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Chediak-Higashi Syndrome

, MD, , PhD, , RN, MS, CRNP, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: January 15, 2015.


Clinical characteristics.

Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism (OCA), immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop the accelerated phase, a lymphoproliferative infiltration of the bone marrow and reticuloendothelial system. 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.


Ophthalmologic findings, history of recurrent or severe infections, and abnormal platelet aggregation studies should prompt evaluation for CHS. Diagnosis is based on identification of abnormal WBC granules on blood smear. LYST is the only gene known to be associated with CHS.


Treatment of manifestations: Initial chemoimmunotherapy followed by transition to continuation therapy for the accelerated phase; allogenic HSCT as soon as possible to cure hematologic and immunologic defects; platelet transfusions as needed for serious bleeding; corrective lenses to improve visual acuity; treatment by rehabilitation specialists for neurologic complications.

Prevention of secondary complications: Prompt aggressive use of antibiotics and antiviral agents for bacterial and viral illnesses; routine immunizations; intravenous DDAVP prior to invasive procedures to help control bleeding.

Surveillance: Yearly ophthalmologic examinations. For atypical or adolescent- or adult-onset CHS: annual abdominal ultrasound examination for hepatosplenomegaly; complete blood count (CBC) for cytopenias; monitoring for liver dysfunction; and measurement of serum ferritin concentration and soluble interleukin-2 receptor.

Agents/circumstances to avoid: Nonsteroidal anti-inflammatory drugs, which can exacerbate the bleeding tendency.

Genetic counseling.

CHS is inherited in an autosomal recessive manner. When both parents are heterozygous, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal diagnosis of CHS is possible if the pathogenic variants have been identified in the family.


Suggestive Findings

Diagnosis of Chediak-Higashi syndrome (CHS) should be suspected in individuals with any of the following:

  • Partial oculocutaneous albinism (OCA). Pigment dilution of the skin and hair may be appreciated at birth on physical examination. However, complete ophthalmologic examination may be necessary to identify the diagnostic finding of reduced iris pigment manifest as iris transillumination. Associated findings of nystagmus and decreased retinal pigmentation may also be present. These findings may be subtle, particularly in individuals with darkly pigmented irides.

    Note: OCA was once thought to be a diagnostic criterion for CHS; however, at least two individuals with atypical CHS had no evidence of OCA [Author, unpublished data]
  • Immunodeficiency. A significant history of infections, particularly bacterial infections of the skin and respiratory tract, is characteristic.

    Natural killer (NK) cells are generally present in normal numbers but with abnormal (reduced) function.

    Neutropenia and impaired neutrophil function (particularly chemotaxis and intracellular bactericidal activity). Note: Immunoglobulins, complement, antibody production, and delayed hypersensitivity are all normal.
  • Mild bleeding tendency. Absent or reduced number and irregular morphology of platelet-dense bodies (required for the secondary wave of platelet aggregation) on whole mount electron microscopy (Figure 1a, 1b) is characteristic.
  • Neurologic features. Neurologic manifestations are variable but include cognitive impairment, peripheral neuropathy, ataxia, and parkinsonism. Symptoms can appear anytime from childhood to early adulthood.
  • WBC giant inclusions. The finding of giant inclusions in polymorphonuclear neutrophils (PMNs) and (to a lesser extent) in lymphocytes is the most reliable diagnostic clinical criterion for CHS, but they may be overlooked in a routinely evaluated CBC unless a peripheral smear is reviewed. The giant granules are seen using routine staining techniques; however, in some atypical cases, the presence of these giant granules can be somewhat subtle. A hematologist, or a clinician experienced in reviewing blood smears for the presence of these giant granules, should review the slide.

    Peroxidase-positive giant inclusions can be seen in leukocytes, megakaryocytes, and other bone marrow precursors (Figure 1c-1e).
  • Pigment clumping on hair. (Figure 1f, 1g). Light microscopy hair analysis is noninvasive and quick. If a blood smear shows enlarged granules, the hair sample should be evaluated for CHS. This assessment can be routinely done with polarized light microscopy [Valente et al 2006].
Figure 1. a.

Figure 1

a. Whole mount electron microscopy of control platelets shows several dense bodies per platelet (arrows), while: b. Some CHS platelets have no dense bodies (asterisk) and others have irregular electron-dense granules (arrows). c. Normal control polymorphonuclear (more...)

