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Chediak-Higashi Syndrome

Author: Roman Janusz Nowicki, MD, PhD, Associate Professor, Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Poland
Contributor Information and Disclosures

Updated: May 29, 2009

Introduction

Background

Chédiak-Higashi syndrome (CHS) was described by Beguez Cesar in 1943, Steinbrinck in 1948, Chédiak in 1952, and Higashi in 1954. Chédiak-Higashi syndrome is a rare childhood autosomal recessive disorder that affects multiple systems of the body. Patients with Chédiak-Higashi syndrome 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. Most patients who do not undergo bone marrow transplantation die of a lymphoproliferative syndrome, although some patients with Chédiak-Higashi syndrome have a relatively milder clinical course of the disease.^1,2,3

Pathophysiology

Chédiak-Higashi syndrome 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.^4,5

The Chédiak-Higashi syndrome 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 Chédiak-Higashi syndrome. 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 Chédiak-Higashi syndrome has not been completely elucidated. Both the axonal type and the demyelinating type of peripheral neuropathy associated with Chédiak-Higashi syndrome have been reported.

Defective melanization of melanosomes occurs in oculocutaneous albinism associated with Chédiak-Higashi syndrome. 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.

Frequency

United States

Chédiak-Higashi syndrome is rare.

International

Chédiak-Higashi syndrome is rare.⁶

Mortality/Morbidity

Death often occurs in the first decade as a result of infection, bleeding, or development of the accelerated lymphomalike phase, but survival into the second and third decades has been reported.

Race

Chédiak-Higashi syndrome affects all races. Al-Khenaizan suggests that Chédiak-Higashi syndrome may be underreported in persons of darker-skinned races.⁷

Age

Symptoms of Chédiak-Higashi syndrome usually appear soon after birth or in children younger than 5 years.

Clinical

History

• Infants born with Chédiak-Higashi syndrome have nonpigmented skin (similar to albinos but in patchy distribution), blonde hair, and blue eyes.
• Signs and symptoms that usually appear soon after birth include the following:
  • Adenopathy
  • Aphthae
  • Gingivitis
  • Hyperhidrosis
  • Miliaria
  • Jaundice
  • Severe and extensive pyoderma
  • Recurrent sinopulmonary infections
  • Fever unrelated to recognizable infection

Physical

• Oculocutaneous albinism is prominent, and, together with photophobia and silvery hair, it is helpful in early diagnosis. The skin is fair, the retinae are pale, and the irides are translucent. The hair is light blonde or silvery gray and may be sparse.
• In Chédiak-Higashi syndrome, patients are affected by frequent and severe pyogenic infections secondary to abnormal functioning of polymorphonuclear leukocytes, which is associated with albinism and a bleeding tendency.
• Recurrent skin infections occur frequently and range from superficial pyoderma to deep subcutaneous abscesses and ulcers that heal slowly and result in atrophic scars. S aureus is the most common causative agent. Deep ulcerations resembling pyoderma gangrenosum have also been described.
• The complete syndrome includes oculocutaneous albinism with photophobia, neurologic features, recurrent infections, and enterocolitis.
• Lymphadenopathy and hepatosplenomegaly are variable.
• Severe gingivitis and oral mucosal ulceration are common. Oral ulcerations and periodontal disease also occur.^8,9
• Chédiak-Higashi syndrome may present with neurologic dysfunction and should be considered in the differential diagnosis of children and young adults first seen with symptoms of spinocerebellar degeneration or movement disorders.
  • Common physical findings include abnormal gait, clumsiness, seizures, paresthesia, mental retardation, and peripheral neuropathy.
  • In many persons with Chédiak-Higashi syndrome, neurologic changes appear in the lymphoproliferative lymphomalike phase.
  • Progressive neurologic deterioration is common in patients who survive early childhood. Generally, such patients eventually enter an accelerated phase of the disease with widespread infiltration by lymphocytes and histiocytes, causing rapid enlargement of the liver, the spleen, and the lymph nodes, and with concurrent severe leukopenia and thrombocytopenia, resulting in death from infection or bleeding.
• The adult form of Chédiak-Higashi syndrome manifests during late childhood to early adulthood and is marked by various neurologic sequelae, including parkinsonism, dementia, spinocerebellar degeneration, and peripheral neuropathy.

Causes

• The underlying defect in Chédiak-Higashi syndrome remains elusive, but the disorder can be considered a model for defects in vesicle formation, fusion, or trafficking.
• Chédiak-Higashi syndrome is inherited in an autosomal recessive pattern. Parental consanguinity is often reported.
  • The Chédiak-Higashi syndrome locus on human chromosome 1 encodes a lysosomal trafficking regulator, formerly termed LYST (currently termed CHS1), which is defective in patients with CHS.^10,11
  • Patients with Chédiak-Higashi syndrome 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.

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