Pediatric Medical Genetics - S.I. Smiyan 2003

Hereditary Nephropathies
De Toni-Debré-Fanconi Syndrome

The most severe form of hereditary tubulopathy, characterized by complex proximal tubular dysfunction accompanied by persistent glucosuria, increased urinary excretion of phosphates, and Aminoaciduria. In the absence of one of these three mandatory features, the term «incomplete de Toni-Debré-Fanconi Syndrome» is used.

Etiopathogenesis. This is an inherited disorder transmitted in an autosomal recessive manner, although the expressivity of the mutant Gene varies significantly. The Essence of the disease is reflected in such names as «glucosamino-Phosphate Diabetes» or «nanism with vitamin D-resistant Rickets.» The idiopathic form of the condition can be regarded as «a manifestation of genetically determined nephron Dysplasia.» Histological examination confirms the shortening and thickening of the proximal tubules. However, disease severity is determined by impairment of both the tubular apparatus and the renal glomeruli. The resulting bodily dysfunctions are driven by excessive losses of glucose, Amino Acids, and phosphates. Secondary consequences include impaired Water reabsorption, bicarbonate wasting, potassium, sodium, and calcium loss, and The Development of acidosis.

Clinical presentation. The disease typically manifests at the end of the first or the beginning of the second year of life. Clinical symptoms are diverse and directly stem from the Pathogenesis of the disorder.

Glucosuria impairs water reabsorption, leading to polyuria, polydipsia, hyposthenuria, and signs of dehydration (unexplained fevers without evidence of an inflammatory process). Glucosuria serves as the earliest sign of the disease. In young children, symptoms of polyuria and polydipsia often go unnoticed, whereas elevated body Temperature immediately alerts parents.

Hyperaminoaciduria is generalized and non-selective in nature, with urine levels showing elevated concentrations of more than 10 amino acids. Although Blood amino acid levels remain within the normal range, a cellular-level deficiency develops throughout the body. This explains the onset of symptoms such as growth deceleration followed by growth retardation, malnutrition (hypotrophy), and progressive delays in intellectual development. The body's overall resistance declines, and children become prone to recurrent respiratory infections. Impaired water reabsorption leads to increased bicarbonate wasting (accompanied by metabolic acidosis), potassium wasting (hypokalemia), and calcium loss.

Metabolic acidosis manifests clinically as lethargy, irritability, and Skin pallor. Hypokalemia causes muscular hypotonia, hyporeflexia, and decreased blood pressure. Hypercalciuria arises as a consequence of metabolic acidosis and can lead to nephrocalcinosis and Nephrolithiasis.

Hyperphosphaturia leads to decreased plasma phosphate levels. Hypophosphatemia creates a calcium-phosphorus imbalance and triggers Osteoporosis. Bone deformities develop, resembling those seen in phosphate diabetes, with the lower body and spine being the most severely affected. Significant deformities and potential fractures may occur. Notably, bone lesions appear later than the manifestations of toxicity, acidosis, hypokalemia, and Protein METABOLISM disorders.

The diagnostic criteria for de Toni-Debré-Fanconi syndrome are as follows:

1. Onset of clinical manifestations at the end of the first or during the second year of life, beginning with glucosuria.

2. Skeletal changes, malnutrition, and developmental delay.

3. Decreased bodily resistance and Immune Response.

4. Manifestations of hypokalemia: muscular hypotonia, hyporeflexia, and low blood pressure.

5. Manifestations of metabolic acidosis: lethargy, irritability, and skin pallor.

6. Urinary abnormalities: glucosuria, hyperaminoaciduria, hyperphosphaturia, and increased bicarbonate excretion; after 2 years of age — hyposthenuria and Ketosis.

Radiological bone changes are characterized by a coarse-fibered Bone Structure, fraying of the metaphyses, and sometimes epiphyseal slippage (epiphysiolysis). Osteoporosis is prominent in the metaphyses of long tubular bones, revealing moth-eaten (cystic) tissue changes and spur-like formations. However, osteoporosis, bone curvature, Kyphosis, and other manifestations of osteopathy do not appear immediately. These changes are preceded by diverse clinical symptoms, and only a comprehensive biochemical evaluation allows for the suspicion and confirmation of de Toni-Debré-Fanconi syndrome.

Differential Diagnosis. The condition must be differentiated from rickets, osteopathies associated with Chronic Kidney Disease, phosphate diabetes, and Renal Tubular Acidosis. The variety of clinical manifestations and laboratory findings (especially urinary abnormalities) helps confirm the diagnosis. Additionally, clinicians should bear in mind that de Toni-Debré-Fanconi syndrome can occur secondarily in cystinosis, heavy metal poisoning, galactosemia, and Glycogen storage disease. The Specific features of these underlying disorders, as well as an earlier or later onset of symptoms, assist in differential diagnosis.

Treatment. To ensure normal growth, a diet restricted in acidogenic (sulfur-containing) foods and enriched with phosphate-rich and alkaline foods is recommended. Potato-based or potato-cabbage diets are particularly beneficial. Protein and water intake should not be restricted, but an excess of CARBOHYDRATES must be avoided.

In the presence of acidosis (decreased plasma pH and serum bicarbonates), the administration of alkaline solutions is indicated, such as 4% sodium bicarbonate intravenously or as an oral mixture. Furthermore, electrolyte balance is corrected by administering a sodium and potassium citrate mixture: 2 g of citric acid, 3 g of sodium citrate, and 3.3 g of potassium citrate per 30 ml of water (1 ml of the mixture contains 1 mmol each of Na and K). This mixture is prescribed at a dose of 45–60 ml per day. Dietary measures (such as carrot soup and dried fruit compotes) also help correct potassium deficiency. Rehydron can likewise be prescribed.

Vitamin D is administered at 10,000–15,000 IU daily under the control of the Sulkowitch test. Agents that enhance The activity of thiol-dependent Enzymes (such as unithiol) are also indicated.

Prognosis. The prognosis for life is favorable if diagnosed and treated in a timely manner. Severe and prolonged metabolic derangements can lead to interstitial nephritis, nephrocalcinosis, and chronic kidney disease (CKD), which worsens the overall prognosis.

Prevention consists of medico-Genetic Counseling (MGC) for families with affected children, the identification of high-risk groups, and their long-term clinical dispensary monitoring.