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

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 Overview
 Differential Diagnoses & Workup
 Treatment & Medication
 Follow-up

 References
 Keywords

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:
o Adenopathy
o Aphthae
 o Gingivitis
o Hyperhidrosis
o Miliaria
o Jaundice
o Severe and extensive pyoderma
o Recurrent sinopulmonary infections
o 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.
o Common physical findings include abnormal gait, clumsiness, seizures, paresthesia, mental
retardation, and peripheral neuropathy.
o In many persons with Chédiak-Higashi syndrome, neurologic changes appear in the
lymphoproliferative lymphomalike phase.
o 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.
o 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
 o 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.

http://emedicine.medscape.com/article/1114607-overview

What is Chediak-Higashi syndrome?

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 unable to fight off invaders such as viruses and
bacteria effectively. 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, and
few people with this condition live to adulthood.

Chediak-Higashi syndrome is also characterized by a condition called oculocutaneous albinism, which causes
abnormally light coloring (pigmentation) of the skin, hair, and eyes. Affected individuals typically have fair
skin and light-colored hair, often with a metallic sheen. Oculocutaneous albinism also causes vision problems
such as reduced sharpness; rapid, involuntary eye movements (nystagmus); and increased sensitivity to light
(photophobia).

Many people with Chediak-Higashi syndrome have problems with blood clotting (coagulation) that lead to easy
bruising and abnormal bleeding. In adulthood, this condition can also affect the nervous system, causing
weakness, clumsiness, difficulty with walking, and seizures.

Most children with Chediak-Higashi syndrome ultimately reach a stage of the disorder known as the accelerated
phase. This severe phase of the disease is thought to be triggered by a viral infection. In the accelerated phase,
defective white blood cells divide uncontrollably and invade many of the body's organs. The accelerated phase
is associated with fever, episodes of abnormal bleeding, overwhelming infections, and organ failure. These
medical problems are usually life-threatening in childhood.

A small percentage of people with Chediak-Higashi syndrome have a milder form of the condition that appears
later in life. People with the adult form of the disorder have less noticeable changes in pigmentation and are less
likely to have recurrent, severe infections. They do, however, have a significant risk of progressive neurological
problems such as tremors, difficulty with movement and balance (ataxia), reduced sensation and weakness in
the arms and legs (peripheral neuropathy), and a decline in intellectual functioning.

How common is Chediak-Higashi syndrome?

Chediak-Higashi syndrome is a rare genetic disorder. Although its exact incidence is unknown, fewer than 200
people with the condition have been reported worldwide.

What genes are related to Chediak-Higashi syndrome?

Chediak-Higashi syndrome is caused by mutations in the LYST gene. This gene provides instructions for
making a protein known as the lysosomal trafficking regulator. Researchers believe that this protein plays a role
in the transport (trafficking) of materials into structures called lysosomes. Lysosomes act as recycling centers
within cells. They use digestive enzymes to break down toxic substances, digest bacteria that invade the cell,
and recycle worn-out cell components. Although the lysosomal trafficking regulator protein is involved in the
normal function of lysosomes, its exact role is unknown.

Mutations in the LYST gene impair the normal function of the lysosomal trafficking regulator protein, which
disrupts the size, structure, and function of lysosomes and related structures in cells throughout the body. In
many cells, the lysosomes are abnormally large and interfere with normal cell functions. For example, enlarged
lysosomes in certain immune system cells prevent these cells from responding appropriately to bacteria and
other foreign invaders. As a result, the malfunctioning immune system cannot protect the body from infections.

In pigment cells called melanocytes, cellular structures called melanosomes (which are related to lysosomes)
are abnormally large. These structures produce and distribute a pigment called melanin, which is the substance
that gives skin, hair, and eyes their color. People with Chediak-Higashi syndrome have oculocutaneous albinism
because melanin is trapped within the giant melanosomes and is unable to contribute to skin, hair, and eye
pigmentation.

Researchers believe that abnormal lysosome-like structures inside blood cells called platelets underlie the
abnormal bruising and bleeding seen in people with Chediak-Higashi syndrome. Similarly, abnormal lysosomes
in nerve cells probably cause the neurological problems associated with this disease.

Read more about the LYST gene.

How do people inherit Chediak-Higashi syndrome?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell
have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the
mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about treatment for Chediak-Higashi

syndrome?
These resources address the management of Chediak-Higashi syndrome and may include treatment providers.

 Gene Review: Chediak-Higashi syndrome

 Genetic Alliance
 MedlinePlus Encyclopedia: Albinism
 MedlinePlus Encyclopedia: Chediak-Higashi syndrome
 MedlinePlus Encyclopedia: Immunodeficiency disorders

You might also find information on treatment of Chediak-Higashi syndrome in Educational resources and
Patient support.

Where can I find additional information about Chediak-Higashi

syndrome?
You may find the following resources about Chediak-Higashi syndrome helpful. These materials are written for
the general public.
  MedlinePlus - Health information (4 links)
 Additional NIH Resources - National Institutes of Health

National Institute of Child Health and Human Development: Primary Immunodeficiency

 Educational resources - Information pages (5 links)

 Patient support - For patients and families (6 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

 Gene Reviews - Clinical summary

 ClinicalTrials.gov - Linking patients to medical research
 PubMed - Recent literature
 OMIM - Genetic disorder catalog

What other names do people use for Chediak-Higashi syndrome?

 Chediak-Steinbrinck-Higashi syndrome
 CHS
 Oculocutaneous albinism with leukocyte defect

See How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about Chediak-Higashi

syndrome?
 See How can I find a genetics professional in my area? in the Handbook.
 Ask the Genetic and Rare Diseases Information Center .
 Submit your question to Ask the Geneticist .

Where can I find general information about genetic conditions?

The Handbook provides basic information about genetics in clear language.

 What does it mean if a disorder seems to run in my family?

 What are the different ways in which a genetic condition can be inherited?
 If a genetic disorder runs in my family, what are the chances that my children will have the condition?
 Why are some genetic conditions more common in particular ethnic groups?

These links provide additional genetics resources that may be useful.

 Genetics and health

 Resources for Patients and Families
 Resources for Health Professionals

http://ghr.nlm.nih.gov/condition=chediakhigashisyndrome