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Chediak-Higashi Syndrome

, MD, , PharmR, PhD, , MD, PhD, , MD, PhD, and , MD.

Author Information

Initial Posting: ; Last Update: July 5, 2018.

Summary

Clinical characteristics.

Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism, immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop the accelerated phase, or hemophagocytic lymphohistiocytosis, a life-threatening, hyperinflammatory condition. 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.

Diagnosis/testing.

The diagnosis of CHS is established in a proband with giant inclusions within leukocytes on peripheral blood smear and/or by the identification of biallelic pathogenic variants in LYST on molecular genetic testing.

Management.

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; L-dopa may be considered for those with parkinsonism; home modifications and intensive rehabilitation for those with ataxia and other neurologic complications; corrective lenses to improve visual acuity; sunglasses to protect sensitive eyes from UV light; sunscreen to prevent sun damage and skin cancer.

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

Surveillance: Routine monitoring for chimerism, as 20%-30% donor chimerism is likely enough to protect against reactivation. Yearly ophthalmologic, neurologic, and dermatologic examinations. For atypical or adolescent- or adult-onset CHS: annual abdominal ultrasound examination for hepatosplenomegaly; complete blood count for cytopenias; measurement of serum ferritin concentration and soluble interleukin-2 receptor; and monitoring for liver dysfunction.

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

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.

Diagnosis

Suggestive Findings

Diagnosis of Chediak-Higashi syndrome (CHS) should be suspected in individuals with any of the following clinical features and supportive laboratory findings.

Clinical features

  • Partial oculocutaneous albinism (OCA); a complete ophthalmologic examination may be necessary to identify the diagnostic finding of reduced iris pigment manifest as iris transillumination or reduced retinal pigmentation.
  • A significant history of infections, particularly bacterial infections of the skin and respiratory tract
  • Mild bleeding tendency
  • Childhood- to early adult-onset neurologic manifestations, including:
    • Cognitive impairment
    • Peripheral neuropathy
    • Ataxia
    • Parkinsonism

Supportive laboratory findings

  • Giant inclusions in polymorphonuclear neutrophils (PMNs) and (to a lesser extent) in lymphocytes
    • This is the most reliable diagnostic criterion for CHS but 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).
  • Normal or reduced number of natural killer cells 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.
  • 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)
  • Pigment clumping on polarized light microscopy hair analysis (Figure 1f, 1g).
Figure 1. a.

Figure 1

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

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 and/or by the identification of biallelic pathogenic variants in LYST on molecular genetic testing (see Table 1).

When the phenotypic and laboratory findings suggest the diagnosis of Chediak-Higashi syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

  • Single-gene testing. Sequence analysis of LYST detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
  • A multigene panel that includes LYST and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Chediak-Higashi Syndrome

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
LYSTSequence analysis 3~90%
Gene-targeted deletion/duplication analysis 4Unknown 5
Unknown 6NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

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

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

6.

Pathogenic variants in other genes are not known to result in CHS. Although it had been previously reported that a lower pathogenic variant 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 oculocutaneous albinism (OCA), immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop the accelerated phase, or hemophagocytic lymphohistiocytosis (HLH), a life-threatening, hyperinflammatory condition. 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.

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 family members. Reduced iris pigmentation may also be subtle, particularly in individuals with darkly pigmented irides. Affected individuals may have 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.

OCA was once thought to be a diagnostic criterion for CHS; however, at least two individuals with atypical CHS had no evidence of OCA [Introne et al 2017].

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 in the classic form of this condition. 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. 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 up to 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 HLH 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. Abnormal function of NK cells and cytolytic T cells is also believed to contribute to development of the accelerated phase [Jessen et al 2011, Gil-Krzewska et al 2016].

Neurologic disease. Despite successful hematologic and immunologic outcomes with allogenic HSCT, neurologic disease still manifests by early adulthood. Findings are the same as those described in untransplanted individuals with atypical or adolescent forms of the disease, but are highly variable and nonspecific [Introne et al 2017].

