CHS is a rare AR, multisystem disease resulting from widespread defects in granule morphogenesis, with giant lysosomes in leukocytes and other cells throughout the body. The disorder is characterized by partial oculocutaneous albinism, frequent (and sometimes fatal) bacterial infections, a mild bleeding diathesis, and peripheral as well as cranial neuropathies associated with defects at the optic chiasm. Those who survive the recurrent infections develop an “accelerated phase” of the disease; one of the hereditary forms of HLH, which, if untreated, is eventually fatal because of a profound pancytopenia that develops.
The most dramatic granule defects are manifested in the various blood cells. Neutrophils contain a highly inhomogeneous population of huge granules derived from coalescence of azurophilic (primary) gran ules. The giant granules are often more prominent in the BM than in the peripheral blood because many of the abnormal myeloid precursors are apparently destroyed before they leave the BM, resulting in moderate neutropenia with absolute neutrophil counts ranging from 500 to 2000 cells/mm3. Granules are also markedly deficient in antimicrobial gran ule enzymes such as cathepsin G and elastase, consistent with a defect in granule morphogenesis. Degranulation is delayed and incomplete in Chédiak-Higashi neutrophils, resulting in impaired bacterial killing. Chemotaxis is also defective, perhaps related to poor deformability because of the presence of the large granules. Monocytes and macro phages exhibit similar giant cytoplasmic granules, with resultant abnormalities in their phagocytic functions. Giant granules are also seen in lymphocytes and are associated with defects in cytotoxic T-lymphocyte and NK cell function. Eosinophils contain large granules, the functional significance of which is not known. Platelets in this disorder have a storage pool deficiency of adenosine diphosphate and serotonin, presumably caused by the abnormal granule morphogenesis in megakaryocytes, leading to a defect in platelet aggregation.
Abnormal giant granules are also present in other cell types. These include melanocytes, which contain abnormal melanosomes that cannot transfer their contents to adjacent keratinocytes; Schwann cells; astrocytes; and certain cells in the liver, spleen, pancreas, gastric mucosa, kidney, adrenal gland, and pituitary gland.
Molecular Genetics
A gene termed CHS1 or LYST (for its presumed function as a lysosomal trafficking regulatory protein) is affected in the majority of CHS cases and is on the long arm of chromosome 1. The encoded protein is very large (3801 amino acids); its specific function is unknown, but recent studies suggest that it may inhibit lysosome fusion with other intracellular membrane vesicles. A variety of frameshift and nonsense mutations that predict synthesis of truncated forms of the protein have been identified in most, but not all, CHS patients studied to date. There is no correlation between the length of the truncated CHS1 protein and the severity of the disease. Disorders similar to human CHS have also been described in many mammalian species, including Aleutian mink, beige mice, blue foxes, cats, killer whales, and Hereford cattle. Identification of the human CHS1 gene was aided by positional cloning of the mouse lyst homolog affected in beige mice.
Clinical Manifestations
The key features of CHS are summarized in Table 1. The dis ease usually presents in infancy or early childhood, with infections involving the lungs, skin, and mucous membranes being most commonly encountered. Dental caries and periodontal disease are also common. The most frequent offending organism is S. aureus. Gram-negative bacteria, Aspergillus spp., and Candida spp. also are responsible for many infections. Platelet granule defects result in easy bruising and epistaxis. There is partial oculocutaneous albinism and photosensitivity. Patients may have a white forelock or an ashen or grayish silver sheen to the hair, which can vary from blond to dark brown. In younger patients, there may be a cartwheel distribution of pigment in the iris and an abnormal red reflex. Neurologic manifestations include peripheral or cranial neuropathies, gait abnormalities, muscle weakness, sensory loss, seizures, or spinocerebellar degeneration. Neurologic symptoms worsen with age.
Table1. Summary of Chédiak-Higashi Syndrome
Approximately 85% of children surviving into the second decade of life develop an accelerated phase of the disease, with fever, lymph adenopathy, and progressive pancytopenia, that is now recognized to be a genetic form of HLH caused by impaired lymphocyte and NK cell function. The development of HLH can sometimes be precipitated by Epstein-Barr virus infection. A reactive-appearing lymphohistiocytic proliferation occurs in the liver, spleen, lymph nodes, and BM, and the prognosis is uniformly fatal unless patients undergo BMT.
Diagnosis
The diagnosis of CHS is made on the basis of the giant peroxidase positive lysosomal granules in the peripheral blood granulocytes or in BM myeloid cells. Identification of large, acid phosphatase–positive lysosomes in amniocytes and chorionic villus cells has been used to diagnose CHS prenatally. Other clinical features characteristic of CHS can support the diagnosis, including mild oculocutaneous albinism; silvery hair, in which microscopic examination reveals giant melanin granules; and a bleeding diathesis. The development of HLH is characterized by diffuse infiltrates of lymphohistiocytic cells seen on biopsy and by pancytopenia. Occasionally, giant granules that resemble those of CHS can be seen in both acute and chronic myelogenous leukemias.
Therapy
The treatment for the stable phase of CHS is similar to that for other neutrophil disorders. Prophylactic antibiotics such as TMP-SMX appear to be beneficial. Parenteral antibiotics are indicated for acute infections, and responses are often slow. Treatment with high-dose ascorbic acid (200 mg/day for infants; 6 g/day for adults) has been found to improve the clinical status of some patients. Although there is some controversy regarding the efficacy of ascorbic acid, given the safety of this medication, it seems prudent to administer it to all patients. The treatment of HLH (accelerated phase) includes combi nations of drugs that suppress the function of activated macrophages and T cells followed by allogeneic HSCT. Indeed, transplantation is ideally performed before or at the beginning of the accelerated phase. Note that transplantation does not prevent the progressive neuropathy of CHS.
