Fanconi anemia is a genetic disease that is transmitted by an autosomal recessive type and is characterized by a violation of hematopoiesis, the formation of malignant neoplasms, malformations, fragility of chromosomes. It is manifested by frequent bleeding, bruising on the skin, lethargy, pallor, a tendency to infections. Diagnostics is carried out by laboratory methods, cytogenetic, molecular genetic and clinical blood tests, myelogram are prescribed. The main methods of treatment are bone marrow transplantation, drug maintenance of hematopoiesis, blood transfusion.
D61.0 Constitutional aplastic anemia
Synonymous names of Fanconi anemia are congenital Fanconi panmyelopathy, hereditary panmyelopathy. The disease is named after the Swiss pediatrician Guido Fanconi, who in 1927 described a congenital aplastic pathology based on the symptoms of three brothers. Fanconi anemia is a rare genetic disease inherited according to the autosomal recessive principle. Epidemiological indicators are low – 1 sick child per 350 thousand newborns. The prevalence is the same among female and male representatives, higher in communities with permitted closely related marriages, for example, among some South African peoples.
The disease is hereditary, develops when a defective gene is transmitted from parents to a child. 15 genes have been identified, mutations of which are manifested by Fanconi anemia. Of these, 14 are located in autosomes and are recessive, 1 type of gene is located on the X chromosome (linked to sex). All these genes are responsible for the production of a certain enzyme involved in DNA repair.
Autosomal recessive inheritance implies that both father and mother must be carriers of pathological genetic information. At the same time, they themselves, as a rule, are healthy. The probability of having a sick child in such a couple is 25%. Genetic panmyelopathy is diagnosed in children and adults who have received the same altered gene from each parent. In extremely rare cases, anemia is provoked by the transmission of a defective X-linked chromosome. Women can be carriers of the mutation, the disease manifests itself only in boys. The risk of developing pathology in the son in the presence of a mutated gene in the mother is 50%.
Normally, there are special enzyme systems in the cells of the body that correct breaks in DNA molecules damaged during biosynthesis or exposure to chemical, physical reagents. With Fanconi anemia, a genetic defect is detected in a cluster of proteins responsible for DNA repair, which leads to increased fragility of chromosomes. As a result, patients develop bone marrow disorders – neoplasia and aplastic anemia. Oncological diseases are most often represented by acute myeloid leukemia – a malignant tumor of the myeloid blood germ, provoking the accumulation of altered white cells that suppress the growth of erythrocytes, platelets and normal leukocytes. With aplastic anemia, as a result of bone marrow dysplasia, the growth and maturation of all three types of blood cells is sharply inhibited.
Fanconi anemia symptoms
More than half of the patients have congenital anomalies of the development of internal organs and skeleton. Bone deformities are manifested by a specific appearance: patients are stunted, with a reduced head size, the absence or noticeable shortening of the thumb on the hands, underdevelopment of the radius, congenital dislocation of the hip and / or the presence of a cervical rib, clubfoot, underdeveloped chin (“bird face”). Hyperpigmentation of the skin in the form of light and brownish spots is characteristic.
Neurological disorders are represented by strabismus, underdevelopment of one or two eyes, drooping of the upper eyelid, ocular tremor, deafness, mental retardation. Patients often have immature genitals, they lack one or both testicles. Common anomalies of the structure of organs include defects of the urinary system: doubling of the ureters or pelvis, horseshoe-shaped kidneys, renal cysts, displaced external opening of the urethra (hypospadias). Congenital heart defects include tricuspid valve atresia, atrial septal defect, mitral stenosis, ventricular septal defect. Patients suffer from kidney and heart failure.
The key symptoms are associated with a gradual increase in disorders in the work of the bone marrow. More often they make their debut in childhood (at 5-10 years old). Due to a decrease in the number of platelets, increased bleeding develops: with wounds, blood does not clot for a long time, nosebleeds easily occur, menstrual discharge is abundant, many “causeless” bruises are found on the body. A decrease in the number of red blood cells is manifested by anemia with characteristic weakness, fatigue, dizziness, fainting, pallor of the skin, palpitations and shortness of breath. The lack of white blood cells contributes to the deterioration of resistance to infections. Subsequently, leukemia, myelodysplastic syndrome, oncological diseases are formed.
