Fanconi syndrome is a hereditary kidney disease characterized by damage to the epithelium of the distal tubules and the nephron loop, which leads to impaired excretory functions and numerous secondary pathologies. Symptoms of this condition are polyuria of a hypotonic nature, hypochromic anemia, skeletal lesions, azotemia develops at the terminal stages. Diagnosis includes ultrasound examination of the kidneys, blood and urine tests, molecular genetic methods of determination. There is no specific treatment for this condition, palliative therapy is used, kidney transplantation is indicated.
General information
Fanconi syndrome (type 1 nephronophthysis, juvenile nephronophthysis) is a genetic disease that affects the kidneys (nephron loops and distal tubules) with the development of a progressive violation of the excretory function of these organs. For the first time this pathology was described in 1951 by the Swiss pediatrician Fanconi, after that, several hundred cases of this condition were identified during the entire observation period. Thus, Fanconi syndrome is a fairly rare disease, its occurrence has not been determined. In addition, kidney damage, which is absolutely identical to this pathology, occurs in a number of other genetic diseases, such as Joubert syndrome or Senor–Loken syndrome type 1. However, in these conditions, kidney disorders are combined with disorders of the functions of other organs and systems (retina, lungs, etc.) – as geneticists have found out, the similarity of pathologies is due to the fact that they are caused by various mutations of the same gene. The mechanism of inheritance of Fanconi syndrome is autosomal recessive, the disease occurs with the same frequency in boys and girls. According to various estimates, this disease is the cause of 2-10% of all cases of chronic renal failure in childhood.
Causes
Fanconi syndrome is caused by a mutation of the NPHP1 gene located on the 2nd chromosome. The product of expression of this gene is a special protein called nephrocystin-1, whose functions currently remain the subject of heated discussions. According to the most common point of view, nephrocystin-1 is part of the cilia of many cells – the epithelium of the loops and tubules of the kidneys and lungs, is contained in the retina of the eye and a number of other organs. As a result of the NPHP1 mutation, the structure of this protein is disrupted, which adversely affects the work of the cilia of the cell, therefore, functions such as the absorption of liquids and salt solutions, as well as the active transport of various ions are significantly disrupted. It was found that nephrocystin-1 is able to bind a number of other proteins and enzymes, a change in its structure may also disrupt these processes, leading to the development of Fanconi syndrome, Joubert or Senor-Loken syndromes.
Due to the poorly understood functions of the nephrocystin-1 protein, the pathogenesis of Fanconi syndrome (as well as other hereditary pathologies caused by defects in the NPHP1 gene) is also not entirely clear. In particular, it is not known what more disrupts the processes of ion and water transport and urine formation in this pathology – a change in the activity of cilia or the inability of nephrocystin-1 to attach other protein molecules to itself. The question of which mutations lead to isolated Fanconi syndrome and which lead to complex disorders is just beginning to be studied. It is reliably known that the primary anomalies in this condition are changes in the loops of the nephron and distal tubules of the kidneys, all other symptoms (hypocalcemia, anemia, malformations of the skeleton) are considered secondary.
As a result of a defect in the NPHP1 gene in the nephron loops and distal tubules, the processes of reabsorption of water and inorganic salts are disrupted, which leads to an increase in the volume of urine produced. Due to polyuria, the body loses a huge amount of calcium and other ions, which causes a response of the parathyroid glands (secondary hyperparathyroidism), the hormone of which begins to flush calcium and phosphorus from the bone tissue. The elements of the skeleton become brittle, they develop ricketlike changes, which very often form part of the clinical picture of Fanconi syndrome. Pathological processes also affect the juxtaglomerular apparatus, as a result of which patients develop hypochromic anemia. Over time, Fanconi nephronophthesis leads to progressive chronic renal failure, which is manifested by azotemia and other concomitant disorders.
Symptoms
In most cases, Fanconi syndrome does not manifest itself in any way in the first years of a child’s life, the first symptoms may occur at the age of 2-3 years – polyuria and nocturia are observed (an increase in the proportion of nocturnal diuresis), thirst (polydipsia) is often registered as a result of fluid loss. These manifestations are poorly expressed and may persist for several years. Deterioration in Fanconi syndrome is noted at the age of 6-10 years, when the above symptoms become more pronounced and they are joined by rickets–like changes in the skeleton, sometimes convulsions, the child’s lag in physical development becomes noticeable. Anemic manifestations are often found: pallor, tachycardia, dizziness and a number of others.
