Pediatric Fanconi Syndrome
Introduction
Introduction to pediatric Fanconi syndrome Fanconisyndrome is characterized by bone marrow hematopoietic failure characterized by multiple renal tubular dysfunctions that cause anemia, amino acids, glucose, phosphate, bicarbonate and others from the proximal or distal tubules. Organic or inorganic substances are lost too much from the urine, resulting in acidosis, hypophosphatemia, hypocalcemia, dehydration, rickets, osteoporosis, and growth retardation. Fanconi syndrome can be divided into congenital or acquired, primary or secondary, complete or incomplete. Clinically, it is rare, the onset is slow, and there are more symptoms than young adults. The prognosis is related to the treatment of morning and evening and the response to treatment. basic knowledge Sickness ratio: 0.0001% Susceptible people: children Mode of infection: non-infectious Complications: vitamin D deficiency rickets pediatric malnutrition leukemia
Cause
The cause of pediatric Fanconi syndrome
(1) Causes of the disease
Most children are genetically related, and older children are often secondary to immune diseases, poisons or drug poisoning, and various kidney diseases.
1. Primary (unexplained or no systemic disease) including hereditary autosomal dominant (AD), autosomal recessive (AR), X-linked recessive (XLR), sporadic, special (ie brush-like) Edge missing type).
2. Secondary (symptomatic) (1) Congenital metabolic disorder: 1 Amino acid metabolism disorder: A. Cystine disease (autosomal recessive, AR), B. Tyrosinemia type I (AR), C. Busby syndrome (AR), D. Luder sheldon syndrome (AD), 2 Carbohydrate metabolism disorders: A. Glycogen storage disease type I (Fanconi-Bickel syndrome, AR), B. galactosemia (AR), C. Hereditary fructose intolerance (AR), 3 others: A. Lowe syndrome (XLR), B. Hepatolenticular degeneration (AR), C. Cytochrome C oxidase deficiency (AR ), D.Dent disease (familial proximal tubular disease, XLR), E. Pearson syndrome, Wilson disease, F. Vitamin B12 deficiency.
(2) Acquired diseases such as: 1 multiple myeloma; 2 nephrotic syndrome; 3 kidney transplantation; 4 tumors; 5 diabetes; 6 acute, chronic interstitial nephritis; 7 acute tubular necrosis; 8 malnutrition; Kidney disease; 10 severe hypokalemia.
(3) Drug damage and poisoning such as: 1 heavy metal (mercury, sodium, lead, cadmium); 2 chemical poison maleic acid, come to children, toluene, cresol, nitrate, etc.; 3 expired tetracycline, propionic acid; Platinum, IFostamide, aminoglycoside antibiotics, vitamin poisoning; 5 rametidine, cimetidine, Chinese herbal medicine such as aristolochic kidney damage.
(two) pathogenesis
1. Pathogenesis The pathogenesis of this disease is not fully understood, and there are several possibilities:
(1) Inflow defects: The flow in the lumen to the tissue is reduced, which is found in the brush-edge missing type.
(2) Increased intracellular leakage into the renal tubule cavity: such as maleic acid poisoning.
(3) Reduced reflux: reduced backflow of cell membrane through the basal side, causing accumulation of intracellular substances; affecting back absorption, such as Fanconi-Bickel syndrome.
(4) Increased perfusion: increased perfusion from the blood to the cells, increased by the reflux lumen of the tight junctions of the cells, such as cytochrome c oxidase deficiency, abnormal renal tubular membrane transport in the histopathological examination showed no specific performance There are experiments suggesting that the intrinsic intracellular ATP activity transport function is incomplete due to phosphate depletion, causing intracellular adenine nucleotide degradation, resulting in ATP depletion. The pathophysiological changes of this disease are shown in Figure 1.
2. Pathology and pathophysiology With the progress of molecular biology, it has been recognized that the occurrence of FA is a complex pathophysiological process. DNA damage recognition or repair defects are the key to FA, and related pathologies are initiated due to abnormal DNA. mechanism.
(1) DNA cross-linking repair defects: FA cells are sensitive to bifunctional cross-linkers (such as DEB, MMC, nitrogen mustard, cyclophosphamide, cisplatin, etc.) capable of producing intrachain and interchain crosslinks, induced by DEB and MMC. The intra-chain cross-linking repair cuts the DNA strand, and the double-stranded DNA is damaged at the same time, there is no template to repair, and it needs to be repaired by non-homologous end joining (NHEJ). In FA cells, the fidelity of non-homologous recombination repair is decreased. , leading to cell defects, on the contrary, homologous recombination by sister chromatid exchange is not defective in FA, except for NHEJ abnormality, the identification of DNA damage is also impaired, so that FA cells are arrested at the G2 checkpoint after replication is completed. .
