in the bones are observed. Arterial hypertension is possible, in the absence of treatment - the formation of chronic renal failure.

As a rule, the first manifestations of the disease manifest in the first year of a child's life. However, in 10 children with pre-Toni-Debre-Fanconi disease we observed, the first symptoms appeared after one and a half years of life. At first, attention is drawn to polyuria and polydipsia, subfebrile condition, vomiting, and persistent constipation. The child begins to lag behind in physical development, bone deformities appear predominantly of the lower limbs of the valgus or varus type. Hypotension develops, and in 5-6 years old children cannot walk on their own. With the progression of tubular disorders to 10-12 years of age, the development of chronic renal failure. In addition to the above symptoms, pathological changes are detected by other organs. Among the 10 children mentioned above, who were under our supervision, 7 had ophthalmic abnormalities, 6 had CNS pathology, 5 had pathology of the cardiovascular system and anatomical anomalies of the urinary system, 4 had pathology of the upper respiratory tract and the gastrointestinal tract, single cases - endocrine disorders and immunodeficiency states.

Forms

Idiopathic (primary):

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

Secondary:

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

[21], [22], [23], [24], [25],

Diagnostics of the fanconi syndrome

Radiopaque examinations of the bones and extensive laboratory tests of blood and urine are necessary to confirm the diagnosis.

[26], [27], [28],

Laboratory diagnosis of Fanconi syndrome

In the biochemical analysis of blood, characteristic signs are a decrease in calcium (<2.1 mmol / l), phosphorus (<0.9 mmol / l), increased alkaline phosphatase activity, metabolic acidosis (BE = 10-12 mmol / l). Glucosuria, phosphaturia, generalized hyperaminociduria (up to 2-2.5 g / 24 h) are detected. At the same time, the loss of glycine, alanine, proline, glutamic acid, that is, the disruption of all transport systems of membrane transfer in the tubules, is noted. Characteristic of tubular type proteinuria is the presence in the urine of light chains of immunoglobulins, lysozyme, beta ₂ -microglobulins. They note 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. Excessive loss of bicarbonate in the urine leads to a pronounced picture of metabolic acidosis. The violation of bioenergy was revealed in the form of a decrease in the activity of enzymes of energy metabolism: a-glycerophosphate dehydrogenase, glutamate dehydrogenase, succinate dehydrogenase. At the same time, almost all patients had a peroxidation disorder in the form of an increase in the blood levels of lactic and pyruvic acids.

Lab tests

• Generalized aminoaciduria.
• Proximal renal tubular acidosis with bicarbonate.
• Phosphaturia, hypophosphatemia, phosphate diabetes.
• Hypostenuria, polyuria.
• Tubular proteinuria (beta ₂ -microglobulin, immunoglobulin light chains, low molecular weight proteins).
• Dizziness.
• Hypocalcemia.
• Gyoponatraemia.
• Giperuricosuria.

[29], [30]

Instrumental diagnosis of Fanconi syndrome

As mandatory instrumental studies in the diagnosis of Fanconi syndrome, radiography of skeletal bones is widely used to detect limb deformities and bone structure disorders - osteoporosis (usually systemic) and lagging bone growth rates from the calendar age of a child. For bone tissue is characterized by coarse-fiber structure, epiphysiolysis is often found. In the distal femoral and proximal tibial bones, the cellular structure of bone tissue and spur-like structures are found. In the later stages of the disease, osteoporosis is detected, fractures of the tubular bones are possible. To determine the severity of osteoporosis using x-ray densitometry.

A radioisotope study reveals accumulation of a radioisotope in the bony zones of the patient’s intensive growth.

When morphological examination of bone tissue biopsy specimens, the structure of the bone beams is broken, lacunae and weak bone mineralization are detected.

Nephrobiopsy notes a peculiar picture of the proximal tubules (in form resemble "swan neck"), reveal epithelium atrophy, interstitial fibrosis. The glomeruli are involved in the process at the very end of the disease. Electron microscopic examination of the epithelium reveals a large number of mitochindria.

[31], [32]

Examples of the wording of the diagnosis

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

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

[33], [34], [35], [36], [37], [38], [39], [40]

Differential diagnosis

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

• galactosemia;
• type I glycogenosis;
• tyrosine;
• 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:

• heavy metal poisoning, chemicals and drugs, especially with an expired date;
• secondary hyperparathyroidism;
• severe burns;
• multiple myeloma;
• diabetes mellitus.

[41], [42], [43], [44]

Treatment of the fanconi syndrome

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

With secondary Fanconi syndrome, its symptoms diminish or disappear altogether with successful treatment of the underlying disease.

Treatment goals

Non-drug and drug treatment of patients with Fanconi's disease is very close in essence, as it provides for the correction of electrolyte disorders (elimination of potassium deficiency and bicarbonate), changes in acid-base balance. Appointment and symptomatic therapy is necessary.

Diet therapy

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

[45], [46], [47], [48], [49]

Drug treatment of Fanconi syndrome

For the elimination of disorders of phosphorus-calcium metabolism, active preparations of vitamin D are widely used: l, 25 (OH) D ₃ or l (OH) D ₃. The initial dose of vitamin D ₃ is 10 000-15 000 ME per day, then the dose is gradually increased to the maximum - 100 000 ME per day. Increasing the dose of vitamin D _{3 is} carried out under the control of calcium and phosphorus in the blood and stop it when these indicators normalize. Be sure to prescription calcium, phytin. Treatment is repeated courses to prevent recurrence. With the normalization of phosphorus-calcium metabolism and the disappearance of signs of acidosis, massage and salt-coniferous baths are shown.

[50]

Surgical treatment of Fanconi syndrome

With pronounced bone deformities, surgical correction is indicated, which is carried out with persistent clinical and laboratory remission of at least 1.5 years.

[51], [52]

Indications for consulting other specialists

In case of marked changes in the kidneys: high proteinuria, hypertension, anatomical anomalies - consultations by a nephrologist and a urologist are shown. In cases of hyperparathyroidism, consultation with an endocrinologist is obligatory. In cases of ophthalmic disorders, an oculist.

[53], [54], [55], [56],

Indications for hospitalization

Indications for hospitalization: pronounced metabolic disorders and skeletal deformity.

[57], [58]

Prevention

Prevention of primary hereditary tubulopathy - Fanconi syndrome - timely medical and genetic counseling in the presence of a similar disease in the family. Genetic risk for siblings (brothers and sisters) is 25%.

[59], [60], [61]

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.

[62], [63], [64], [65]