Chediak-Higashi syndrome is a condition that affects many parts of the body, particularly the immune system. This disease damages immune system cells, leaving them less able to fight off invaders such as viruses and bacteria. As a result, most people with Chediak-Higashi syndrome have repeated and persistent infections starting in infancy or early childhood. These infections tend to be very serious or life-threatening. Chediak-Higashi syndrome is also characterized by a condition called oculocutaneous albinism , which causes abnormally light coloring pigmentation of the skin, hair, and eyes.
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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. 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. Chediak—Higashi syndrome CHS is a rare autosomal-recessive disorder, characterized by oculocutaneous albinism, recurrent infections, microscopic finding of large granules in hematopoietic and other cells, bleeding diathesis and neurologic abnormalities.
The accelerated phase of CHS is characterized by lymphocyte and macrophage activation with diffuse lymphohistiocytic infiltration of liver, spleen, lymph nodes, central nervous system and bone marrow. This is the most frequent cause of mortality in patients with CHS. Published reports suggest that allogeneic hematopoietic cell transplantation HCT may be effective therapy for the accelerated phase of CHS; however, these studies are limited by small numbers of patients.
Additionally, most reports describe outcomes only after human leukocyte antigen HLA -matched sibling transplants. Participating centers register and provide basic information on all consecutive transplantations. Detailed demographic, disease and transplant characteristics and outcome data are collected on a sample of registered patients including virtually all adult unrelated donor transplants in the US.
Patients are followed longitudinally. Computerized error checks, physician review of submitted data, and on-site audits of participating centers ensure data quality. The diagnosis of CHS was based on the constellation of clinical findings of oculocutaneous albinism, giant leukocyte granules, neutropenia, recurrent infections and neurological dysfunction with or without abnormal natural killer cell function.
The cases in this review were ascertained before publication of the genetic defect responsible for CHS. Diagnosis of acute and chronic graft-versus-host disease GVHD was based on local institutional criteria with overall grade assigned retrospectively by the CIBMTR based on stage of involvement reported for each individual organ.
Surviving patients were censored at last follow-up. The probability of overall survival was calculated using the Kaplan—Meier estimator and the confidence interval, calculated with the use of a log transformation. Patient and transplant characteristics are shown in Table 1. Median age at transplantation was 5 range, 1—19 years. Twenty-two patients had a history life-threatening accelerated phase of CHS before transplantation and of these, 11 were in accelerated phase at transplantation.
Ten patients were transplanted before development of symptoms or signs of accelerated phase and these data were not available for three patients. Thirteen patients received allografts from an HLA-identical sibling.
Among recipients of alternative related donor transplants, three received allografts from an HLA-identical parent, three from a one-antigen mismatched parent or sibling, and the remaining four, from haplo-identical parents.
Five received allografts from an HLA-identical unrelated donor and the remaining seven, from one-antigen mismatched donors HLA A and B at the antigen level by intermediate resolution and allele-level DRB1. All received bone marrow grafts except 1 who received peripheral blood.
The most common preparative regimen utilized the combination of oral busulfan and intravenous cyclophosphamide. The median follow-up of the study population is 80 months range 14— The median time to neutrophil and platelet recovery was 18 range, 7—35 days and 32 15— days, respectively.
Two patients failed to achieve hematopoietic recovery; both received bone marrow grafts from alternative related donors. One patient died before second transplantation and the other underwent a second transplant, achieved hematopoietic recovery but died from persistent disease day 47 after second transplant.
Both patients were in accelerated phase at transplantation. Thirty-three patients were evaluable for acute GVHD. Table 2 shows survival and disease status of patients after transplantation by disease status pre-transplant and donor type. One patient is alive, 10 years after HCT with recurrent disease presence of leukocyte granules 7. One of the patients in remission from CHS developed myelodysplastic syndrome. She received a second allogeneic transplant 4 years after the first transplant and remains free of both diseases, 9 years from the first transplant and 5 years from the second.
Data on donor—recipient chimerism were available for 13 of 22 surviving patients. Overall, 13 patients died after HCT from either persistent disease or a transplant-related complication. Nine patients died within days of transplantation early mortality. Of these, six received allografts from an alternative related donor, one from an HLA-matched sibling, and the remaining two, from an unrelated donor.
We describe outcomes after allogeneic transplantation for 35 patients with CHS. In general, these data suggest allogeneic transplantation from an HLA-matched sibling or an unrelated donor may be an effective treatment for hematologic and immunologic correction of CHS, and a history of symptoms of accelerated phase does not preclude a successful outcome. Survival after alternative related donor HCT was poor. This may be explained by the presence of symptoms of accelerated phase at transplantation in most of these recipients.
The absence of symptoms of accelerated phase at transplant appears to predict fewer recurrences. A recent retrospective review of transplantation for CHS indicates a high rate of neurocognitive sequelae in patients who have survived into their third decade after HCT.
It is not known to what extent the experience of the accelerated phase before HCT contributes to later neurocognitive deficits, and, conversely, whether HCT at a younger age could reduce or delay later neurologic deterioration. The occurrence of mild central or peripheral neuropathy in this series cannot be excluded, despite reports of excellent performance scores in the survivors and is a limitation of any registry-based study. Further, ours is a relatively young cohort, the median age of surviving patients is 12 years and the two oldest patients are 21 years of age.
Importantly, this patient has maintained a low level of donor chimerism for almost 10 years and without symptoms of the accelerated phase of this disease.
Early mortality after transplantation was high with most deaths nine of 13 occurring within days after transplantation. Persistent disease was the most common cause of early mortality and occurred in patients transplanted in accelerated phase.
Although GVHD was more frequent after unrelated donor transplantation this did not affect mortality. Although the study period spans over two decades, we did not observe differences in overall survival by year of transplantation.
Our inability to detect differences in survival outcomes may be explained by the small cohort and over half of the deaths were due to recurrent disease occurring in patients with active disease at transplantation. The current report has several limitations: small sample size, lack of detailed information on immune reconstitution and post-transplant extrahematopoietic manifestations such as neurological outcomes.
Nevertheless, the data suggest HLA-matched and unrelated donor HCT with a myeloablative preparatory regimen offer a cure for an otherwise lethal disease. The poor outcome associated with accelerated phase disease at transplantation warrant confirmation in a larger study.
Future studies of HCT treatment for CHS, as with other hemophagocytic disorders, should build in longitudinal neurocognitive monitoring as well as examine the role of alternative related donor HCT in patients without active disease at transplantation.
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Genetic testing for LYST mutations can confirm the diagnosis. Treatment includes prophylactic antibiotics, interferon gamma, and sometimes corticosteroids. Sometimes stem cell transplantation is curative. Giant lysosomal granules develop in neutrophils and other cells eg, melanocytes, neural Schwann cells.
Hematopoietic cell transplantation for Chediak–Higashi syndrome
The features of Chediak-Higashi syndrome are decreased pigmentation of hair and eyes partial albinism , photophobia, nystagmus, large eosinophilic, peroxidase-positive inclusion bodies in the myeloblasts and promyelocytes of the bone marrow, neutropenia, abnormal susceptibility to infection, and peculiar malignant lymphoma. Death often occurs before the age of 7 years. See Hermansky-Pudlak syndrome , a similar but distinct entity. Kritzler et al.