Chediak-Higashi syndrome

PURPOSE OF REVIEW: Chediak-Higashi syndrome, a rare autosomal recessive disorder, was described over 50 years ago. Patients show hypopigmentation, recurrent infections, mild coagulation defects and varying neurologic problems. Treatment is bone marrow transplant, which is effective in treating the hematologic and immune defects, however the neurologic problems persist. The CHS1/LYST gene was identified over 10 years ago and homologous CHS1/LYST genes are present in all eukaryotes. This review will discuss the advances made in understanding the clinical aspects of the syndrome and the function of CHS1/LYST/Beige. RECENT FINDINGS: Clinical reports of Chediak-Higashi syndrome have identified mutations throughout the CHS1/LYST gene. The nature of the mutation can be a predictor of the severity of the disease. Over the past decade the CHS1/LYST family of proteins has been analyzed using model organisms, two-hybrid analysis, overexpression phenotypes and dominant negatives. These studies suggest that the CHS1/LYST protein is involved in either vesicle fusion or fission. SUMMARY: Although CHS is a rare disease, the Chediak-like family of proteins is providing insight into the regulation of vesicle trafficking. Understanding the basic mechanisms that govern vesicle trafficking will provide essential information regarding how loss of CHS1/LYST affects hematologic, immunologic and neurologic processes.     

Gamma-delta T cells in Chediak-Higashi syndrome

Lymphocytes from children with Chediak-Higashi syndrome (CHS) have impaired natural killer (NK) activity and lack antibody-dependent cell-mediated cytotoxicity. Study of T cells bearing an alternate T cell receptor comprised of gamma- and delta-chains, which typically demonstrate NK activity in vitro, was undertaken in CHS patients. We demonstrate that the cellular machinery for lysis of target cells in vitro is present in CHS-derived gamma delta T cell clones. We also show that the proportion of gamma delta T cells among peripheral blood mononuclear cells is significantly increased in CHS, the first example of a specific immunodeficiency disorder with a relative expansion of these T cells.     

The Chediak-Higashi syndrome: microtubules in monocytes and lymphocytes

Recent investigations of Chediak-Higashi syndrome (CHS) leukocytes have suggested that defective cell function and formation of giant granules may be due to an inability of the cells to assemble microtubules because of an abnormality in synthesis of cyclic 3',5'-guanosine monophosphate (cGMP). In the present study we have examined normal and CHS lymphocytes and monocytes for the presence and frequency of centriole-associated microtubules. No statistically significant differences between the mean numbers of centriole associated microtubules in normal and CHS mononuclear cells could be detected. Results of the study fail to support the hypothesis that microtubule assembly is a fundamental defect in all CHS leukocytes.     

Platelet function in the Chediak-Higashi syndrome.

Platelet function studies were performed on two patients with the Chediak-Higashi syndrome, one of whom had a history of easy bruising unrelated to thrombocytopenia. Both patients had prolonged bleeding times, abnormal platelet aggregation, and a defect of platelet storage granules, manifested by reduced platelet ADP, an increased ATP/ADP ratio, increased adenine nucleotide specific radioactivity after 3H-adenine labeling, and decreased platelet uptake of radioactive 5-hydroxytryptamine. These findings confirm preliminary data in animals with the Chediak-Higashi syndrome, provide and explanation for impaired primary hemostasis in these patients, and illustrate another disorder in which platelet storage-pool deficiency occurs.     

T-cell lymphoma and the Chediak-Higashi syndrome

The majority of patients with Chediak-Higashi syndrome (CHS) develop a lymphoproliferative disorder during the accelerated phase of the disease. Controversy exists regarding the benign versus malignant nature of this cellular proliferation. For the first time, we have characterized the immunologic cell markers on the cellular infiltrate in a lymph node from a patient with CHS. The infiltrate was composed almost entirely of T cells, with histopathologic features consistent with a non-Hodgkin's T-cell lymphoma.     

Hematopoietic cell transplantation for Chediak-Higashi syndrome

We reviewed outcomes after allogeneic hematopoietic cell transplantation (HCT) in 35 children with Chediak-Higashi syndrome (CHS). Twenty-two patients had a history of the life-threatening accelerated phase of CHS before HCT and 11 were in accelerated phase at transplantation. Thirteen patients received their allograft from an human leukocyte antigen (HLA)-matched sibling, 10 from an alternative related donor and 12 from an unrelated donor. Eleven recipients of HLA-matched sibling donor, three recipients of alternative related donor and eight recipients of unrelated donor HCT are alive. With a median follow-up of 6.5 years, the 5-year probability of overall survival is 62%. Mortality was highest in those with accelerated phase disease at transplantation and after alternative related donor HCT. Only four of 11 patients with active disease at transplantation are alive. Seven recipients of alternative related donor HCT had active disease at transplantation and this may have influenced the poor outcome in this group. Although numbers are limited, HCT appears to be effective therapy for correcting and preventing hematologic and immunologic complications of CHS, and an unrelated donor may be a suitable alternative for patients without an HLA-matched sibling. Early referral and transplantation in remission after accelerated phase disease may improve disease-free survival.     