(2) Hypersensitivity of FA cells to oxygen: A theory holds that FA cells are damaged by accumulated oxygen free radicals, which are produced by the following mutagens, such as: high oxygen tension, - Radiation, decoysers and active hydroxyl-producing drugs, FA cells, red blood cell superoxide dismutase (SOD) levels are reduced, while white blood cell SOD concentrations are normal, there are also red blood cell SOD, catalase and glutathione The levels of oxidases are normal and glutathione transferase levels are elevated. In FA, the levels of SOD in fibroblasts are normal, and the concentrations of Mn-SOD, catalase and glutathione peroxidase are increased. The role of oxidants may be limited to the hematopoietic system. SOD or catalase may be added to the lymphocyte culture of FA to reduce the number of breaks. Other researchers have found that SOD, catalase or cysteine can reduce MMC-induced breaks. The culture of lymphocytes under high oxygen tension resulted in an increase in the number of arbitrary breaks in some FA cells, and there was no increase in normal cells and all FA cells after addition of MMC. Clarke et al. studied the apoptosis of FA cells, showing Exposure to MMC at 5% oxygen concentration is identical to normal cells, and hypersensitivity to MMC at 20% oxygen concentration, suggesting that the toxic effect on FA cells is caused by the oxygen reaction product (ROS) produced by MMC, rather than DNA exchange. In combination, the oxygen sensitivity of FA involves the ability to control complex systems of ROS overproduction or tolerate oxygen-induced damage. In addition to mitochondria, intracellular ROS production is largely due to the cytochrome P450 enzyme system, and studies have shown that FANCC protein Interaction with NADPH cytochrome P450 reductase, FANCG protein and cytochrome P4502E1 (CYP2E1), both enzymes produce ROS, hypoxic tension and antioxidants are used to improve growth and reduce FA cell-independent or MMC-induced Chromosome breaks.
Prevention
Pediatric Fanconi Syndrome Prevention
The etiology of this disease is unknown. It may be caused by genetic factors such as viral infection and physical and chemical factors during embryonic period, resulting in genetic variation and chromosomal abnormalities, leading to bone marrow hematopoietic stem cell damage and other congenital malformations. At the same time, attention should be paid to pregnancy care and active prevention. Various infections, especially viral infectious diseases, avoid physical and chemical factors, damage to toxic substances.
Complication
Complications of pediatric Fanconi syndrome Complications Vitamin D deficiency rickets pediatric malnutrition leukemia
Complication
Often complicated by developmental disorders, anti-vitamin D rickets and malnutrition, osteoporosis and even fractures, hypokalemia, hypophosphatemia, hyperchloremia, death from uremia acidosis or secondary infection.
2. Multiple congenital malformations
FA patients diagnosed in infancy have a higher proportion of characteristic physical abnormalities, such as deformities including thumb and tibia, kidney, head, eyes and ears, and gastrointestinal malformations. Conversely, FA patients diagnosed in older children, body Abnormally rare, short stature and skin pigmentation problems appear with age. Typical abnormalities in FA patients include: short stature, lack of development or lack of thumb or cheekbones, small eyeballs, microcephaly, skin pigmentation, Light brown spots and pigmentation spots, as well as characteristic facial manifestations such as widening of the base of the nose, supracondylar folds and small jaws, approximately one-third of patients with renal abnormalities, including renal hypoplasia, horseshoe kidney or double ureter, reproduction Phloem insufficiency (female menstrual cramps later, irregular menstruation, early menopause, gynecological tumors; male gonads, incomplete urethra development), rare abnormalities including defects in the gastrointestinal tract, heart and central nervous system, only blood Patients with abnormal bone marrow and no congenital malformations are called Estren-Dameshek syndrome, and these patients represent only a subset of the FA category.
3. Tumor susceptibility
There are more than 200 cases of leukemia and tumors in patients with FA, the total incidence is more than 15%, acute leukemia accounts for more than 100 cases, accounting for 10% of FA patients, mainly acute myeloid leukemia, the risk of developing MDS is 10%~ 35%, patients with clonal cytogenetic abnormalities were significantly more likely to develop MDS or AML than those with normal karyotypes, clonal cytogenetic abnormalities involving chromosomes 1 and 7, and other abnormalities including partial or complete deletion of chromosomes, Translocation and marker chromosomes, the risk of developing solid tumors in patients with FA increases with age, most of them are squamous cell carcinomas, most commonly involving the digestive tract and the female reproductive system.
4.FA heterogeneity
Congenital malformations, genitourinary system and hand abnormalities can be found in relatives of FA patients. Some FA patients have physical deformities such as short stature, but no hematological diseases. Pefidou and Barrett noticed the related heterogeneity. There is an increase in HbF levels, a decrease in the number of natural killer cells and a poor response to mitomycin, and the heterogeneity of FA can also be detected by chromosome break analysis.
