Chediak-Higashi syndrome
Chediak-Higashi syndrome is a rare autosomal recessive disorder characterized by a defect in lysosomal trafficking, leading to a host of medical complications. Individuals with this condition often experience recurrent infections, prolonged bleeding, increased bruising, and neurological damage. A notable symptom is partial albinism, which results in decreased pigmentation of the skin, eyes, and hair. The underlying genetic defect primarily involves the LYST gene, crucial for the proper function of immune cells and melanocytes. As a result, affected individuals face an increased susceptibility to infections and may exhibit physical characteristics such as enlarged liver and spleen.
Diagnosis typically involves identifying giant granules in white blood cells through blood smears. Although there are no specific treatments, allogenic hematopoietic stem cell transplantation has shown promise for some patients. Prevention focuses on vigilant infection management and genetic counseling for families with a history of the syndrome. Unfortunately, the prognosis can be severe, with many affected individuals experiencing life-threatening complications, especially in early childhood, though some may survive into adulthood.
Chediak-Higashi syndrome
ALSO KNOWN AS: CHS
DEFINITION Chediak-Higashi syndrome is a rare autosomal recessive disorder that is associated with a defect in many cells of the body which leads to recurrent infections, prolonged bleeding, increased bruising, and neurologic damage. Affected individuals also have a defect in melanin production that causes decreased pigmentation (partial albinism) of the skin, eyes, and hair.
Risk Factors
The primary risk for developing Chediak-Higashi syndrome is a family history of the disease. Consanguinity, or the close familial relationship between parents, is commonly found in affected individuals. The incidence of the disease is unknown, but as of 2023, there had been fewer than five hundred total reported cases. The US National Library of Medicine's Genetics Home Reference website reported in July 2014 that there have about two hundred cases have been reported worldwide.
Etiology and Genetics
The main genetic defect in Chediak-Higashi syndrome is of the LYST gene, also known as the CHS1 gene, located on the long arm of chromosome 1 and localized on band 42 (chromosome 1, q42.1-2). Most mutations of this gene result in the absence of lysosomal trafficking protein. Milder forms of the defect encode a partially functioning protein. There are also atypical forms of the syndrome found in adults that do not map to this gene location.
The protein expressed by this gene is important in the fusion of vesicles within the cell. These vesicles include lysosomes of leukocytes and fibroblasts, dense bodies of platelets, and melanosomes of melanocytes. A defect or lack of this protein causes these structures to become larger in size and irregular in shape, which changes how they function.
One of the important features of this syndrome is the effect on the immune system. The lysosome is unable to fuse with the phagosome and cannot release the toxic granules important for killing ingested bacteria. The larger shape and rigid structure of the lysosome inside the cell make it difficult for the leukocytes to leave the blood circulation to fight infection in the tissues. This increases the vulnerability to skin infections and abscess formation. Targeted cell killing by natural killer cells and cytotoxic T cells is abnormal as well. In fibroblasts, the enlarged lysosomes inhibit wound healing. These defects of the cells in the immune system are responsible for the increased infection risk in patients with this syndrome.
Because other cells in the body require lysosomal trafficking protein to function properly, a number of defects are associated with Chediak-Higashi syndrome. Platelets perform poorly during clot formation because they are unable to access important substances from the dense bodies. In epidermal melanocytes, the oversized melanosomes do not transfer melanin to the surrounding keratinocytes, which could explain the lack of pigment seen in the skin, hair, and eyes in this syndrome.
A complication of the syndrome, seen in more than 80 percent of affected individuals, is an accelerated phase of a nonmalignant infiltration of lymphocytic cells in the bone marrow. This lymphoma phase of the disease often results in death. People with milder atypical disease and those children who have successfully been treated by stem cell transplantation often develop neurologic symptoms in early adulthood.
Symptoms
The primary symptoms of Chediak-Higashi syndrome are an increased susceptibility to infection, particularly of the skin, lungs, and mucous membranes. Outwardly, affected individuals may have pale eyes and skin, with a metallic sheen to their hair. Other physical characteristics can include an enlarged liver and spleen. Later in life, they also have increasing signs of neurological problems, including visual problems, muscle weakness, and difficulty with sensation in the lower extremities. They often have difficulty walking and can have seizures. The cause of the progressive peripheral neuropathy is not understood.
Screening and Diagnosis
The presence of giant inclusions within white blood cells on a peripheral blood smear is the only clinical diagnostic test currently available for this disease. Giant granules can also be found in cells from skin, muscle, and nerves. The numbers of both platelets and white cells in the blood are low, and there are other signs that the hematological system is not working properly, such as an enlarged spleen and liver. Neurologically, the brain may appear smaller on MRI or CT scans due to atrophy.
Treatment and Therapy
There are no specific treatments for Chediak-Higashi syndrome. Allogenic hematopoietic stem cell transplantation appears to have been successful in some patients. In addition, great care must be taken in preventing and treating infections with early diagnosis, aggressive antibiotic therapy, and surgical drainage of abscesses. Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be used because they interfere with normal clotting function.
Prevention and Outcomes
Prenatal testing is currently not available on a routine basis. However, it may be of some value for families in which the mutation has been identified. Genetic counseling is recommended for prospective parents with a family history of Chediak-Higashi syndrome.
Death often occurs in the first ten years of life either from chronic infections or as the result of the lymphoma-like complication. However, some persons have survived longer.
Bibliography
Ajitkumar, Anitha, Siva Naga S. Yarrarapu, and Kamleshun Ramphul. “Chediak-Higashi Syndrome.” National Library of Medicine, 24 July 2023, www.ncbi.nlm.nih.gov/books/NBK507881/. Accessed 9 Sept. 2024.
"Chediak-Higashi Syndrome." Medline Plus, 1 Jan. 2014, medlineplus.gov/genetics/condition/chediak-higashi-syndrome/. Accessed 9 Sept. 2024.
Nussbaum, Robert L., Roderick, R. McInnes, and Huntington F. Willard. Thompson and Thompson Genetics in Medicine. 7th ed. New York: Saunders, 2007. Print.
Perkins, Sherrie L., and Mitchell S. Cairo. Hematological Malignancies in Children, Adolescents and Young Adults, January 2012, DOI:10.1142/7687. Accessed 9 Sept. 2024.
Pritchard, Dorian J., and Bruce R. Korf. Medical Genetics at a Glance. 3d ed. Hoboken: Wiley, 2013. Digital file.
Stevenson, Roger E., et al., eds. Human Malformations and Related Anomalies. 2d ed. New York: Oxford UP, 2006. Print.