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1018 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1019

ABNORMALITIES OF THE CELLULAR The CHS blood cell membranes are more fluid than cells of nor-
RESPONSES AS THE RESULTS OF DEFECTS IN mal individuals, 281,294 and the altered membrane structure could lead
to defective regulation of membrane activation, as well as promoting
CYTOPLASMIC MOVEMENT fusion of neutrophil azurophilic granules with each other. Conceiv-
Degranulation Abnormalities ably, changes in membrane fluidity may affect cell function by reducing
Chédiak-Higashi Syndrome expression of Mac-1 (CD11b/CD18). The altered membrane fluidity
Definition and History This rare autosomal recessive disease was could result in elevated levels of intracellular cyclic adenosine mono-
initially recognized as one in which neutrophils, monocytes, and lym- phosphate, which appears in this disorder and is reflected in the reduced
phocytes contained giant cytoplasmic granules. Chédiak-Higashi chemotactic responses. 281
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syndrome (CHS) is now recognized as a disorder of generalized cellu- The gene that is mutated in CHS is CHS1 (syn. LYST) found on
lar dysfunction characterized by increased fusion of cytoplasmic gran- chromosome 1q. Its size indicates a protein of more than 400 kDa is
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ules. Pigmentary dilution affecting the hair, skin, and ocular fundi encoded. During early development, granule biogenesis is normal;
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results from pathologic aggregation of melanosomes and is associated with perforin in NK cells and granule enzymes in myeloid cells synthe-
with failure of decussation of the optic and auditory nerves sized and routed correctly to the granules. However, once formed the
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(Table 66–2). Patients with this syndrome exhibit an increased sus- granules fuse to form giant organelles. Several studies led to the sug-
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ceptibility to infection, which begins in infancy. Infections most com- gestion that the enlarged lysosomes found in CHS cells are the results
monly involve the skin and respiratory systems. The susceptibility to of abnormalities in membrane fusion, which could occur during the
infection can be explained in part through defects in neutrophil chemo- biogenesis of the lysosomes. It has been hypothesized that this CHS1
taxis, degranulation, and bactericidal activity. The presence of giant protein interacts with attachment proteins on lysosomes (v-SNAREs)
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granules in the neutrophil interferes with their ability to traverse narrow and that this mutated protein leads to indiscriminate interactions with
passages between endothelial cells. Other features of the disease include v-SNARE to yield uncontrolled fusion of lysosomes with each other. 297
neutropenia, thrombocytopathy, natural killer cell abnormalities, 281,285 Clinical Features Characteristically patients with CHS have light
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and peripheral neuropathies. Similar genetic syndromes have been skin and silvery hair. They frequently complain of solar sensitivity and
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described in mice, mink, cats, rats, cattle, and killer whales. 286 photophobia. Other eye findings can include horizontal or rotatory nys-
Although CHS carries the names of Moises Chédiak and Ototaka tagmus. Infections are common and involve the mucous membranes,
Higashi, the disorder was first described by Béguez César, a Cuban pedi- skin, and respiratory tract. They are susceptible to both Gram-positive
atrician in 1943. Initially characterized by neutropenia and abnormal and Gram-negative bacteria, as well as fungi, with Staphylococcus aureus
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granules in leukocytes, the syndrome was further delineated in 1948 by being the most common infecting organism. Attenuated NK function
Steinbrinck’s description of a second case. In 1952, Chédiak reported probably contributes to the increased susceptibility to infection as well.
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the hematologic characteristics of the disorder, and in 1953 Higashi Neurologic signs and symptoms are variable in CHS and may include a
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emphasized the giant peroxidase-containing granules within patients’ peripheral and cranial neuropathy, autonomic dysfunction, weakness,
neutrophils. Besides the susceptibility to infections, patients often suf- and sensory deficit; and ataxia may also be a prominent feature.
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fer a fatal lymphohistiocytic infiltration known as the accelerated phase Patients with CHS have prolonged bleeding times with normal
occurring months from birth to several years later. 290 platelet counts, resulting from impaired platelet aggregation associated
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Epidemiology By 2008, 300 cases worldwide had been described, with a deficiency of the storage pools of ADP and serotonin. Elec-
with concentrations in the United States, Japan, northern Europe, and tron micrographs reveal normal numbers of α granules in platelets, but
Latin America. Patients of African descent have also been described. decreased numbers of platelet dense bodies. 286
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Etiology and Pathogenesis CHS is caused by a fundamental defect The accelerated phase of CHS is characterized by lymphocytic
in granule morphogenesis that results in abnormally large granules in proliferation in the liver, spleen, marrow, and central nervous system.
multiple tissues. 282,291 Giant granules are seen in Schwann cells, leuko- The accelerated phase may occur at any age and is now recognized as
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cytes, and macrophages of the liver and spleen, and certain cells of the a genetic form of hemophagocytic lymphohistiocytosis (HLH). Typ-
pancreas, gastric mucosa, kidney, adrenal gland, and pituitary gland. ically, the patient develops hepatosplenomegaly and high fever in the
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Giant melanosomes form and prevent the even distribution of melanin, absence of bacterial sepsis. The pancytopenia becomes worse at this
which results in pigmentary dilution of the hair, skin, iris, and optic fun- stage, producing hemorrhage and an increased susceptibility to infec-
dus. Although the giant lysosomes are the primary morphologic feature tion. The onset of the accelerated phase may be related to the inability
of the disorder, only cells relying on the secretion by these lysosomes of these patients to contain and control the Epstein-Barr virus (EBV)
manifest pathologic defects. In the early stages of myelopoiesis some leading to HLH (Chap. 70). The lymphocyte expansion into the tissue is
of the normal-size azurophil granules coalesce to form giant granules associated with excessive cytokine production and massive tissue necro-
that result in large secondary lysosomes that contain reduced content sis and organ failure leading to the propensity to recurrent bacterial and
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of hydrolytic enzymes, including proteinases, elastase, and cathepsin viral infections, fever, and prostration usually resulting in death. At
G. Many of the myeloid precursors die in the marrow, resulting in autopsy, the lymphohistiocytic infiltrates in the liver, spleen, and lymph
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a moderate neutropenia, with white cell counts of about 2.5 × 10 /L nodes are extensive, but not neoplastic by histopathologic criteria. 298
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and absolute neutrophil counts ranging from 0.5 to 2.0 × 10 /L. The Laboratory Features The laboratory test diagnostic for CHS is
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marrow itself appears normal to hypercellular. In spite of the normal examination of granular cell morphology. The pathognomonic feature
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ingestion of particles and active oxygen metabolism, these neutrophils is giant peroxidase-positive granules that can be seen in neutrophils.
kill microorganisms relatively slowly. This delay reflects a slow and A microscopic examination of hair shafts reveal large, speckled pigment
inconsistent delivery of diluted amounts of hydrolytic enzymes from clumps as opposed to the normal pattern of finally divided pigment of
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the giant granules into the phagosomes, which may predispose the host melanin spread along the length of the shaft. Similar giant granules
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to bacterial infection. 291,292 In this syndrome, monocytes have the same can occasionally be present in CML and acute myelocytic leukemia.
functional derangements as neutrophils, and in an analogous fashion Molecular diagnosis of CHS remains difficult and is not commercially
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perforin-deficient natural killer (NK) cells show profoundly impaired available. Heterozygotes for CHS are considered completely normal and
cytotoxic activity and are unable to kill many targets. 293 cannot be detected clinically or biochemically.

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