Chediak-Higashi Syndrome

Updated: May 25, 2018
  • Author: Roman J Nowicki, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Practice Essentials

Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive lysosomal disorder characterized by frequent infections, oculocutaneous albinism (OCA), bleeding diathesis, and progressive neurologic deterioration. In 85% of cases, CHS patients develop the accelerated phase characterized by pancytopenia, high fever, and lymphohistiocytic infiltration of liver, spleen, and lymph nodes. Treatment of accelerated-phase CHS is difficult and the prognosis is poor. All affected individuals, including adolescents and adults with atypical CHS and children with classic CHS who have successfully undergone allogenic hematopoietic stem cell transplantation (HSCT), develop neurologic findings during early adulthood.

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Background

Chédiak-Higashi syndrome (CHS) is a rare childhood autosomal recessive disorder that affects multiple systems of the body. Patients with CHS exhibit hypopigmentation of the skin, eyes, and hair; prolonged bleeding times; easy bruisability; recurrent infections; abnormal natural killer cell function; and peripheral neuropathy. Morbidity results from patients succumbing to frequent bacterial infections or to an accelerated-phase lymphoproliferation into the major organs of the body. The accelerated phase of CHS is termed hemophagocytic lymphohistiocytosis (HLH), and it develops in 50-85% of patients; it is fatal if not treated. Most patients who do not undergo bone marrow transplantation die of a lymphoproliferative syndrome, although some patients with CHS have a relatively milder clinical course of the disease. The adult form of CHS has a milder course, with no lymphohistiocytic infiltration. It is characterized by neurological manifestations such as polyneuropathy, parkinsonism, dementia, and ataxia. In young adults, a combination of these defects with oculocutaneous albinism or recurrent infections should bring CHS into consideration. Diagnosis is established by the presence of characteristic eosinophilic peroxidase-positive giant granules in leukocytes.

CHS was first described over 60 years ago by Beguez-Cesar (1943) in three siblings bearing the main clinical features of neutropenia and abnormal granules in leukocytes. Chédiak, a Cuban hematologist, reported another case in 1952, and, in 1954, Higashi, a Japanese pediatrician, described a series of cases characterized by misdistribution of myeloperoxidase in the neutrophilic granules of affected patients. [1, 2, 3]

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Pathophysiology

Chédiak-Higashi syndrome (CHS) is an autosomal recessive immunodeficiency disorder characterized by abnormal intracellular protein transport. The Chédiak-Higashi syndrome gene was characterized in 1996 as the LYST or CHS1 gene and is localized to bands 1q42-43. The CHS protein is expressed in the cytoplasm of cells of a variety of tissues and may represent an abnormality of organellar protein trafficking. [4]

The CHS gene affects the synthesis and/or maintenance of storage/secretory granules in various types of cells. Lysosomes of leukocytes and fibroblasts, dense bodies of platelets, azurophilic granules of neutrophils, and melanosomes of melanocytes are generally larger in size and irregular in morphology, indicating that a common pathway in the synthesis of organelles responsible for storage is affected in patients with CHS. In the early stages of neutrophil maturation, normal azurophil granules fuse to form megagranules, whereas, in the later stage (ie, during myelocyte stage), normal granules are formed. The mature neutrophils contain both populations. A similar phenomenon occurs in monocytes. The impaired function in the polymorphonuclear leukocytes may be related to abnormal microtubular assembly.

The disease is often fatal in childhood as a result of infection or an accelerated lymphomalike phase; therefore, few patients live to adulthood. In these patients, a progressive neurologic dysfunction may be the dominant feature. Neurologic involvement is variable but often includes peripheral neuropathy. The mechanism of peripheral neuropathy in CHS has not been completely elucidated. Both the axonal type and the demyelinating type of peripheral neuropathy associated with CHS have been reported.

Defective melanization of melanosomes occurs in oculocutaneous albinism associated with CHS. In melanocytes, autophagocytosis of melanosomes occurs.

Most patients also undergo an accelerated phase or accelerated reaction, which is a nonmalignant lymphohistiocytic lymphomalike infiltration of multiple organs that occurs in more than 80% of patients. This lymphomalike stage is precipitated by viruses, particularly by infection by the Epstein-Barr virus. It is associated with anemia, bleeding episodes, and overwhelming infections leading to death. Infections most commonly involve the skin, the lungs, and the respiratory tract and are usually due to Staphylococcus aureus, Streptococcus pyogenes, and Pneumococcus species.