  • Progressive neurologic findings can include:
  • Neurodegeneration following successful bone marrow transplantation was first described by Tardieu et al [2005] in 11 children who were transplanted at their center.
    • 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. Some of these affected individuals may be diagnosed after the third decade of life [Weisfeld-Adams et al 2013]. 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
  • In some cases, neurodegeneration (similar to that seen in the classic phenotype) as the predominant manifestation, with only mild alterations in pigmentation, immune function, and bleeding
  • Abnormal granules within leukocytes (present in all individuals with an atypical phenotype)

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 variants are associated with severe, childhood-onset form and missense variants 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 biallelic missense variants 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].

Prevalence

Fewer than 500 cases have 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 seven types of oculocutaneous albinism (OCA type 1, OCA type 2, OCA type 3, OCA type 4, OCA type 5, OCA type 6, and OCA type 7) and OA (ocular albinism) all feature visual impairment and varying degrees of iris/retinal depigmentation. Characteristic skin and hair findings vary from complete absence of pigment to reduced pigment, except in individuals with OA, in whom skin and hair pigment may be normal, and in OCA type 3, which is characterized by bright copper-red hair and lighter tan skin. 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 an autosomal recessive disorder characterized by OCA and a bleeding diathesis secondary to absent platelet-dense bodies. Of the at least ten subtypes of HPS, HPS2 (caused by biallelic pathogenic variants in AP3B1) most closely resembles CHS.

HPS2 has been reported in at least 30 individuals [Jessen et al 2013; Huizing et al, unpublished] (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 pulmonary fibrosis. Patients with HPS2 are at risk for HLH, although the risk is less than for CHS and GS. The distinction between CHS and HPS2 depends on identifying giant intracellular granules within the neutrophils of those individuals with CHS.

Griscelli syndrome (GS) (OMIM PS214450). Mild skin hypopigmentation and silvery gray hair are present, but platelet function is normal. Griscelli syndrome may be caused by biallelic pathogenic variants in:

Cross syndrome (OMIM 257800). Cross syndrome is characterized by hypopigmentation, ocular defects, and severe developmental delay reflecting extensive central nervous system involvement. An infectious component is absent from this diagnosis.

Immunodeficiency due to defect in MAPBP-interacting protein (OMIM 610798) is a novel immunodeficiency syndrome 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. Biallelic pathogenic variants in LAMTOR2 are causative; inheritance is autosomal recessive.

Familial hemophagocytic lymphohistiocytosis (FHL) 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 FHL, without treatment, is less than two months; progression of hemophagocytic lymphohistiocytosis and infection account for the majority of deaths in untreated individuals. Familial HL, inherited in an autosomal recessive manner, is caused by biallelic variants in PRF1, STX11, STXBP2, or UNC13D.

Vici syndrome (OMIM 242840). 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]. Biallelic pathogenic variants in EPG5 are causative; inheritance is autosomal recessive.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Chediak-Higashi syndrome (CHS), the evaluations detailed in Table 2 are recommended if they have not already been completed.

Table 2.

Recommended Evaluations Following Initial Diagnosis in Individuals with Chediak-Higashi Syndrome

Organ SystemEvaluationComment
HematologicHistory of unexplained, persistent, or recurrent feverTo assess for evidence of the accelerated phase 4
Assessment for hepatosplenomegaly by physical examination & ultrasound imaging
Complete blood count 1
Ferritin concentration 2
Soluble interleukin-2 receptor level 2
Consideration of bone marrow biopsy 3
ImmunologicScreening for history of frequent or unusual infectionsReferral to immunologist &/or hematologist as needed
GastrointestinalSerum triglyceride concentrationTo assess for liver dysfunction 5
Fibrinogen level
NeurologicComplete neurologic evaluation
Consideration of lumbar punctureTo assess for evidence of hemophagocytosis in cerebrospinal fluid
OcularOphthalmology evaluationFor signs of reduced pigment & refractive errors
OtherConsultation w/clinical geneticist &/or genetic counselor
1.

For evidence of cytopenia involving at least two cell lines

2.

Elevated serum ferritin and soluble interleukin-2 receptor level are associated with the accelerated phase.

3.

