Syndrome de Toni-Debreu-Fanconi in children, women and men: causes, symptoms, diagnosis, treatment

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Fanconi syndrome( full name - de Toni-Debreu-Fanconi) is a congenital pathology that manifests itself in severe dysfunction of the proximal renal tubules, namely, secondary absorption( absorption into the blood) of substances filtered by the kidneys, which leads to glucosuria( increased sugar inurine), phosphaturia( impaired metabolism of phosphorus and calcium), aminoaciduria( increased excretion of amino acids in the urine) and a decrease in the concentration of hydrocarbonates that regulate the acidity of the blood.

De-Tony-Debreu-Fanconi Syndrome

Fanconi Syndrome is a very rare disease, mainly found in children, and according to medical statistics, its frequency corresponds to 1 sick infant per 350,000 newborns of both sexes.

In adults, it is extremely rare to develop against the background of acquired pathologies. Pathology code according to ICD-10: E72.O.

Causes of

The nature and causes of the genetic defect of Fanconi syndrome have not been adequately studied today.

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It is suggested that at the heart of the pathology lie either the defects of the transport proteins of the renal tubules or a gene mutation that distorts the function of enzymes regulating the reverse absorption of glucose, amino acids and phosphorus.

There are data on studies of point defects in mitochondria, which lead to improper functioning of the renal tubules.

The disease is also associated with intolerance to fructose, chronic poisoning with toxins( heavy metals, ifosfamide, aminoglycosides), vitamin D deficiency, amyloidosis, insufficiency of a number of cellular enzymes( pyruvate carboxylase, phosphoenolpyruvate carboxylase and others), tyrosinemia, metachromatic leukodystrophy, galactosemia, cystinosis, glycogenoses.

According to other experts, Fanconi syndrome can be an isolated pathology - namely - one of the most severe forms of rachitis-like pathologies that are hereditary.

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Studies confirm that in the Fanconi syndrome, cellular energy metabolism involving ATP( adenosine triphosphate) and intercellular transport in the tubules of the main element of the kidney nephron is disrupted.

Since in medicine they have not yet come to an unambiguous conclusion about the causes of Fakoni's syndrome, this condition is also denoted by other terms: "glucophosphamide diabetes", "idiopathic renal Fanconi syndrome", "D-resistant rickets", "kidney nanism with D-resistant rickets"," Hereditary Fanconi syndrome. "

Forms and pathogenesis of

There are two types of Fanconi syndrome:

  • is hereditary( congenital, idiopathic), which refers to the primary form;
  • acquired, which is considered as a secondary form of the disease.

The hereditary( genetic) kind of specialists is associated with the defect of the X chromosome, which is inherited by the dominant and recessive type, so the genetic prognosis of its manifestation in the future offspring is not an easy task. If the pathology refers to the congenital( primary form) type, it is detected in the child in the breast period up to a year. Therefore, the primary form is called "infant".

The degree of gene mutation causes the degree of severity of the syndrome itself. So, the hereditary full Fanconi syndrome reveals itself in the presence of 3 basic biochemical defects, which include glucosuria, aminoaciduria, phosphaturia, incomplete - with two of them.

Usually genetically determined pathology is accompanied by other congenital ailments: cystinosis, Wilson syndromes, Denta, Lowe, fructose intolerance, tyrosinemia( inability of the body to efficiently cleave amino acid tyrosine), galactoseemia( sugar-glucose conversion dysfunction), excessive glycogen storage.

Development of Fanconi Syndrome

Acquired syndrome( secondary), unlike congenital, is not accompanied, but is a consequence of already existing pathologies:

  • type I tyrosinemia;
  • cystinosis( impaired metabolism of the amino acid cystine followed by kidney damage);
  • fructose intolerance;
  • Wilson-Konovalov's disease;
  • galactosemia;
  • glycogenosis( abnormal accumulation of glycogen in tissues and organs) type XI;
  • hereditary renal pathology;
  • amyloidosis( a violation of protein metabolism leading to sclerosis, atrophy, organ dysfunction);
  • tubulointerstitial nephropathies( nephritis with tissue damage, renal tubules);
  • hyperparathyroidism( endocrine disease, in which the normal content of calcium and phosphorus in the blood is disturbed);
  • malignant formations: myeloma, ovarian, lung, pancreatic, lung, lung disease, lymphogranulomatosis;
  • deep burns.