Note: Because the finding of WBC giant inclusions is the most reliable clinical diagnostic criterion, the combination of any other of the above features should prompt review of a peripheral blood smear evaluating for giant inclusions.

Establishing the Diagnosis

The diagnosis of Chediak-Higashi syndrome is established in a proband with giant inclusions within leukocytes on peripheral blood smear. Molecular genetic testing to detect biallelic pathogenic variants in LYST, the only gene known to be associated with CHS, may be performed to confirm the diagnosis or to guide clinical management (see Table 1).

Molecular testing approaches can include:

  • Sequence analysis of LYST first followed by deletion/duplication analysis if only one or no mutation is found;
  • Use of a multi-gene panel that includes LYST and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Table 1.

Summary of Molecular Genetic Testing Used in Chediak-Higashi Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
LYSTSequence analysis 2~90%
Deletion/duplication analysis 3Unknown
Unknown 4NA

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Pathogenic variants in other genes are not known to result in CHS. Although it had been previously reported that a lower mutation detection rate suggested the possibility of locus heterogeneity [Karim et al 2002], the detection method in use was single-strand conformational polymorphism (SSCP) analysis, which has a lower rate of detection than sequencing of the entire open reading frame [Zarzour et al 2005]. However, because the function of the lysosomal trafficking regulator protein encoded by LYST is largely unknown, it is possible that pathogenic variants in other genes whose products interact with LYST could also result in CHS.

Clinical Characteristics

Clinical Description

Chediak-Higashi syndrome (CHS) is characterized by OCA, immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop the accelerated phase, a lymphoproliferative infiltration of the bone marrow and reticuloendothelial system. All affected individuals (including adolescents and adults with atypical CHS and children with classic CHS who have successfully undergone allogenic hematopoietic stem cell transplantation) develop neurologic findings.

Partial OCA. Pigment dilution is highly variable, but can involve hair, skin, and eyes. In classic forms of CHS, the hair has a “silvery” or metallic appearance. Skin pigment dilution may not be appreciated unless compared to that of more darkly pigmented family members. Reduced iris pigmentation is associated with decreased retinal pigmentation and nystagmus. Visual acuity varies from normal to moderate impairment. Quantitative data are not available and are difficult to obtain given the young age of individuals with the classic presentation.

Pigment clumping within the shaft of the hair is generally observed under the light microscope (Figure 1g) [Smith et al 2005].

Immunodeficiency. Frequent infections usually begin in infancy and are often severe. Bacterial infections are most common, with Staphylococcus and Streptococcus species predominating; viral and fungal infections can also occur [Introne et al 1999]. Infections of the skin and upper respiratory tract are the most common. More recently, case reports have identified periodontitis as an important manifestation of immunologic dysfunction [Hart & Atkinson 2007, Khocht et al 2010]. In some instances periodontitis can be the clinical finding leading to correct diagnosis [Bailleul-Forestier et al 2008].

Individuals with atypical CHS may not have a history of unusual or severe infections.

Bleeding tendency. Clinical manifestations are generally mild and include epistaxis, gum/mucosal bleeding, and easy bruising. The bleeding diathesis in CHS may also be subtle, i.e., generally not requiring medical intervention. Bleeding problems may not be listed as a health concern by affected persons.

Accelerated phase. The accelerated phase, occurring in 85% of individuals with CHS [Blume & Wolff 1972], can occur at any age. Clinical manifestations include fever, lymphadenopathy, hepatosplenomegaly, anemia, neutropenia, and sometimes thrombocytopenia. Originally thought to be a malignancy resembling lymphoma, the accelerated phase is now known to be a hemophagocytic lymphohistiocytosis characterized by multiorgan inflammation. The accelerated phase and its complications are the most common cause of mortality in individuals with CHS [Eapen et al 2007].

Triggers of the accelerated phase remain unclear. Infection with Epstein-Barr virus is thought to hasten development of the accelerated phase, although this relationship has never been proven. Absence of NK cell function is also believed to contribute to development of the accelerated phase.