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Etiology

Chédiak-Higashi syndrome (CHS) is inherited in an autosomal recessive pattern. Parental consanguinity is often reported. The genetic hallmark of CHS is mutations in the CHS1/LYST gene located on band 1q42-43. Mutations of this gene result in a defect in granule morphogenesis in multiple tissues. The gene encodes a protein called the lysosomal trafficking regulator, which regulates the synthesis, transport, and fusion of cytoplasmic vesicles. The abnormalities observed in these vesicles result in grossly enlarged and nonfunctional lysosomes, which are identified during cytology as giant, coalesced, azurophilic granules present mostly in granulocytes and monocytes, but also in fibroblasts, melanocytes, astrocytes, Schwann cells, and hematopoietic cells. These granules are specific to CHS, and their presence in granulocytes from peripheral blood and bone marrow is the basis of diagnosis. Clinical CHS phenotypes correlate with molecular genotypes. CHS patients with deletions in the LYST gene usually present with a fulminant accelerated phase early in life, whereas, those with missense mutations have a better prognosis, characterized by the absence of an accelerated phase and no neurological involvement. [3, 5, 6] Although defects in cytotoxic T-cell lytic secretory granule secretion and neutrophil phagocytosis are suggested to contribute to the immunodeficiency in CHS, the underlying molecular mechanisms are unknown.

Patients with CHS exhibit alterations in neutrophils. These alterations include neutropenia, which may be profound; decreased deformability, resulting in impaired chemotaxis; and delayed phagolysosomal fusion, resulting in impaired bactericidal activity.  

Clinical features resulting from LYST mutations in CHS have much in common with immunodeficiencies caused by Toll-like receptor (TLR) signaling defects, such as conditions caused by autosomal recessive mutations in TLR adapters, IRAK-4 and MyD88 (OMIM# 610799, 607676, 612260). Like mutations in LYST, reduced function of IRAK-4 and MyD88 results in selective impairment of cell responsiveness to TLRs other than TLR-3, and limited presence of interleukin 6 protein when exposed to TLR agonists. These conditions feature noninvasive pyogenic bacterial infections affecting skin and the upper respiratory tract, with occasional periodontal disease. However, patients with MyD-88 and IRAK-4 deficiency show no impaired defense against viral infections, owing to their normal functional natural killer cells and their retained ability to signal through TLR-3/-7/-9 and other non-TLR viral receptors. In contrast, patients with the classic CHS phenotype develop life-threatening hemophagocytic lymphohistiocytosis following infections with viruses, which may result from dysfunctional natural killer cells lacking cytotoxic activities as well as defective trafficking in TLR-3/-7/-9 signaling. Loss of expression or proper localization of TLR-2 and TLR-4, together with the lack of response of cell production of proinflammatory cytokines, leads to exacerbated bacterial burden and delayed clearance. [7]

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Epidemiology

Frequency

Chédiak-Higashi syndrome (CHS) is rare, with fewer than 500 cases published worldwide over the last 20 years. [8, 5] In a nationwide survey in Japan, 15 patients were diagnosed during a period of 11 years (2000-2010), indicating that one or two patients with CHS were diagnosed each year. [3] The exact prevalence is difficult to determine as some individuals are reported in the literature more than once. In addition, the phenotypic variability that has more recently been appreciated suggests that many mildly affected individuals may be unrecognized or unreported.

Race

CHS affects all races. Al-Khenaizan suggests that CHS may be underreported in persons of darker-skinned races. [9]

Age

Symptoms of CHS usually appear soon after birth or in children younger than 5 years. The mean age of onset is 5.85 years; however, most patients die before age 10 years. [3]

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Prognosis

Chédiak-Higashi syndrome (CHS) usually leads to early death from infection or, less commonly, hemorrhage. Intractable respiratory and cutaneous infections usually prove fatal before a child with CHS reaches age 10 years. Longer survival is possible, but the lymph nodes, spleen, and liver become enlarged and a malignant lymphoma develops. A few patients have survived to age 20 years.

In CHS patients who survive beyond childhood, neurological problems persist and/or increase in magnitude. Approximately 50-85% of patients develop a fatal accelerated phase, namely hemophagocytic lymphohistiocytosis (HLH), characterized by pancytopenia, high fever, hemophagocytosis, and marked infiltration of organs by lymphocytes, leading to multiorgan dysfunction. Treatment of HLH is difficult, and the prognosis is poor. CHS patients with deletions in the LYST gene usually present with a fulminant accelerated phase early in life, whereas those with missense mutations have a better prognosis, characterized by the absence of HLH and no neurological involvement. [3]

Price et al report a patient with CHS whose pregnancy, labor, and delivery were not affected. The infant and placenta were normal. [10]

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Patient Education

Measures to prevent routine infections include education of the child and caregivers regarding effective hygiene and meticulous attention to oral and dental care. Skin protection and sunglasses should be used to prevent sunburn and to protect sensitive eyes from ultraviolet light. While these patients can safely receive all killed or inactivated vaccines, live vaccines are contraindicated. [11]

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