In addition, the syndrome can provoke such conditions:

  • organ transplantation with low tissue compatibility;
  • deficiency of vitamin D;
  • poisoning with uranium, bismuth, mercury, lead, cadmium;
  • contact with toluene, maleic acid, lysol;
  • use of nephrotoxic pharmacological agents such as: Gentamicin, platinum drugs, tetracycline-based overdue medications, didanosine, cidofovir, anticancer chemotherapy drugs - Ifosfamide, Streptozocin.

Symptoms and signs

In hereditary( congenital) form

Primary symptoms are manifested in the first months of life, rarely - after a year and a half.

First of all, the following conditions are noted in a newborn child:

  • frequent urination( polyuria);
  • increased thirst( polydipsia);
  • prolonged constipation;
  • frequent attacks of causeless vomiting;
  • asthenia( general fatigue), muscle weakness;
  • unexplained "temperature jumps" up to 37.5 - 38 C;
  • bloated tummy.

As a rule, during the period when the onset of vomiting and temperature rise of the baby are shown to the pediatrician. An experienced specialist should determine that the combination of disturbing parents of signs is not related to ARI, ARVI or enterovirus infection.

After mild and rather vague symptoms in the following year - one and a half clearly recorded symptoms typical of Fanconi syndrome:

  1. Early Nanism( short stature), caused by the constant elimination of the most important amino acids, glucose, calcium, phosphates from the body. The first six months of normal growth and weight are replaced by a deficit of body weight( up to 30%) and growth( from 2 to 21%).
  2. Rickets caused by massive excretion of calcium and phosphates become noticeable after 10 to 12 months of life, and has features characteristic of the Fanconi syndrome: the baby's head is usually slightly deformed, but the large bones of the legs and arms show significant curvatures - deformities in the varus type,the baby is bent "wheel", or valgus( in the form of the letter "X").Twist and bones of the chest, spine.
  3. Delay in mental and physical development.
  4. Uncommunicability, fearfulness, lack of consistency.
  5. Polydipsia and polyuria can progress and regress without passing definitively.
  6. Moderate muscular hypotension, expressed in slowness, difficulty in movement, leading to the fact that children 5-6 years old are unable to walk.
  7. Pain in bones, moderate intensity, interfering with the child's walking. Stronger at the level of the legs, pelvis and spine. Gait, if a child walks, becomes a "duck", unsure.
  8. High probability of fractured tubular bones due to a deficiency of minerals in bone tissue.
  9. Osteomalacia or softening of bones due to destruction of bone tissue as a result of lack of calcium and phosphorus salts.
  10. Reduced immune defense against infections, which is manifested in frequent viral diseases, otitis, pneumonia.
  11. Paralyzes caused by lack of potassium.
  12. Ophthalmic pathologies, such as: retinitis pigmentosa, congenital cataract.
  13. Development of pathologies of the nervous system, ENT( ear, nose, pharynx, larynx) and gastrointestinal organs, cardiovascular system, anatomical abnormalities of the urinary system due to massive metabolic disorders.
  14. In isolated cases, endocrine disorders of

In the course of progression of tubular disorders( disruption of transport of organic substances, minerals, electrolytes) to 10-12 years in children, the probability of developing chronic renal failure is increased, which threatens his life.

Visible Symptoms of Fanconi Syndrome in Children

In adult patients with secondary

development If the acquired Fanconi syndrome develops in adults with other diseases or pathological conditions, its manifestations are often combined with manifestations of a provocative disease.