Neurologic disease. Despite successful hematologic and immunologic outcomes with allogenic hematopoietic stem cell transplantation (HSCT), neurologic disease still manifests by early adulthood. Findings are similar to those described in individuals with atypical or adolescent forms of the disease. Tardieu et al [2005] reported on the neurologic outcomes of 11 children at their center who had received successful transplants. All 11 exhibited neurologic manifestations primarily consisting of low cognitive abilities, balance abnormalities and ataxia, tremor, absent deep-tendon reflexes, and motor and sensory neuropathies. The authors concluded that the neurologic changes were a result of long-term progression of the disease rather than neurotoxic effects of the transplant-conditioning regimen or the accelerated phase.

Atypical phenotypes. An unknown fraction of individuals with CHS have atypical or milder phenotypes [Karim et al 2002, Westbroek et al 2007], which are likely underrecognized. Atypical phenotypes are characterized by the following:

  • OCA that is generally subtle or absent
  • Insignificant infections or severe infections during childhood that become much less frequent later in life
  • Reduced platelet-dense bodies with subtle bleeding manifestations
  • Progressive neurologic findings that can include intellectual disabilities, peripheral neuropathy, balance abnormalities, tremor, parkinsonism [Bhambhani et al 2013, Weisfeld-Adams et al 2013], and spastic paraplegia [Shimazaki et al 2014]. The scope of neurologic manifestations is poorly defined because many individuals may be undiagnosed.
  • Neurologic findings are highly variable and nonspecific. Individuals with atypical CHS may have neurodegeneration as the predominant manifestation and only mild alterations in pigmentation, immune function, and bleeding. However, individuals with the atypical phenotype all have abnormal granules within leukocytes.

Genotype-Phenotype Correlations

Clinical phenotypes of CHS have been correlated with molecular genotypes [Karim et al 2002, Zarzour et al 2005]:

  • In general, loss-of-function mutations are associated with severe, childhood-onset form and missense mutations with milder adolescent- or adult-onset forms of the disorder [Karim et al 2002, Zarzour et al 2005, Westbroek et al 2007]. However, exceptions have been reported: individuals with two missense mutations who present with the severe, childhood onset form and HLH [Sánchez-Guiu et al 2014].
  • It has been shown that the clinical severity of the disease also correlates with the cellular phenotype. Detailed studies of fibroblasts and melanocytes from individuals with CHS with different clinical phenotypes illustrated the range of enlargement of intracellular granule abnormalities in different CHS cell types [Westbroek et al 2007].


Fewer than 500 cases had been reported in the literature [Kaplan et al 2008]. 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.

Differential Diagnosis

The diagnosis of Chediak-Higashi syndrome (CHS) should be considered in individuals with pigment dilution defects of the hair, skin, or eyes; congenital or transient neutropenia; immunodeficiency; and otherwise unexplained neurologic abnormalities or neurodegeneration. Each of these findings may be variably represented in affected individuals; therefore, heightened suspicion is needed to pursue an accurate diagnosis.

Oculocutaneous albinism. The four types of oculocutaneous albinism (OCA1, OCA2, OCA4, and XLOA) all feature visual impairment and varying degrees of iris/retinal depigmentation. Except in individuals with XLOA, in whom skin and hair pigment may be normal, the characteristic skin and hair findings vary from complete absence of pigment to reduced pigment. Neither an infectious history resulting from neutropenia nor neurologic abnormalities accompany the OCA types. OCA is common enough (~1:18,000) that it may coexist with other conditions, including primary immunodeficiencies.

Hermansky Pudlak syndrome (HPS). Like CHS, HPS is characterized by OCA and a bleeding diathesis secondary to absent platelet-dense bodies. Of the at least nine subtypes of HPS, HPS2 (caused by pathogenic variants in AP3B1) most closely resembles CHS.

HPS2 is currently described with molecular analysis in only nine individuals (see Hermansky-Pudlak Syndrome). In addition to the albinism and bleeding diathesis, individuals with HPS2 also have congenital neutropenia, a recurrent pattern of severe bacterial infections, and neurologic features including developmental delay, balance abnormalities, and tremor. The distinction between CHS and HPS2 depends on identifying giant intracellular granules within the neutrophils of those individuals with CHS.

Griscelli syndrome (GS). Mild skin hypopigmentation and silvery gray hair are present, but platelet function is normal. Griscelli syndrome may be caused by pathogenic variants in:

Cross syndrome. Cross syndrome is manifested by hypopigmentation, ocular defects, and severe developmental delay reflecting extensive central nervous system (CNS) involvement. An infectious component is absent from this diagnosis.

