What causes Chédiak-Higashi syndrome (CHS)?

Updated: Aug 08, 2019
  • Author: Roman J Nowicki, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Chédiak-Higashi syndrome (CHS) is inherited in an autosomal recessive pattern. Parental consanguinity is often reported. The genetic hallmark of CHS is mutations in the CHS1/LYST gene located on band 1q42-43. Mutations of this gene result in a defect in granule morphogenesis in multiple tissues. The gene encodes a protein called the lysosomal trafficking regulator, which regulates the synthesis, transport, and fusion of cytoplasmic vesicles. The abnormalities observed in these vesicles result in grossly enlarged and nonfunctional lysosomes, which are identified during cytology as giant, coalesced, azurophilic granules present mostly in granulocytes and monocytes, but also in fibroblasts, melanocytes, astrocytes, Schwann cells, and hematopoietic cells. These granules are specific to CHS, and their presence in granulocytes from peripheral blood and bone marrow is the basis of diagnosis. Clinical CHS phenotypes correlate with molecular genotypes. CHS patients with deletions in the LYST gene usually present with a fulminant accelerated phase early in life, whereas, those with missense mutations have a better prognosis, characterized by the absence of an accelerated phase and no neurological involvement. [5, 8, 9] Although defects in cytotoxic T-cell lytic secretory granule secretion and neutrophil phagocytosis are suggested to contribute to the immunodeficiency in CHS, the underlying molecular mechanisms are unknown.

Patients with CHS exhibit alterations in neutrophils. These alterations include neutropenia, which may be profound; decreased deformability, resulting in impaired chemotaxis; and delayed phagolysosomal fusion, resulting in impaired bactericidal activity.  

Clinical features resulting from LYST mutations in CHS have much in common with immunodeficiencies caused by Toll-like receptor (TLR) signaling defects, such as conditions caused by autosomal recessive mutations in TLR adapters, IRAK-4 and MyD88 (OMIM# 610799, 607676, 612260). Like mutations in LYST, reduced function of IRAK-4 and MyD88 results in selective impairment of cell responsiveness to TLRs other than TLR-3, and limited presence of interleukin 6 protein when exposed to TLR agonists. These conditions feature noninvasive pyogenic bacterial infections affecting skin and the upper respiratory tract, with occasional periodontal disease. However, patients with MyD-88 and IRAK-4 deficiency show no impaired defense against viral infections, owing to their normal functional natural killer cells and their retained ability to signal through TLR-3/-7/-9 and other non-TLR viral receptors. In contrast, patients with the classic CHS phenotype develop life-threatening hemophagocytic lymphohistiocytosis following infections with viruses, which may result from dysfunctional natural killer cells lacking cytotoxic activities as well as defective trafficking in TLR-3/-7/-9 signaling. Loss of expression or proper localization of TLR-2 and TLR-4, together with the lack of response of cell production of proinflammatory cytokines, leads to exacerbated bacterial burden and delayed clearance. [10]

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