The Chediak-Higashi Syndrome

1. Two siblings with the Chediák-Higashi syndrome are reported. One, athree-year-old boy, died with malignant lymphoma; the other, a six-year-oldgirl, is alive and well.

2. Results of studies of white blood cell function and antibody productionwere normal, indicating that the increased susceptibility to infection of someChediák-Higashi syndrome patients is probably not attributable to abnormalleukocytes or to deficient antibody production.

3. Results of investigations of some aspects of tryptophan metabolism indicated an interesting, unique, and as yet unexplained absence of 5-hydroxytryptamine in the peripheral blood.

4. A review of the reported cases of Chediák-Higashi syndrome indicatesthat these patients have a striking predisposition to a peculiar type of malignant lymphoma.

5. An unusual perivascular infiltrate of histiocytes has been noted in postmortem sections of brain of patients with this anomaly. It is not clear whetherthis is a manifestation of the malignant lymphoma or a reflection of the basicdisease process.

Submitted on March 8, 1962 Accepted on May 17, 1962     

Biochemical studies on the leukocytes in Chediak-Higashi syndrome.

Blood leukocytes from a patient with Chediak-Higashi syndrome (CHS) were compared with normal cells for their capacity of extruding (exocytosis) the lysosomal enzyme myeloperoxidase during phagocytosis or after a treatment with the ionophore A23187 and Ca2+. A decreased rate and extent of exocytosis in phagocytizing CHS cells was observed also with the Ca2+ ionophore. This suggests that a defect in Ca2+ mobilization is not responsible for the impaired secretion of granule content. Isolated granules of CHS cells and of leukocytes were treated with the detergent Triton X-100. Since the solubilization of myeloperoxidase from the CHS granules was much lower than from the normal ones, we suggest that the former organelles have a more resistant membrane.     

Leukocyte-platelet interactions in a murine model of Chediak-Higashi syndrome

Chediak-Higashi (CH) syndrome, a genetic disease affecting man and other animals, is partially characterized by defective platelets that lack serotonin and dense bodies and by impaired leukocyte function where chemotaxis, degranulation, and bacterial killing are decreased. The effects of normal platelets containing serotonin and of reagent serotonin on the subnormal microbicidal activity of CH leukocytes were evaluated. The peripheral blood leukocytes of the beige mouse, an animal model with CH syndrome, were used with Staphylococcus aureus as the bacterial challenge. Addition of as few as two normal platelets/leukocyte resulted in normal levels of microbicidal activity of CH leukocytes. A similar normalization of leukocyte function was seen when 1-100-micrometer serotonin was added to the incubation mixture. Based on this work and work of others, a plausible explanation for these observations is that normal platelets interact with CH leukocytes, releasing serotonin, which results in reversal of the CH leukocyte defect in bacterial killing.     

A platelet abnormality in the Chediak-Higashi syndrome of man

Platelets from two probands homozygous for the Chediak-Higashi syndrome have approximately 10% of the normal number of serotonin-containing dense bodies as visualized electron microscopically in air-dried whole mounts. Since transport of serotonin across the platelet plasma membrane proceeds at a normal rate, and the few dense bodies present appear to store normal amounts of serotonin, the absence of dense bodies may account for the low platelet serotonin values found in these patients.     

Chediak-Higashi syndrome: studies in long-term bone marrow culture

The granulocyte defects of Chediak-Higashi syndrome (CHS) include neutropenia, characteristic giant lysosomal granule morphology, and functionally abnormal cell motility, degranulation, and bacterial killing. Findings of elevated levels of adenosine 3', 5' cyclic monophosphate nucleotide (cAMP) and of concanavalin A (Con A) capping have suggested a pathogenic role of a cyclic-nucleotide-related defect in microtubule polymerization, but not all patients exhibit these abnormalities. In order to test which defects derive from the cells' genetic program and which from the host environment, we examined granulocytes produced by CHS bone marrow progenitors in long-term in vitro bone marrow cultures. These cells exhibited the characteristic giant-granule morphology and defective cell motility of CHS. However, culture-derived CHS granulocytes had normal cAMP contents and normal spontaneous capping of Con A. Granulopoiesis diminished dramatically after five weeks in culture, with accompanying autophagocytosis by mononuclear phagocytes. In mixing experiments, the phenotype of the mature granulocytes corresponded to the genotype of the hematopoietic component of the culture rather than the stroma. These results indicate that the hallmark giant-granule morphology and cell motility defect of CHS are expressions of the genetic program of the hematopoietic cells. However the abnormalities in resting cyclic nucleotide levels and in Con-A capping may be secondary manifestations of the disease and are not essential to the pathogenesis of the chemotactic defect.