The most common complication is considered to be frequent infectious diseases. Patients develop ARVI, sore throat, rhinitis, bronchitis, flu, typhus, herpes. The recurrent nature of diseases and their severe course lead to the destruction of organs, accompanied by the risk of sepsis. Another complication of hereditary anemia is malignant neoplasms – leukemia, epithelial tumors of the neck and head, genitals. Cancer in such patients is difficult to treat due to increased fragility and reduced DNA repair. This phenomenon limits the use of radiation therapy, cytotoxic drugs. Clotting disorder causes large blood loss.
The examination of patients is carried out by oncologists, hematologists, pediatricians, geneticists. Diagnosis begins with the analysis of anamnestic data and complaints. The doctor finds out whether this hereditary disease exists in close relatives, specifies the time of the appearance of the first signs of the disease, early visits to doctors. During examination, assesses the general condition of the patient, reveals the presence of developmental abnormalities, hyperpigmented spots, bleeding, bruising. In most cases, it is not difficult to detect typical bone deformities, underdevelopment of the eyes. To confirm the diagnosis and distinguish Fanconi anemia from acquired anaplastic anemia, a number of laboratory tests are carried out:
- Сlinical blood test. Changes in the cellular composition of blood are characteristic. At the early stages of hematopoiesis disorders, thrombocytopenia and leukopenia are diagnosed, at later stages – pancytopenia (a sharp decrease in the volume of erythrocytes, leukocytes and platelets). Moderate hemolysis is possible without hyperbilirubinemia, but with reticulocytosis. The ESR value has been increased to 60-80 mm/h.
- Cytogenetic study of cells. A test is performed with diepoxybutane, mitomycin C, indicating the frequency and spectrum of chromosomal aberrations. In favor of genetic anemia, the indicators of the DEB test are considered to be more than 45%, the borderline level is 11-45% (the percentage of cells with chromosomal breaks).
- Molecular genetic analysis. Genes are being investigated, mutations in which can lead to the development of the disease. In 60-70% of cases, mutations are found in a pair of FANCA genes, in 14% – in the FANCC allele, in 10% – in the FANCG genes. The frequency of mutations in other pairs is 0.2-3%.
- Myelogram. According to the study, an increase in the number of plasma cells and macrophages phagocytizing fats is determined. The content of undifferentiated cells is within the normal range. The concentration of myelocytic germ cells was reduced, the lymphocyte index was increased.
The main therapy is aimed at restoring the process of hematopoiesis. Treatment methods are selected individually, depending on the severity of the disease, the age of the patient, the presence and severity of congenital anomalies. Additionally, infections and oncopathologies are treated, rehabilitation measures are carried out. The following methods are used to eliminate anemia:
- BMT. Bone marrow transplantation is the most effective in the long term, but it has contraindications and is often accompanied by the development of complications. The optimal age for surgery is up to ten years. Donors can be healthy sisters and brothers who meet the compatibility criteria. Preliminary intensive therapy (conditioning) is associated with the risk of toxic effects on organs. After transplantation, there is a high probability of acute or chronic immune conflict between donor and recipient cells.
- Drug stimulation of hematopoiesis. If transplantation is not possible, patients are shown conservative treatment that temporarily improves their condition. The production of blood cells is stimulated by androgens (male sex hormones) and hematopoietic growth factors – erythropoietin, stem cell factor, interleukins-1-12. Immunosuppressants are used in parallel. Drug therapy is able to maintain a high quality of life of patients for many years, but its effectiveness is gradually decreasing.
- Transfusion of blood components. With pronounced side effects or contraindications to etiotropic therapy (transplantation, stimulation of hematopoiesis), hemotransfusion procedures are prescribed. Washed erythrocytes are transfused – donor red blood cells, freed from surface proteins. With bleeding and a decrease in platelet levels, platelet mass is injected into patients.
Prognosis and prevention
The life expectancy of patients is determined by the degree of bone marrow dysfunction. Sometimes patients live up to 40 years without treatment, but often die in childhood from severe anemia or cancer. The prognosis is most favorable with timely allogeneic bone marrow transplantation, after which there is a chance of full restoration of normal hematopoiesis and an increase in life span. Since the disease is genetic, it is impossible to prevent its development. Prevention is reduced to medical and genetic consultation of couples from risk groups planning pregnancy, as well as to prenatal diagnosis of pathology, during which blood is drawn from the umbilical vein of the fetus and a DEB test is performed. With a positive result, the issue of termination of pregnancy is considered.