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Chediak-Higashi Syndrome
Last Updated: June 2, 2003
Synonyms and related keywords: Bequez Cesar syndrome, Chédiak-Steinbrinck-Higashi syndrome, CHS, immunodeficiency disorder, abnormal
intracellular protein transport, LYST gene, CHS1 gene
AUTHOR INFORMATION
Section 1 of 9
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Author: Roman Nowicki, MD, PhD, Head of Mycology Laboratory, Associate Professor, Department of Dermatology, Venereology & Allergology,
Medical University of Gdansk, Poland
Coauthor(s): Henryk Szarmach, MD, Emeritus Chairman, Professor, Department of Dermatology, Medical University of Gdansk,
Poland
Roman Nowicki, MD, PhD, is a member of the following medical societies: American Academy of Dermatology, European Academy of Dermatology
and Venereology, European Society for Dermatological Research, and Polish Association of Dermatology
Editor(s): Jacek C Szepietowski, MD, PhD, Professor and Vice-Head, Department of Dermatology, Venereology and Allergology, University of
Medicine at Wroclaw, Poland; Michael J Wells, MD, Staff Physician, Department of Dermatology, Texas Tech University Health Sciences Center;
Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and
Community Health, UMDNJ-New Jersey Medical School; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown
University; and William D James, MD, Program Director, Vice-Chair, Albert M Kligman Professor, Department of Dermatology, University of
Pennsylvania School of Medicine
Disclosure
INTRODUCTION
Section 2 of 9
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Background: Chédiak-Higashi syndrome (CHS) was described by Beguez Cesar in 1943, Steinbrinck in 1948, Chédiak in 1952,
and Higashi in 1954. CHS is a rare childhood autosomal recessive disorder characterized by immune deficiency; partial
oculocutaneous albinism; easy bruisability and bleeding as a result of deficient platelet dense bodies; recurrent infections with
neutropenia, impaired chemotaxis, and bactericidal activity; and abnormal natural killer (NK) cell function.
Pathophysiology: CHS is an autosomal recessive immunodeficiency disorder characterized by abnormal intracellular protein
transport. The CHS 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.
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.
Frequency:

In the US: CHS is rare.

Internationally: CHS is rare.
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: CHS affects all races.
Age: Symptoms of CHS usually appear soon after birth or in children younger than 5 years.
CLINICAL
Section 3 of 9
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History:

Infants born with CHS 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:
Physical:
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

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 CHS, 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.

CHS 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 CHS, 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 CHS 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 CHS remains elusive, but the disorder can be considered a model for defects in vesicle formation, fusion, or
trafficking.

CHS is inherited in an autosomal recessive pattern. Parental consanguinity is often reported.
o
The CHS locus on human chromosome 1 encodes a lysosomal trafficking regulator, formerly termed LYST (currently termed CHS1),
which is defective in patients with CHS.
o
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.
DIFFERENTIALS
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Bacterial Infections of the Mouth Including Gingivitis and Periodontitis
Cutaneous T-Cell Lymphoma
Griscelli Syndrome
Pyoderma Gangrenosum
Section 4 of 9
Other Problems to be Considered:
Postinflammatory hypopigmentation
Poliosis
WORKUP
Section 5 of 9
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Lab Studies:

Routine blood smear: Diagnosis of CHS is made by recognition of the characteristic giant granules in neutrophils, eosinophils, and granulocytes
by using light microscopy of a routine blood smear. Laboratory findings include neutropenia and hypergammaglobulinemia.

Bone marrow smears: Bone marrow smears reveal giant inclusion bodies in leukocyte precursor cells. The granules are peroxidase positive
and contain lysosomal enzymes, suggesting that they are giant lysosomes, or in the case of melanocytes, that they are giant melanosomes.
The diagnostic hallmark is the occurrence of giant inclusion bodies in the peripheral leukocytes and their bone marrow precursors.

Fluorescence cytometric analysis: In addition to the characteristic leukocytic dysfunctions, fluorescence cytometric analysis of cellular
granularity and surface molecules offer useful diagnostic information.
Imaging Studies:

Oral radiographs reveal extensive loss of alveolar bone, leading to tooth exfoliation in most cases.
Other Tests:

Light and electron microscopic examinations of biopsy specimens of periodontal tissues reveal massive bacterial invasion of epithelial tissue,
epithelial cells, and connective tissue.

Ultrastructural observations of periodontal polymorphonuclear leukocytes reveal defective granulation, with abnormal granules not discharging
their lysosomal content against the engulfed bacteria. Viable dividing bacteria are found in the cytoplasm.