Nevertheless, the following basic signs are revealed:

  1. Increased urine volume per day( up to 2 liters and more) and acute thirst, also characteristic of patients of early childhood.
  2. General and muscle weakness, bone pain.
  3. High probability of persistent increase in blood pressure( hypertension) on the background of renal dysfunction.
  4. Osteomalacia( destruction of bones).
  5. Acidosis( increased blood acidity) due to delayed oxidation products in the body, leading to hypokalemia( potassium deficiency).
  6. Nephrocalcinosis is a high deposition of calcium salts in the kidneys with fever, chills, nausea, severe pains in the abdomen, groin, ovaries characteristic for this condition.
  7. Hypokalemia( low potassium intake), causing severe heart complications, including life-threatening arrhythmias.
  8. Fast( if untreated) formation of chronic kidney deficiency

In women

The most unfavorable variant of the Fanconi syndrome is realized in its development in women in the postmenopausal period. At this time, against the background of a decrease in the production of hormones, there is a natural decrease in bone density( osteopenia).

When this condition is combined with increased bone fragility due to a lack of minerals, there is a high probability of severe compression fractures of the vertebrae, cervical neck and subsequent disability.

Diagnosis

In order to correct or refute the diagnosis, with the help of renategography, bone examination and in-depth biochemical studies of blood and urine are performed.

Laboratory

Detected changes in urine and blood biochemistry:

Characteristics of Indicators of
low calcium and phosphorus content of of less than 2.1 mmol / L and 0.9 mmol / L, respectively
acidosis( acidification of blood) BE = 10 -12 mg / dL
Glucosuria( increase in sugar in the urine) 2-3% and above
hyperaminoiduria( urinary excretion of important amino acids alanine, arginine, glycine, prolate) up to 2 - 2.5 g / day
excretion of calcium in the urine 1,5 - 3,5 mmol / day
increase in pH( acidity) of urine due to an anomalyvery high loss of bicarbonates to 6.0
increase in the relative density of urine 1,025 - 1,035

The examination also reveals:
  • increased alkaline phosphatase activity;
  • excessive excretion of sodium, potassium salts from the body;
  • proteinuria( appearance of protein in the urine) in the presence of light chains of immunoglobulins, lysozyme, low-molecular proteins, beta 2-microglobulins;
  • increase in the clearance( rate of filtration) of uric acid with its reduced serum content
  • a decrease in the activity of energy-exchange enzymes: succinate dehydrogenase, a-glycerophosphate dehydrogenase, glutamate dehydrogenase;
  • increase in blood levels of lactic and pyruvic acid.

Instrumental

Diagnosis of Fanconi syndrome requires mandatory use of bone radiography to detect deformity of the skeleton, extremities, detection of signs of osteomalacia, osteoporosis, and in children - additionally - bone growth retardation in comparison with the norm according to the calendar age.

The following abnormalities in bone tissue are observed:

  • is coarse-grained, cellular structure with lacunae, poor mineralization, abnormal growths in the form of "thorns" in the femoral and tibia;
  • signs of epiphysiolysis( partial or complete arrest of bone growth in length in the unripe skeleton, resulting in asymmetry of the limbs);
  • fractures of tubular bones( at a late stage) against the backdrop of osteoporosis, the extent of which is determined by X-ray densitometry;
  • accumulation of radioisotope in areas of intense bone growth.

In the kidney:

In the electronic study of a biopsy of the kidney tissue( biopsy), a characteristic change in the shape of the tubules in the form of a "swan neck", thinning, atrophy( decrease in volume) of epithelial tissue in the presence of an increased amount of mitochondria in it, fibrosis( abnormal proliferation) of connective tissue.

Necessary research:

What organs are examined
Which body is examined
Which body is examined
Which body is examined
Which body is examined
Which body is examined How is examined? analysis
analysis Kidneys kidneys, ureters, general and biochemical, alkaline phosphatase, inorganic phosphorus, calcium in blood( ionized and total), urine common and Nechiporenko
Bones, cartilage and bone tissue Ultrasound, X-ray, study

Differential

Pathology should be distinguished from all isolated diseases that can provoke the onset of acquired syndromenkoni acquired unhealthy conditions and intoxications.