Deficiency of endosomal adaptor p14. In 2007, this novel immunodeficiency syndrome was identified in four members of a Mennonite pedigree [Bohn et al 2007]. Clinical features include partial albinism, short stature, congenital neutropenia, and lymphoid deficiency. Neutrophils show altered azurophilic granule ultrastructure and less than normal microbicidal function of phagosomes, in contrast to the giant inclusions seen in neutrophils in CHS. Neurologic dysfunction was not described in members of this pedigree.

Familial hemophagocytic lymphohistiocytosis (FLH) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes manifesting as acute illness with prolonged fever, cytopenias, and hepatosplenomegaly. Onset is typically within the first few months of life and, on occasion, in utero, although later childhood or adult onset is more common than previously suspected. Neurologic abnormalities that may be present initially or may develop later include: increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Rash and lymphadenopathy are less common. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FLH, without treatment, is less than two months; progression of hemophagocytic lymphohistiocytosis and infection account for the majority of deaths in untreated individuals. Familial LH, inherited in an autosomal recessive manner, is caused by biallelic mutation of one of five genes, corresponding to five disease subtypes (FHL1 – FLH5).

Vici syndrome. A small number of individuals with cutaneous hypopigmentation, combined immunodeficiency, agenesis of the corpus callosum, bilateral cataracts, and cleft lip and palate have been described. Cognitive impairment, seizures, and severe respiratory infections were observed [Dionisi Vici et al 1988, del Campo et al 1999, Chiyonobu et al 2002, Miyata et al 2007].


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Chediak-Higashi syndrome (CHS), the following are recommended:

  • Assessment for evidence of the accelerated phase including [Filipovich 2006]:
    • History of unexplained, persistent, or recurrent fever
    • Splenomegaly
    • Cytopenia of at least two cell lines
    • Signs of liver dysfunction including hypertriglyceridemia and/or hypofibrinogenemia
    • Elevated serum ferritin concentration
    • Elevated soluble interleukin-2 receptor level
    • Evidence of hemophagocytosis in bone marrow and/or cerebrospinal fluid
  • Comprehensive neurologic examination
  • Screening for a history of frequent or unusual infections
  • Screening for clinical signs of lymphoma. The hemophagocytic lymphohistiocytosis associated with CHS may have this clinical appearance.
  • Medical genetics consultation

Treatment of Manifestations

Hematologic and immunologic defects

  • The only treatment that cures the hematologic and immunologic defects is allogenic hematopoietic stem cell transplantation (HSCT). A conditioning regimen, described in detail by Haddad et al [1995], generally includes a combination of etoposide, busulfan, and cyclophosphamide. The current standard of care is HSCT as soon as the diagnosis is confirmed and the accelerated phase has either been ruled out or is in remission.
  • The most favorable outcome is achieved when HSCT is performed prior to development of the accelerated phase.
  • If signs of the accelerated phase are present, hemophagocytosis must be brought into clinical remission before HSCT can be performed.
  • Guidelines for treatment of the accelerated phase, revised in 2004 [Henter et al 2007], are the same as those for familial hemophagocytic lymphohistiocytosis (HLH-2004 protocol). Combination therapy consists of etoposide, dexamethasone, and cyclosporine A. Select individuals may also receive intrathecal methotrexate and prednisilone. Remission is achieved in 75% of individuals within eight weeks [Filipovich 2006]; however, relapses are common and response to treatment declines over time. Once remission occurs, prompt HSCT is recommended.
  • The overall five-year survival rate in 35 children with CHS who underwent HSCT was 62% [Eapen et al 2007]. Success was highest with HLA-matched siblings or unrelated donors; transplantation during the accelerated phase had a higher mortality rate. Individuals in remission following symptoms of the accelerated phase can have successful outcomes following HSCT [Eapen et al 2007].

Ocular abnormalities

  • Correction of refractive errors may improve visual acuity.
  • Sunglasses should be used to protect sensitive eyes from UV light.

Skin hypopigmentation. Skin protection varies depending on the degree of hypopigmentation. Regardless, all individuals should use sunscreen to prevent sun damage and skin cancer.

Neurologic abnormalities. Because of the progressive nature of the neurologic symptoms, older patients should engage rehabilitation specialists early in the course of the disease.