Symptom
Symptoms of pediatric Fanconi syndrome Common symptoms Inability to repeatedly infect metabolic acidosis constipation weight loss polydipsia hypophosphatemia hypokalemia polyuria dehydration
1. Primary Fanconi syndrome
It is an autosomal recessive genetic disease. The average age at diagnosis is 6.5 years for males and 8 years for females. The age of onset ranges from birth to 48 years old. The ratio of male to female is 1.2:1. There is no ethnic or regional difference in the incidence. There are many siblings, and the diagnosis of early patients is made when aplastic anemia (leukemia or tumor) occurs. Recently, the patient's siblings have positive chromosome breaks or characteristic somatic abnormalities. Anemia can also make a diagnosis of FA, FA is a syndrome, clinical manifestations mainly include three aspects: bone marrow failure, various developmental abnormalities and increased susceptibility to cancer.
(1) Alter classification: According to the characteristics of hematology, Alter equals 1991 to divide FA into 6 clinical subtypes: 1 severe aplastic anemia, relying on blood transfusion, androgen ineffective or not receiving androgen therapy, 2 severe aplastic disorder Anemia, dependent on blood transfusion, is receiving androgen therapy, but poor efficacy, 3, severe aplastic anemia, independent of blood transfusion, androgen therapy, 4, severe aplastic anemia, independent of blood transfusion, not accepted Androgen therapy or androgen therapy is ineffective, 5 have characteristics of bone marrow failure, such as mild anemia, neutropenia, thrombocytopenia; red blood cells, increased HbF, stable condition, no blood transfusion and androgen therapy, 6 normal blood, normal HbF Or mild abnormalities, no blood transfusion and androgen therapy.
(2) Anconi syndrome does not all have the above three characteristics, 1 infant type: also known as acute type, characterized by: A. early onset, 6 to 12 months of onset, B. often due to polydipsia, polydipsia, more Urine, dehydration, weight loss, vomiting, constipation, inability to see a doctor, C. growth retardation, developmental disorders, anti-vitamin D rickets and malnutrition, osteoporosis and even fractures, D. renal all-amino acid urine, but plasma amino acids Normal, E. hypokalemia, hypophosphatemia, alkaline acidase activity, hyperchloremia metabolic acidosis, urinary titratable acid and NH4 can be reduced, urine sugar is increased or increased, blood glucose is normal, F. Poor prognosis, can die of uremia acidosis or secondary infection, 2 infant type: late onset (after 2 years old), the symptoms are lighter than infants, with anti-vitamin D rickets and growth retardation as the most prominent performance, 3 adult type: features: A. 10 to 20 years old or later onset, B. a variety of renal tubular dysfunction; such as diabetes, all amino acid urine, high phosphate urine, hypokalemia, perchloric acid poisoning, C. Chondrosis is often prominent, D. Late renal failure can occur.
(3) Hematological abnormalities: The most important clinical feature of FA is hematological abnormality. FA is the most common type of hereditary bone marrow failure syndrome. The incidence of homozygotes in AA, MDS and AML is significantly increased. The blood cell count is normal, the earliest detected abnormality is macrocytosis, followed by thrombocytopenia and neutropenia. The probability of hematologic abnormalities before the age of 40 is 98%. The most common hematological abnormality is thrombocytopenia. And complete blood cell reduction, associated with low bone marrow hyperplasia, 53% of patients with whole blood cell reduction, 38% of patients with thrombocytopenia, after 20 years of follow-up, 84% of patients developed whole blood cell reduction, a small number of patients with anemia The incidence of neutropenia is reduced. Some patients have myelodysplastic syndrome (MDS) or acute leukemia (especially acute myeloid leukemia). Clinically, patients with FA have bleeding, pale and/or repeated infection.
(4) Other manifestations: 28 patients with short stature were tested for growth hormone (GH) levels, 22 patients had GH deficiency, 15 patients with GH hormone therapy had 12 patients with high height, and none of patients had hematopoietic improvement. Patients treated with GH One case died of acute myeloid leukemia. Recently, 44% of patients have GH deficiency, 36% have hypothyroidism, and the role of recombinant GH in growth and hematopoiesis needs further observation, and between GH treatment and leukemia. Maybe the contact needs to be discussed carefully.
2. Secondary Fanconi syndrome
Performance varies according to the cause.
Examine
Examination of pediatric Fanconi syndrome
Blood picture
Blood routine examination showed that the three lines showed different degrees of decline, anemia was positive cells positive pigmentation, red blood cells were accompanied by mild abnormalities and red blood cell size unevenness, reticulocytes decreased, but sometimes up to 3%, white blood cells and neutral The proportion of granulocytes decreased, and platelet decreased first. In some patients, the life span of red blood cells was shortened, and the level of fetal hemoglobin (HbF) increased by 3% to 15%.
