NORD gratefully acknowledges Sarah Tomer, Editorial Intern from the University of Notre Dame, and Wendy Introne, MD, Staff Clinician, National Human Genome Research Institute, for assistance in the preparation of this report.
Chediak-Higashi syndrome (CHS) is a rare, inherited, complex, immune disorder that usually occurs in childhood characterized by reduced pigment in the skin and eyes (oculocutaneous albinism), immune deficiency with an increased susceptibility to infections, and a tendency to bruise and bleed easily. Neurological deficits are also common. CHS is transmitted as an autosomal recessive genetic condition.
The symptoms of CHS may be apparent during early infancy. Hair is typically blond or light brown with a silvery tint. Affected children may be abnormally sensitive to light (photosensitivity) because of the reduced pigment in the eyes and skin, and may exhibit rapid, involuntary, eye movements (nystagmus). More important and more serious are the effects of CHS on the patient’s immune and nervous systems.
In CHS, white blood cells contain abnormal granules that are markedly enlarged. These granules can be seen by looking at the blood cells under the microscope, and if present, are diagnostic of CHS. These abnormal granules affect the ability of the white blood cells to fight infection. Children are susceptible to frequent bacterial, viral, and fungal infections, particularly of the skin and respiratory tract. Children with CHS can also have abnormally low levels of white blood cells. Children with this disorder may bruise easily or bleed excessively when injured. Platelet numbers are usually normal, but the platelets do not function properly causing easy bruising or prolonged bleeding.
The disease can be categorized into classic and atypical (mild) forms. Individuals with the atypical form may have fewer or less severe, infections and milder symptoms. Children with the classic form of the disease are at risk for developing the accelerated phase. The accelerated phase occurs in up to 85% of patients and can occur at any age. The accelerated phase is caused by an excess production of lymphocytes by the immune system. Patients can develop symptoms such as fever, swollen lymph nodes, enlargement of the liver and spleen, anemia, low WBC count, and low blood platelet count. This is a serious condition and needs to be treated right away.
Neurological symptoms occur in early adulthood. Symptoms involving the nervous system include an unsteady posture and walk (ataxia) and loss of sensation in the arms and legs (peripheral neuropathy).This can progress to physical weakness and disability. Some patients can have symptoms that resemble Parkinson’s disease.
Chediak-Higashi syndrome is inherited as an autosomal recessive genetic trait. The responsible gene has been mapped to chromosomal locus 1q42.1-q42.2 and is known as LYST gene.
The abnormal gene affects the “traffic patterns” or movement of proteins within the cells. Proteins (or enzymes) that are meant to go from one part of the cell to another may be misdirected or fail to be transported.
For example, a granule in which the skin pigment (melanin) is made is interfered with so that the pigment cannot be transported to the appropriate skin cell. Similarly, a defect in the transport within a white blood cell (WBC) renders the cell helpless in killing infective agents like viruses or bacteria and causing the immune problems.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q42.1” refers to band 42.1 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait, which are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits an abnormal gene for the same trait from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Chediak-Higashi syndrome is a very rare disorder that affects males and females in equal numbers. It is often obvious at birth or shortly thereafter. There does not appear to be a higher risk for any particular ethnic or racial group. There are less than 500 cases of the disease on record. 85% of affected individuals progress to the accelerated phase.
The diagnosis of CHS is usually made by the presence of ‘giant granules’ in microscopic analysis of white blood cells. ‘Giant inclusion bodies’ can also be seen in the cells that develop into white blood cells (leukocyte precursor cells) in the bone marrow.
Pigment clumping in hair that can be seen under light microscopy is another method for diagnosis that would be done if a blood smear showed enlarged granules.
Management varies depending of the stage of the disease at the time of diagnosis. Ideally, bone marrow transplant should be performed before the patient develops the accelerated phase. Bone marrow transplant corrects the immune and bleeding abnormalities and prevents the development of the accelerated phase. If the accelerated phase occurs, hemophagocytosis must be in remission before a bone marrow transplant can occur. Those patients are given chemotherapy to get the accelerated phase into remission. Bone marrow transplant can occur after the patient is in remission. Before major procedures, a drug to prevent excessive bleeding, DDVAP, can be administered.
Other than these options, treatment of CHS is symptomatic. When bacterial or fungal infections occur, they should be vigorously treated with antibiotic or antifungal drugs. Acute viral infections may be treated with the anti-viral drugs. Platelet transfusions may be necessary if bleeding becomes excessive after injury or surgery.
People with CHS should minimize unprotected sun exposure. When affected individuals are exposed to sunlight, sunglasses and sunscreens applied to the skin can be helpful. Genetic counseling may be of benefit for people with CHS and their families.
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