In addition, in infants the pediatrician is obliged to differentiate the state of acute vitamin D deficiency in Fanconi's syndrome from its overabundance when using artificial supplements or a calcium metabolism disorder.

Differences in hypervitaminosis D and de Fanconi syndrome in children up to one year:

Parameters Hypervitaminosis D Deanconi
Syndrome Often Rarely
Symptoms( similar) Dryness of the skin, pallor, acute thirst, vomiting, prolonged constipation, lack of weightand growth, enlargement of the liver Dryness of the skin, pallor, acute thirst, vomiting, prolonged constipation, lack of weight and growth, increased liver
Symptoms( differing) Hypertension( frequent blood pressure rises) Depletion, polyuria, hypotensionNia muscles, increased blood pressure offline
Blood Excess calcium in the acute period. Reduced content of phosphorus. Alkaline phosphatase, sugar, protein - normal Calcium is more often normal( can be lowered).Glucose, protein reduced. Phosphorus is reduced sharply. The activity of alkaline phosphatase is sharply increased - in 2 - 3 times. Acidity of blood increased
Urine Sulkovich's test for calcium excretion is positive. The presence of protein, blood( more than 2 - 3 red blood cells in the field of vision), leukocytes. Sugar aminoazot, as a rule, is normal Sulkovich's test is negative. Protein, phosphates, sugar increased, aminoaciduria
Bones Calcification zones enlarged, consolidated Osteoporosis of tubular bones, calcium deficiency in calcification areas

Specialists dealing with Fanconi syndrome and its complications: nephrologist, orthopedist, hematologist, endocrinologist, urologist, ophthalmologist, geneticist.

Treatment

Rational, well thought-out therapy can reduce the impact on the brain, bone system and organs of excessive loss of essential amino acids, minerals, glucose and protein, excreted in the urine.

Therefore, treatment for the syndrome is aimed at the following tasks:

  1. The maximum possible correction of potassium deficiency, bicarbonates, changes in the acid-base balance of blood to reduce acidosis.
  2. Phosphate-diabetes therapy( D-resistant rickets) with emphasis on the inadmissibility of fluid restriction.
  3. Treatment of the underlying disease that provokes the development of acquired syndrome in adults.

Medication

For the mitigation of losses of phosphorus and calcium, special preparations with vitamin D are used, these are l, 25( OH) D3 and l( OH) D3.

Initial doses of vitamin D3 per day 10 - 15 thousand ME.Increase in the dose is carried out gradually, increasing it every 12 to 14 days( under the control of the Sulkovich sample and the content of phosphorus in the blood).In the absence of signs of intoxication and a slight excretion of calcium in the urine, it is allowed to increase the dose, bringing to 100-150 thousand ME per day, and continue therapy to normal values ​​in the blood of phosphorus and alkaline phosphatase. With the stabilization of their values, the dose should not be increased further.

Vitamin D therapy is administered in several courses to prevent crises in the progression of the rickets in the bones.

The optimal option is the use of active metabolites D3 - Oxidevit( 0.5 - 1.5 mcg per day), calciotriol( Rockaltrol).

Include calcium preparations( calcium gluconate per day up to 1.5 - 2 grams), phosphorus( 0.5 - 1 grams per day), phytin.

Inorganic phosphates use a mixture of Albright, taking it 1 large spoon 4 to 5 times a day. Apply phosphate in the form of a solution and tablets in doses calculated at 10 mg per kilogram of weight, 4 times a day( with vitamin D preparations, to avoid hyperparathyroidism).

With a pronounced potassium deficiency, Panangin, Asparkam is used.

For all purposes, CBS or acid-base blood is monitored continuously. Normally, the blood has a slightly alkaline reaction, and the pH in the range of 7.35 - 7.45.With acidosis, when the pH drops below 7.35, the blood acquires an increased acidity.

In these cases intravenous infusion of a solution of sodium hydrogen carbonate 4% or drink solution( 50-60 ml per day), which includes citric acid - 2 grams, sodium citrate - 3 grams, potassium citrate - 3.3 g, water 100 ml. In 1 ml of this alkaline mixture contains 1 mmol of sodium and potassium. High blood acidity is also neutralized with the help of drinking soda( sodium bicarbonate).