Prevention of Secondary Complications

Patients should be protected from infectious exposures as much as is practical. Antibiotics and antiviral agents should be used promptly and aggressively to treat bacterial and viral illnesses. A study by Wolff et al [1972] did not find antibiotic prophylaxis to be beneficial; however, in situations of recurrent bacterial infections, it should be considered.

Antibiotic prophylaxis should be given prior to dental or invasive procedures Widespread use of prophylactic antibiotics prior to invasive dental procedures has been under scrutiny. However, for individuals with compromised immune systems and neutropenia who will be undergoing invasive dental procedures or procedures that cause significant bleeding, prophylaxis should be considered according to American Heart Association guidelines [Tong & Rothwell 2000].

Immunizations are generally well tolerated and should be administered.

Intravenous DDAVP (0.2-0.4 µg/kg/dose over 15 to 30 minutes) can be given 30 minutes prior to invasive procedures to help control bleeding. For serious trauma or extensive bleeding, platelet transfusion may be necessary.


No guidelines for surveillance of classic CHS exist. Current standard of care initiates evaluation for bone marrow transplantation as quickly as feasible after the diagnosis is confirmed.

For atypical or adolescent- or adult-onset CHS, annual screening should include the following:

  • Abdominal ultrasound examination to monitor for hepatosplenomegaly
  • CBC to evaluate for cytopenias
  • Evaluation for signs of liver dysfunction including hypertriglyceridemia and/or hypofibrinogenemia
  • Measurement of serum ferritin concentration
  • Soluble interleukin-2 receptor measurement
  • Consideration of bone marrow biopsy and/or lumbar puncture if history or physical examination suggests CNS involvement or other manifestations of the accelerated phase

If clinical status changes, the above tests should be repeated.

For both classic and atypical CHS, annual ophthalmologic examination is appropriate.

Agents/Circumstances to Avoid

All nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen) are to be avoided as they can exacerbate the bleeding tendency.

Evaluation of Relatives at Risk

It is appropriate to evaluate the older and younger sibs of a proband as early as possible. Early diagnosis may provide the opportunity to perform HSCT prior to the development of the accelerated phase.

  • If the family-specific pathogenic variants are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
  • If the pathogenic variants in the family are not known, examination of peripheral blood for the presence of giant inclusions within white blood cells can be used to clarify the disease status of at-risk sibs.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In the limited cases of pregnancy in females with CHS reported in the literature [Price et al 1992, Weisfeld-Adams et al 2013], presence of the disease had no impact on the pregnancy, labor, or delivery. The infants were normal. The pregnancy also did not appear to affect the course of disease in the affected mothers.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Chediak-Higashi syndrome (CHS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • At conception, if the parents of a proband are both heterozygotes, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of a LYST pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with CHS are obligate heterozygotes (carriers) for a LYST pathogenic variant.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the LYST pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the LYST pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the LYST pathogenic variants have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Medline Plus
  • National Library of Medicine Genetics Home Reference
  • Hermansky-Pudlak Syndrome Network, Inc.
    One South Road
    Oyster Bay NY 11771-1905
    Phone: 800-789-9HPS
    Fax: 516-624-0640
  • International Patient Organisation for Primary Immunodeficiencies (IPOPI)
    Main Road
    Downderry Cornwall PL11 3LE
    United Kingdom
    Phone: +44 01503 250 668
    Fax: +44 01503 250 668
  • National Organization of Albinism and Hypopigmentation (NOAH)
    PO Box 959
    East Hampstead NH 03826-0959
    Phone: 800-473-2310 (toll-free); 603-887-2310
    Fax: 800-648-2310 (toll-free)
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Phone: 49-761-270-34450

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Chediak-Higashi Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Chediak-Higashi Syndrome (View All in OMIM)


Molecular Genetic Pathogenesis

Interestingly, the neurologic findings of adult-onset Chediak-Higashi syndrome (CHS) resemble those of the recently described ENU-induced homozygous LystIng3618 mouse, which manifests age-dependent neurologic impairment and Purkinje cell degeneration [Rudelius et al 2006].

Gene structure. LYST is a large gene with 55 exons. The 13.5-kb gene transcript produces a protein of 3,801 amino acids with a molecular weight of 430 kd. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. See Table 2. To date, more than 40 pathogenic variants have been identified throughout the gene. These include missense and nonsense mutations, and small deletions and insertions in the coding region.