2. Bone marrow
Bone marrow is similar to acquired aplastic anemia. When aplastic anemia occurs, FA patients have low bone marrow hyperplasia and fat, reduced hematopoietic components, decreased proportion of erythroid and granulocyte, and sometimes megaloblastic changes in erythrocytes, and megakaryocytes are significantly reduced. The number of non-hematopoietic cells such as lymphocytes, tissue basophils, and reticulocytes is relatively increased.
3. Hormone levels
Twenty-eight patients with short FA were tested for growth hormone (GH) levels, 22 patients had GH deficiency, and 15 patients with GH hormone therapy had 12 patients with high growth. None of the patients had hematopoietic improvement, and one of the patients treated with GH died of acute pith. Leukemia, recently reported that 44% of patients have GH deficiency, 36% of patients have hypothyroidism, the role of recombinant GH in growth and hematopoiesis needs further observation, and the possible link between GH treatment and leukemia needs to be carefully explored.
4. Diagnostic laboratory examination
Diagnostic tests are chromosome breaks, which stimulate the cultured peripheral blood lymphocytes with phytohemagglutinin. FA patients have a high rate of cell breakage, fissures, rearrangements, interchanges and intranuclear replication when adding a cleavage agent such as DEB or In MMC, these chromosomal abnormalities were significantly increased. The peripheral blood lymphocytes of FA homozygotes plus DEB culture had an average of 8.96 breaks per cell, and normal cells had an average of 0.06 breaks. The other method for diagnosing FA was flow cytometry. The slow growth of cells in FA patients is due to the prolongation of the G2 phase of the cell cycle. Cells treated with an alkylating agent cannot divide, but there is chromosome replication and accumulation in the G2 phase, which can be detected due to an increase in the amount of DNA contained.
5. Other
Half of the patients had amino acid urine, which was more common with proline urine. The level of erythropoietin increased in patients with FA, and the long-term presence of i antigen in red blood cells (normal people disappeared before 2 years old). X-ray examination, including chest X-ray and bone examination ; B-ultrasound or echocardiography and other imaging examinations, according to clinical needs, X-ray examination can find osteoporosis, rickets performance; cystine storage disease, eye slit lamp examination shows corneal cystine crystal Calm and so on.
Diagnosis
Diagnosis and diagnosis of pediatric Fanconi syndrome
diagnosis
The disease is based on aplastic anemia, growth retardation, rickets, polyuria and dehydration, acidosis, electrolyte imbalance and other clinical manifestations; blood biochemical examination see hypokalemia, hypophosphatemia, hyponatremia, hypochlorous acid Poisoning, high AKP, hypouric acid, diabetes, normal blood sugar, full amino acid urine, low urine pH and low urine and titratable acid; X-ray examination for osteoporosis, rickets performance, are helpful for diagnosis, pay attention to family History, should pay attention to the diagnosis of primary disease, such as cystine storage disease, eye slit lamp examination can be seen in the cornea with cystine crystal deposition, increased cystine content in bone marrow or blood leukocytes and see cystine crystals, The exact diagnosis of this disease is very important. Because many types of Fanconi syndrome can achieve good results through specific treatment and symptomatic treatment, the cause diagnosis is particularly important.
Differential diagnosis
1. VATER/VACTERL (vertebral defects, anal atresia, tracheoesophageal fistula, renal defects and radial limb defects) patients with spinal defects, hilar atresia, tracheoesophageal fistula, humerus and kidney dysplasia, and the clinical manifestations of FA overlap.
2. Thrombocytopenia-Tibial Deficiency Syndrome (TAR) is an autosomal recessive hereditary disease with thrombocytopenia and humeral loss at birth or in the neonatal period, but bilateral thumb present, no hematological malignancies Or the increased risk of solid tumors, unlike FA.
3. Congenital pure red blood cell aplastic anemia (DBA) is characterized by mature defects of erythroid progenitor cells, positive cells or large cell anemia appear within 1 year old, more than 1/3 of patients have congenital malformations, often involving the head (small jaw, cleft lip), upper limbs and genitourinary system, most patients are sporadic, a few are autosomal dominant or recessive, the above three diseases of the DEB / MMC test without chromosome breaks, can be identified with FA.
4. Nijmegen rupture syndrome is a rare autosomal recessive disorder caused by NBS1 mutation, characterized by immunodeficiency, microcephaly and hypersensitivity to ionizing radiation. Most patients are Yugoslavia, the most recent one. In the study, 8 Russian NBS patients, 3 had hematopoietic abnormalities or AML, therefore, clinically very similar to FA, if the diagnosis is difficult, you can consider NBS mutation examination, Table 1 is the characteristics of Fanconi syndrome under various causes. And the difference.