In the future, with Fanconi syndrome, signs of renal insufficiency of the tubular type begin to increase. As the retention of nitrogenous metabolic products in the body increases, the smell of ammonia from the mouth and from the body increases, secondary hyperparathyroidism develops due to the loss of a significant amount of salts (especially calcium ions) in the urine. Polyuria, polydipsia and other kidney disorders are becoming more pronounced. Ultimately, Fanconi nephronophthesis leads to severe renal failure requiring regular hemodialysis or transplantation of a donor kidney. Sometimes this condition is combined with congenital oculomotor apraxia of Kogan, manifested by the inability of eye movements in the horizontal plane in children younger than 2-3 years.
Diagnostics
To determine Fanconi nephronophthesis, general and biochemical blood and urine tests, ultrasound examination of the kidneys, the study of the patient’s hereditary history, molecular genetic diagnostic methods are used. A large amount of important diagnostic information is provided by such methods as determination of endogenous creatinine clearance (Rehberg test), excretory urography, computed tomography of the kidneys with contrast. With Fanconi syndrome in patients, an increase in daily diuresis is detected (which can be determined during a urine test according to Zimnitsky), while the density of urine is reduced and in most cases equals the osmolarity of blood plasma (isostenuria). From other indicators of the general urinalysis, minor proteinuria is most often recorded (no more than 1 g / day), sometimes microhematuria is possible. Against this background, patients with Fanconi nephronophthisis have a strong thirst due to the loss of a significant volume of fluid.
The blood picture in Fanconi nephronophthesis includes hypochromic anemia, hypocalcemia and a significant decrease in the concentration of other inorganic ions, which is a consequence of the so-called salting syndrome. The clearance of endogenous creatinine steadily decreases as the disease develops. On ultrasound of the kidneys in patients with Fanconi syndrome in the initial stage, there is a violation of differentiation and differentiation of the cortical and medulla, in the latter, the formation of cysts with a diameter of 2-8 millimeters is possible. In the future, the kidneys decrease somewhat in size, signs of interstitial fibrosis can be detected in them.
When studying the hereditary history of a patient, similar clinical manifestations are often found in relatives, thanks to this it is possible to prove the autosomal recessive nature of inheritance. Genetic diagnosis of Fanconi syndrome is performed by direct sequencing of the NPHP1 gene to detect mutations (usually deletions or point). In addition, this technique helps to differentiate the disease from other complex syndromes also caused by defects in this gene (for example, Joubert syndrome). The methods of modern genetics are able to reveal the hidden carrier of the defective NPHP1 gene, which can be used as part of medical and genetic counseling of the family before conception of a child.
Treatment and prognosis
There is no specific treatment for Fanconi syndrome, any supportive measures are unable to significantly increase the survival rate of patients – as a rule, this pathology leads to severe renal failure under the age of 20 years. The only effective method of treating the disease is kidney transplantation, and performed as early as possible, before the appearance of significant irreversible secondary disorders. Prior to the operation, symptomatic treatment of Fanconi syndrome is performed, including saline solutions, copious drinking, and calcium preparations. To eliminate anemia, it is necessary to use exogenous erythropoietins – for example, erythropoietin-alpha. If Fanconi nephronophthesis has caused kidney failure, hemodialysis, a special diet and a balanced water-salt regime are prescribed.
The prognosis of the disease depends on the prospects of kidney transplantation – if this operation is not possible, the outcome is unfavorable, most patients die before the age of 20 from increasing renal insufficiency. Supportive and symptomatic therapy, as well as the use of hemodialysis, according to most experts, can increase the patient’s life expectancy for several more years. However, only kidney transplantation can give a chance for life to a patient with Fanconi nephronophthisis. When deciding on an operation, many factors are evaluated: the general condition of the patient’s body, the presence and severity of secondary disorders, concomitant diseases. After the transplant, pathological changes in the donor kidney, similar to Fanconi nephronophthesis, do not develop.