Table 2.

Selected LYST Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
(961T>C) 2
(11362G>A) 2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


Normal gene product. LYST encodes a 430-kd cytoplasmic protein with unknown biologic function called LYST (lysosomal-trafficking regulator) or CHS1. LYST is a member of the BEACH (beige and Chediak-Higashi) family of proteins, which are defined by the presence of a BEACH motif. The LYST N terminus has several ARM/HEAT repeats known to play a role in membrane interaction [Kaplan et al 2008], whereas the C-terminal BEACH motif consists of a WIDL-enriched sequence followed by several WD-40 domains known to serve as a platform for protein-protein interaction [Jogl et al 2002, De Lozanne 2003, Kaplan et al 2008].

Abnormal gene product. Many cell types in individuals with CHS manifest enlarged lysosomes or lysosome-related organelles (LROs); this is the main cellular characteristic of CHS [Introne et al 1999, Ward et al 2002, Clark & Griffiths 2003, Westbroek et al 2007]. In fibroblasts, enlarged lysosomes show a perinuclear distribution, and fusion with the plasma membrane in the wound healing process is inhibited [Huynh et al 2004]. In epidermal melanocytes of individuals with CHS, oversized melanosomes accumulate in the perinuclear area and are not transferred to surrounding keratinocytes, which could explain the skin hypomelanosis observed in CHS [Westbroek et al 2007]. Enlarged mature lytic granules in CHS cytotoxic T-lymphocytes (CTLs) are unable to mediate targeted cell killing [Stinchcombe et al 2000], and peptide loading onto MHC class II molecules and antigen presentation are delayed [Faigle et al 1998]. Most CHS platelets show absent dense bodies; a few platelets harbor enlarged and irregularly shaped dense bodies (Figure 1a, 1b) [White 2003, Zarzour et al 2005, Westbroek et al 2007].

The precise biologic role of CHS1 remains unknown. For years speculations suggested that this BEACH domain containing protein had a role in the regulation of membrane fusion events and lysosomal size [Tchernev et al 2002, Tanabe et al 2000, Möhlig et al 2007, Morimoto et al 2007]. Recently, it was proposed that CHS1 acts in membrane fusion and fission events as a scaffold protein [Cullinane et al 2013].


Literature Cited

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  • Bhambhani V, Introne WJ, Lungu C, Cullinane A, Toro C. Chediak-Higashi syndrome presenting as young-onset levodopa-responsive parkinsonism. Mov Disord. 2013;28:127–9. [PMC free article: PMC3581862] [PubMed: 23436631]
  • Blume RS, Wolff SM. The Chediak-Higashi syndrome: studies in four patients and a review of the literature. Medicine (Baltimore) 1972;51:247–80. [PubMed: 5064229]
  • Bohn G, Allroth A, Brandes G, Thiel J, Glocker E, Schäffer AA, Rathinam C, Taub N, Teis D, Zeidler C, Dewey RA, Geffers R, Buer J, Huber LA, Welte K, Grimbacher B, Klein C. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nature Medicine. 2007;13:38–45. [PubMed: 17195838]
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Chapter Notes

Author Notes

Dr. Introne is a pediatrician and medical and biochemical geneticist who performs clinical research on rare diseases at the National Institutes of Health

Dr. Westbroek is a biochemist who studies the cell biology of organelle and vesicle biogenesis and trafficking in various cell types derived from patients with rare diseases.

Gretchen Golas is a pediatric nurse practitioner who provides clinical assessment and care to children with rare diseases at the National Institutes of Health.

Dr. Adams is a pediatrician, medical geneticist, and biochemical geneticist who performs clinical and basic research into rare diseases at the National Institutes of Health.


The authors would like to thank Dr. William Gahl and Dr. Alan Wayne for their commitment to the care of these individuals and dedication to furthering our understanding of the disease.

Revision History

  • 15 January 2015 (me) Comprehensive update posted live
  • 16 February 2012 (me) Comprehensive update posted live
  • 27 July 2010 (cd) Revision: prenatal testing available clinically
  • 11 August 2009 (cd) Revision: sequence analysis available clinically
  • 3 March 2009 (me) Review posted live
  • 2 October 2008 (wji) Original submission

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