Abstract
Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive congenital immunodeficiency caused by mutations in CHS1, a gene encoding a putative lysosomal trafficking protein. In the majority of patients, this disorder is typically characterized by infantile-onset hemophagocytic lymphohistiocytosis (HLH), which is lethal unless allogeneic transplantation is performed. A small number of individuals have the attenuated form of the disease and do not benefit from transplant. Improved outcomes of transplantation have been reported when performed before the development of HLH, thus it is important to quickly differentiate patients that present with the childhood form of disease and to prematurely enroll them into a transplantation protocol. In addition, this would also preclude those that exhibit clinical phenotypes of adolescent and adult CHS from this treatment. Patients with an absence of cytotoxic T lymphocyte (CTL) function have a high risk for developing HLH, and could therefore benefit the most from early hematopoietic stem cell transplantation (HSCT). However, although normal CTL cytotoxicity or bi-allelic missense mutations do not exclude the occurrence of HLH in childhood, a more conservative approach is justified. This article summarizes recent advances in the clinical characterization of CHS patients, provides updates on promising new testing methods, and focuses on specific therapeutic approaches.
Highlights
Chediak-Higashi syndrome (CHS; MIM #214500; ORPHA167) is a rare autosomal recessive disorder characterized by variable degrees of oculocutaneous albinism, recurrent pyogenic infections, a tendency for mild bleeding, and late neurologic dysfunction
Patients with absent cytotoxic T lymphocyte (CTL) cytotoxicity might have an indication for early hematopoietic stem cell transplantation (HSCT) because of their high risk of developing hemophagocytic lymphohistiocytosis (HLH) [27]
Normal CTL cytotoxicity or bi-allelic missense mutations do not exclude the occurrence of HLH in childhood, but a more conservative approach seems to be justified [18,27]
Summary
Chediak-Higashi syndrome (CHS; MIM #214500; ORPHA167) is a rare autosomal recessive disorder characterized by variable degrees of oculocutaneous albinism, recurrent pyogenic infections, a tendency for mild bleeding, and late neurologic dysfunction. A reasonably straightforward genotype-phenotype correlation of the disease has been suggested: early reports indicate frameshift, nonsense, and splice site mutations resulting in an absent CHS1/LYST protein correlate with severe childhood CHS, whereas milder adolescent or adult forms of CHS present with at least one missense mutation probably encoding a partially functioning protein [5,34,39] This linkage was not observed in other studies [14,27,35,45], and few exceptions are known. While the use of cord blood HSCT in HLH has often proved problematic, RIC has been used in an unrelated cord blood setting with promising results, and engraftment rates of 80% [80]
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