Prenatal diagnosis can be made by examination of hair from fetal scalp biopsy specimens and of leukocytes from fetal blood samples.
Histologic Findings: A skin biopsy specimen usually appears entirely normal but may show melanin macroglobules and perhaps sparse dermal
melanin. Ultrastructural examination reveals large abnormal type stage IV melanosomes that are transferred to keratinocytes with difficulty and are
degraded rapidly.
TREATMENT
Section 6 of 9
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Medical Care:

Administration of acyclovir; high-dose intravenous gamma globulin; and microtubulytic drugs, such as vincristine, vinblastine, and colchicine, is
effective in the management of the accelerated phase.

Ascorbic acid corrects the microtubular defects in vitro but has no clinically ameliorative effect.

Some authors have demonstrated that interferon partially restores the function of NK cells.
Surgical Care:

Bone marrow transplantation (BMT) is the treatment of choice. BMT corrects the immunologic status but does not affect pigment dilution. BMT
is indicated before the accelerated phase of the disease develops. Without BMT, children with CHS usually die before age 10 years.

Debridement and drainage of deep abscesses may be performed.
Consultations: A physician who specializes in hematologic disorders should be involved in the care of these patients.

Neurologic consultation: Neurologic involvement, such as loss of deep tendon reflexes due to peripheral neuropathy, cerebellar ataxia,
intellectual impairment, nystagmus, and the Babinski sign, is often observed in the course of CHS.

