Chediak-Higashi syndrome is one of the forms of congenital immunodeficiency, which is characterized by a phagocytosis defect and oculocutaneous albinism. The disease has an autosomal recessive inheritance mechanism and occurs with various types of LYSR/CHS1 mutations. Clinically, the pathology is manifested by discoloration of the hair and iris of the eyes, recurrent bacterial and fungal infections, hemophagocytic lymphohistiocytosis. The diagnostic program includes a myelogram, clinical and immunological blood tests, genetic counseling. Bone marrow transplantation is recognized as the most effective method of treatment.
ICD 10
E70.3 Albinism
General information
Chediac-Higashi syndrome (CHS) is a rare form of generalized cellular dysfunction, which was described in 1952 by the Cuban doctor Chediac and in 1954 by the Japanese pediatrician Higashi. The molecular genetic basis of pathology was studied in detail only after 34 years. The medical literature describes about 500 cases of the disease in young children. Despite its rare occurrence, the syndrome does not lose its relevance in practical genetics and pediatrics, since it has an unfavorable course and requires improvement of treatment methods.
Causes
Chediak-Higashi syndrome is caused by a mutation of the LYSR/CHS1 gene localized on the long arm of the 1st chromosome. It consists of 53 exons and encodes a protein responsible for the formation and transport of cellular organelles. The disease is inherited in an autosomal recessive way. There are 63 known variants of genetic mutations that differ in the severity of pathophysiological disorders. The most favorable are the missense mutations, in which the MFX has a mild phenotype.
Pathogenesis
The LYST genetic mutation disrupts the formation of the corresponding protein and changes the course of the processes regulated by it. With the syndrome, giant intracellular granules are formed, which are located in lysosomes, cytolytic vesicles, melanosomes. They disrupt the functions of cells, primarily cytotoxic T-lymphocytes, which are responsible for phagocytosis of foreign microorganisms. The restoration of plasma cell membranes is also disrupted.
Pathogenetic changes reduce the activity of phagocytic lymphocytes and natural killers. Uncontrolled fusion of lysosomes and impaired chemotaxis are the causes of the inability of cells to digest phagocytized microorganisms. Pathogens stay inside immune cells for a long time, avoiding the toxic effects of antibiotics. In addition to the immune function, the transport of melanin is disrupted, which is associated with the manifestations of albinism.
In Chediak-Higashi syndrome, giant peroxidase-positive granules appear in blood and bone marrow cells, which are the result of the combination of primary and secondary lysosomes. Morphologically, the disease is characterized by lymphohistiocytic infiltration of the liver parenchyma, lymph nodes, and spleen. Erythrophagia processes also occur.
Symptoms
The disease manifests itself in the first years of life. A typical external sign is partial albinism. The hair color varies from light yellow to gray, which depends on the type of mutation and ethnicity. The iris of the eyes has a blue or light gray shade. Patients are sensitive to light: if they stay in a brightly lit room for a long time, their eyes begin to water and hurt. Photosensitivity is accompanied by a decrease in vision, strabismus.
The second characteristic syndrome in HCV is recurrent bacterial infections. Most often, pathologies are caused by streptococcal and staphylococcal pathogens, with a critical decrease in immune function, opportunistic infections join. From an early age, children suffer from prolonged bronchitis, pneumonia, otitis media, furunculosis. Against the background of antibiotic therapy, fungal infections often develop – oropharyngeal candidiasis.
A diverse neurological symptomatology is characteristic of SCHH. Most children develop ataxia, sensory and motor disorders. The intensity of clinical manifestations correlates with the overall severity of the disease and the age of the patient. As a result of progressive neurodegeneration, signs of mental retardation arise and worsen.
Complications
An unfavorable consequence of the syndrome is the “acceleration” phase – hemophagocytic lymphohistiocytosis. It occurs in 65-85% of patients by the age of 7-10 years of life, often provoked by the Epstein-Barr virus (EBV). The complication is characterized by an inflammatory reaction, uncontrolled activation of macrophages and damage to internal organs. Clinically, this is manifested by fever, jaundice, pancytopenia and hepatosplenomegaly.
