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Pathogenesis of Chediak-Higashi syndrome
Last reviewed: 04.07.2025
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Chediak-Higashi syndrome is inherited in an autosomal recessive manner and is based on a disorder of intracellular protein transport. In 1996, the genetic nature of Chediak-Higashi syndrome was deciphered, which is associated with mutations in the LYST/CHS1 gene; it is localized on the long arm of chromosome 1 (lq42-43). The product of this gene is involved in the biogenesis of lysosomes, melanosomes, and secretory granules of cytotoxic cells.
Mutation in the CHS gene leads to disruption of intracellular (ranula) formation in various cells. Leukocyte and fibroblast leukosomes, platelet dense bodies, azurophilic granules of neutrophils, and melanocyte melanosomes in CHS are usually significantly larger in size and morphologically altered, indicating a single pathway for synthesizing organelles responsible for storing synthesized substances. In the early stages of neutrophil maturation, normal azurophilic granules merge to the size of megagranules, whereas at later stages (e.g., at the myelocyte stage), normal-sized granules may form. Mature neutrophils contain both populations. A similar phenomenon is observed in monocytes.
Disruption of melanin production by melanosomes leads to the development of albinism. Autophagocytosis of melanosomes is observed in melanocytes.
Approximately 80% of patients with Chédiak-Higashi syndrome develop the so-called acceleration phase, which is a non-malignant lymphoma-like infiltration of various organs, most often caused by Epstein-Barr virus infection. Clinically, anemia, episodic bleeding, severe, often fatal, infections are observed. The infectious process, which is usually caused by Staphylococcus aureus, Streptococcus pyogenes and Pneumococcus sp, most often involves the skin, respiratory tract, and lungs. The acceleration phase resembles that in other diseases accompanied by lymphocyte/macrophage activation syndrome, in particular, HLH and Griselli syndrome.
As a rule, the acceleration phase and/or severe infection lead to the death of patients at an early age, however, there are descriptions of adult patients in the literature. In such patients, the dominant symptom of the disease was progressive neurological dysfunction, most often in the form of peripheral neuropathy, the mechanism of development of which remains unclear. Axonal and demyelinating types of peripheral neuropathy have also been described in patients with Chediak-Higashi syndrome.
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