Hematologic consultation: The accelerated phase resembles lymphoma. Allogenic bone marrow or stem cell transplantation is the treatment of
choice to correct the hematologic manifestation of the disease.
Activity: Some activity limitations are advised because of the bruising problem and the bleeding tendency.
MEDICATION
Section 7 of 9
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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Antiviral agents -- These agents inhibit DNA synthesis and viral replication. Nucleoside analogs are initially
phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit HSV polymerase
with 30-50 times the potency of human alpha-DNA polymerase.
Drug Name
Acyclovir (Zovirax) -- Inhibits activity of both HSV-1 and HSV-2. Has affinity for
viral thymidine kinase and once phosphorylated causes DNA chain
termination when acted on by DNA polymerase.
Adult Dose
30 mg/kg IV tid for 2-3 wk
Pediatric Dose
10 mg/kg IV tid for 2-3 wk
Contraindications
Documented hypersensitivity
Interactions
Concomitant use of probenecid or zidovudine prolongs half-life and increases
CNS toxicity
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Caution in renal failure or when using nephrotoxic drugs; maintain adequate
hydration
Drug Category: Immune modulators -- These agents inhibit key steps in immune reactions.
Drug Name
Immune globulin intravenous (Sandoglobulin, Gammagard, Gamimune,
Gammar-P) -- Neutralize circulating myelin antibodies through anti-idiotypic
antibodies; down-regulates proinflammatory cytokines, including INF-gamma;
blocks Fc receptors on macrophages; suppresses inducer T and B cells and
augments suppressor T cells; blocks complement cascade; promotes
remyelination; may increase CSF IgG (10%).
Adult Dose
100-200 mg/kg IV q4wk; not to exceed 1 g/kg/dose
Pediatric Dose
Contraindications
Interactions
Administer as in adults
Documented hypersensitivity; IgA deficiency; anti–IgE/IgG antibodies
Increases toxicity of live virus vaccine (MMR); do not administer within 3 mo of
vaccine
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Check serum IgA before IVIG (use an IgA-depleted product, eg, Gammagard
S/D); infusions may increase serum viscosity and thromboembolic events;
infusions may increase risk of migraine attacks, aseptic meningitis (10%),
urticaria, pruritus, or petechiae (2-30 d postinfusion); increases risk of renal
tubular necrosis in elderly patients and in patients with diabetes, volume
depletion, and preexisting kidney disease; laboratory result changes
associated with infusions include elevated antiviral or antibacterial antibody
titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia
Drug Name
Interferon alfa 2a and 2b (Roferon-A, Intron A) -- Protein product
manufactured by recombinant DNA technology. Mechanism of antitumor
activity is not clearly understood; however, direct antiproliferative effects
against malignant cells and modulation of host immune response may play
important roles.
Adult Dose
9 mcg SC 3 times/wk for 24 wk
Pediatric Dose
Contraindications
Not established
Documented hypersensitivity
Interactions
Theophylline may increase interferon alpha toxicity; cimetidine may increase
antitumor effects; zidovudine and vinblastine may increase toxicity of
interferon alpha
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Caution in brain metastases, cardiac disease, autoimmune disease,
immunosuppressed transplant patients, severe hepatic or renal
insufficiencies, seizure disorders, depression, multiple sclerosis, or
compromised CNS; may cause spastic diplegia in children; may cause GI
tract hemorrhage, leukopenia, hyperglycemia, and elevate hepatic
transaminase levels; may potentiate risk of renal failure
Drug Category: Antineoplastic agents -- These agents inhibit cell growth and proliferation. Useful in the accelerated phase of
the disease.
Drug Name
Vincristine (Vincasar PFS, Oncovin) -- Mechanism of action is uncertain. May
involve a decrease in reticuloendothelial cell function or an increase in platelet
production. Reduce dose by 50% if direct bilirubin level >3 mg/100 mL.
Adult Dose
1.4 mg/m2/wk IV
Pediatric Dose
<10 kg: 0.05 mg/kg/wk IV initial
>10 kg: Administer as in adults; not to exceed 2 mg
Contraindications
Documented hypersensitivity; demyelinating form of Charcot-Marie-Tooth
syndrome; IT administration may cause death
Interactions
Acute pulmonary reaction may occur when taken concurrently with
mitomycin-C; asparaginase, CYP450 3A4 inhibitors (eg, itraconazole,
quinupristin/dalfopristin, sertraline, ritonavir), GM-CSF (eg, sargramostim,
filgrastim), or nifedipine increase toxicity; CYP450 3A4 inducers (eg,
carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects
Pregnancy
D - Unsafe in pregnancy
Precautions
Caution in patients with severe cardiopulmonary or hepatic impairment,
leukopenia, and patients with preexisting neuromuscular disease; may cause
acute uric acid nephropathy, hypertension, hypotension, and leukopenia
Drug Name
Vinblastine (Alkaban-AQ, Velban) -- Inhibits microtubule formation, which, in
turn, disrupts the formation of the mitotic spindle, causing cell proliferation to
arrest at metaphase. Use hematologic parameters as a guide. If direct
bilirubin level >3, then reduce dose by 50%.
Adult Dose
5-10 mg/m2 q4wk; not to exceed 18.5 mg
Pediatric Dose
Contraindications
3-6 mg/m2 initial; then administer as in adults
Documented
hypersensitivity;
bacterial
infections
granulocytopenic) and bone marrow suppression
(especially
if
Interactions
Phenytoin plasma levels may be reduced when administered concomitantly
with vinblastine; with mitomycin, the toxicity of vinblastine may significantly
increase
Pregnancy
D - Unsafe in pregnancy
Precautions
Caution in patients with ulcers of the skin, cachexia, impaired liver function,
and neurotoxicity; when patient is receiving mitomycin C, monitor closely for
shortness of breath and bronchospasm
Drug Category: Anti-inflammatory agents -- Systemically interfere with events leading to inflammation.
Drug Name
Colchicine -- Decreases leukocyte motility and phagocytosis in inflammatory
responses.
Adult Dose
0.5-0.6 mg PO bid/tid
Pediatric Dose
Contraindications
Not established
Documented hypersensitivity; severe renal, hepatic, GI, or cardiac disorders;
blood dyscrasias
Interactions
Sympathomimetic agent toxicity and effect of CNS depressants significantly
increased with colchicine
Pregnancy
D - Unsafe in pregnancy
Precautions
Risk of renal failure, hepatic failure, permanent hair loss, bone marrow
suppression, numbness or tingling in hands and feet, disseminated
intravascular coagulopathy, and decreased sperm count; dose-dependent GI
upset is common
FOLLOW-UP
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Further Outpatient Care:

Regular monitoring is needed.
Deterrence/Prevention:

Hygiene should be meticulous to avoid bacterial infections.
o
The skin should be washed 2 times a day with disinfectant soap to prevent skin infections.
o
Cutting the fingernails to a short length helps to reduce autoinoculation.
Complications:

The skin is frequently involved, with pyodermas and deep abscesses.
Section 8 of 9

The thrombocytopenia and depletion of coagulation factors lead to petechiae, bruising, and gingival bleeding.
Prognosis:

Patients with CHS are susceptible to bacterial and viral infections. Intractable respiratory and cutaneous infections usually prove fatal before the
child with CHS reaches the age of 10 years. Longer survival is possible, but the lymph nodes, the spleen, and the liver become enlarged, and a
malignant lymphoma develops.
BIBLIOGRAPHY
Section 9 of 9
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Bibliography
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NOTE:
Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used
their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and
human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are
they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses,
indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER
Chediak-Higashi Syndrome excerpt
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