Despite the improvement of diagnostics and medical care for patients with Chediac-Higashi syndrome, the mortality rate remains high. More than 85% of children do not live to the age of 10. Among the main causes of death are sepsis against the background of prolonged bacterial infections, the formation of malignant neoplasms. When treated with HSCT, there is a risk of developing a graft-versus-host reaction with a mortality rate of about 50%.
Diagnostics
The disease has characteristic external signs, so it can be suspected at a pediatrician’s appointment. In addition to examining the hair, eyes and skin, a standard physical examination is performed, the work of the lungs and heart is studied, abdominal palpation and liver size determination are performed. To confirm the diagnosis of Chediak-Higashi syndrome, a geneticist’s consultation and additional examination methods are required, including:
- Abdominal ultrasound. Sonography determines the enlargement of the liver, pancreas and spleen. With progressive disease, diffuse changes in the hepatic parenchyma, free fluid in the peritoneal cavity are observed.
- Chest x-ray. X-ray examination of the chest often reveals signs of pneumonia, hydropericardium, pleurisy. For a more detailed diagnosis, MSCT is prescribed.
- Blood test. Anemia, thrombocytopenia, neutropenia are detected in the hemogram. A biochemical blood test shows an increase in the level of triglycerides and ferritin. According to the results of the coagulogram, a decrease in the concentration of fibrinogen is determined.
- Clarifying studies. Low cytotoxic activity of NK cells is detected in the blood of patients with HCV, the level of soluble CD25 is more than 2400 units/ml. The pathognomonic sign of the disease in the myelogram is the detection of peroxidase–positive granules in bone marrow cells.
- Genetic diagnostics. Due to the high cost and complexity of the determination of the exact type of LYSR/CHS1 mutation in HC is rarely prescribed. Such information is of clinical importance for determining the prognosis, drawing up a program of genetic counseling of family members.
Differential diagnosis
If Chediak-Higashi disease is suspected, it is necessary to exclude other variants of immunodeficiency accompanied by albinism and hemophagocytosis – Griscelli and Germansky-Pudlak syndromes. In difficult cases, differential diagnosis is carried out with a familial form of hemophagocytic lymphohistiocytosis, isolated oculocutaneous albinism, Cross-McKusick-Breen syndrome.
Treatment
Conservative therapy
Medicinal methods are preventive in nature. To prevent severe infections, individual courses of antibacterial and antifungal therapy are carried out, antiviral drugs are prescribed according to indications. Intravenous immunoglobulins, drugs to stimulate granulocytopoiesis are administered monthly. To prevent photophthalmia, patients are recommended to wear darkening glasses, avoid being in the bright sun.
Intensive treatment is prescribed during the “acceleration” period. Immunosuppressors and glucocorticosteroids in high doses are used to correct the inflammatory process. With concomitant damage to the central nervous system, drugs are injected into the spinal canal or subarachnoid space. If complications are caused by EBV infection, monoclonal antibodies are used. A well-chosen treatment regimen allows achieving remission in 75% of patients within 2 months.
Surgical treatment
Hematopoietic stem cells transplantation( HSCT) from bone marrow is the most promising treatment option, which increases the chances of prolonging life in Chediak-Higashi syndrome. HSCT is recommended to be performed before the start of the “acceleration” period: in this case, the overall 5-year survival rate is 62%. With a late bone marrow transplant, the probability of success is no more than 42%.
To reduce the load on the child’s body, training is carried out in the conditioning mode with reduced intensity. The best results are achieved when performing transplantation from an HLA-compatible related donor. In the post-transplant period, immunosuppressive therapy continues, patients are in special sterile boxes to prevent the development of infections.
Prognosis and prevention
Patients with the classic form of CHS live no more than 10 years and die in the “acceleration” phase. During early bone marrow transplantation, the patient’s quality of life improves, the survival rate increases, but the prognosis remains relatively unfavorable. A married couple who had a child with Chediak-Higashi syndrome, when planning the next pregnancy, a geneticist’s consultation is shown.