Some specialists recommend Uniothiol as a means of increasing the activity of thiol-dependent enzymes on the basis of practical results.

In cystinosis appoint: Dithiothrenal at a rate of 25 mg per kilogram of the patient's weight after 3 hours;Cysteamine in a daily dose of 90 mg / kg.

Hormonal anabolics, including Methyltestosterone, have a good effect on the work of the kidney tubules.

Important! With increased glycosuria( excretion of sugar in the urine) leading to mental retardation in infants, the intravenous infusion of glucose solutions with hypokalemia( lack of potassium) is absolutely contraindicated because of the high risk of vascular collapse.

Diet therapy

Diet in Fanconi syndrome, in fact, is one of the basic components of therapy.

Recommended:

  1. Increased consumption of potatoes, cabbage to reduce excessive excretion of amino acids
  2. Limitation in the use of salt.
  3. The use of "alkaline" products, including milk( if well tolerated), natural fruit juices.
  4. Active use of products containing potassium( prunes, dried apricots, raisins, Moro carrot soup).
  5. Since the same products often contain both the necessary phosphates and sulfur-containing amino acids, which are harmful in large quantities, it is necessary to maintain a balance.

Foods rich in phosphates: cheese, cottage cheese, milk, kefir, wheat bran, buckwheat, oatmeal, rice, pearl barley, peas, pumpkin seeds, Brazil nut, pine nuts;

Foods high in acidogenic( sulfur-containing) amino acids - taurine, methionine and cystine: fish, crabs, shellfish, eggs, sesame seeds, wheat germ, oats, corn, almonds, beans, lentils, peanuts, buckwheat, brown rice, semolina,pearl barley and millet.

Power features for limiting sugar loss in the urine:

  • frequent intake of food in small portions for pancreas discharge;
  • dosed amount of carbohydrates( sometimes excluding sweets with a high sugar content) in order to avoid excessive blood glucose, as this will also increase the excretion in the urine.

However, in the diet of children with "sweet urine", that is, having a high level of sugar in the urine( glycosuria), provide enough sugar and sweet desserts. This is extremely necessary to reduce the degree of mental retardation. For reference: normal blood sugar values ​​up to 2 years in mmol / liter: from 2.78 to 4.4;from 2 to 14 years in the range of 3.3 to 5.5.

Physiotherapy

With normal parameters of phosphorus and calcium metabolism and eliminating the symptoms of acidosis, massage and baths with bioactive substances of needles and sea salt, beneficial for the nervous, respiratory, cardiovascular system, stabilize metabolic processes are prescribed.

Surgical

In severe bone deformities, surgical correction is successfully used, which is prescribed in a state of stable remission of 12-18 months duration, confirmed by clinico-laboratory data.

In the development of renal failure to save lives and improve the condition is capable of kidney transplantation.

Treatment in a hospital is indicated with pronounced metabolic disturbances, including hypo- and hyperglycemia, deformations of the skeleton.

Prevention

Modern prevention of congenital syndrome Fanconi in the presence of a similar pathology in the family is the preliminary genetic counseling. The risk of developing the disease for the so-called sibs, that is, sisters and brothers - about 25%.

In the secondary form of the syndrome, its symptoms decrease or completely disappear with active treatment of the underlying disease or acquired pathological condition.

Forecast

The prognosis of the disease depends on the form( primary, secondary) of the syndrome, the severity of the manifestations, and the initiation of treatment.

For example, the symptomatology of the acquired syndrome disappears when the cause-provoker is eliminated.

However, even with severe changes in the kidneys: pyelonephritis, tubulointerstitial nephritis, renal insufficiency, with an early drug effect on the pathological process and prolonged therapy, a certain balance is established in homeostasis, in which the prognosis of a normal quality of life for decades is good.

In medical practice there are medical histories, when the children of 7-8 years old hereditary Fanconi syndrome almost "stopped" with the onset of a prolonged remission, a clear improvement in the state of the child and even - recovery.

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