To assess for hemophagocytosis

4.
5.

Hypertriglyceridemia and hypofibrinogenemia are suggestive of liver dysfunction, which can be associated with the accelerated phase.

Treatment of Manifestations

Table 3.

Treatment of Manifestations in Individuals with Chediak-Higashi Syndrome

ManifestationTreatmentConsiderations/Other
Hematologic and immunologic defectsGuidelines for treatment of the accelerated phase are the same as for familial hemophagocytic lymphohistiocytosis (HLH). 1, 2, 3, 4Combination therapy consists of etoposide & dexamethasone, w/continuation phase adding cyclosporine A.
Select individuals may also receive intrathecal methotrexate.
Hematopoietic stem cell transplantation (HSCT) 5, 6, 7, 8HSCT is often initiated as soon as the diagnosis is confirmed.
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. 4
ParkinsonismTrial of L-dopa therapy 9
AtaxiaIntensive rehabilitation (or coordinative physiotherapy)Treatment is best provided by a multidisciplinary team comprising a neurologist, physiatrist, & physical & occupational therapists.
Canes/walkers to prevent falls
Home modifications to accommodate motorized chairs, as needed
Weighted eating utensils & dressing hooks
Weight control, as obesity can exacerbate difficulties w/ambulation & mobility
Refractive errors &/or light sensitivityCorrective lenses for refractive errorsReferral to ophthalmologist
Sunglasses to protect sensitive eyes from UV light
Low vision rehabilitation & adaptive therapy
Skin hypopigmentationSunscreenTo prevent sun damage & skin cancer
1.

Better HLH control at the time of HSCT leads to better long-term outcome.

2.

Recent evaluation of HLH-2004 protocol did not find statistical evidence for superiority over the HLH-94 regimen; therefore, HLH-94 remains the standard of care [Bergsten et al 2017].

3.

The remission induction rate may be as high as 71% when considering all heritable causes of HLH [Filipovich & Chandrakasan 2015].

4.

This treatment is also effective at inducing remission in CHS so that HSCT can be performed [Trottestam et al 2009].

5.

This is the only treatment that cures the hematologic and immunologic deficits.

6.

The conditioning regimen is at the discretion of the treatment center; however, reduced-intensity conditioning regimens have demonstrated improved survival over traditional myeloablative protocols.

7.

Although not specific for CHS, in a cohort of 40 individuals with genetic forms of HLH including CHS, the three-year post-HSCT survival was 92% following reduced-intensity conditioning regimens [Marsh et al 2010].

8.

The overall five-year survival rate in 35 children with CHS who underwent HSCT was 62% [Eapen et al 2007].

9.

Prevention of Secondary Complications

Table 4.

Prevention of Secondary Complications in Individuals with Chediak-Higashi Syndrome

ManifestationPreventionConsiderations/Other
InfectionInactivated vaccine administration according to typical scheduleLive vaccines are not recommended. 1
Protection from infectious exposures as much as practical
Antibiotic & antiviral agents should be used promptly & aggressively for bacterial & viral illnesses, respectively.Consideration of prophylactic antibiotics in those w/recurrent infections 2, 3
Bleeding
tendency
Intravenous DDAVP (0.2-0.4 µg/kg/dose over 15-30 minutes) 30 minutes prior to invasive proceduresFor serious trauma or extensive bleeding, platelet transfusion may be necessary.
Skin cancerSunscreen (see Treatment of Manifestations)
1.
2.
3.

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 [AAPD reference manual].

Surveillance

No consensus guidelines for surveillance of classic CHS exist. Generally, evaluation for bone marrow transplantation is initiated after the diagnosis is confirmed (see Treatment of Manifestations).

Table 5.

Recommended Surveillance for Individuals with Chediak-Higashi Syndrome

Organ SystemEvaluationFrequency
HematologicMonitoring of chimerism 1, 2Routine
NeurologicNeurologic examinationAt least annually
OcularOphthalmologic examinationAt least annually
SkinDermatologic examination 3At least annually
1.

Especially in those who undergo HSCT with reduced-intensity conditioning as the incidence of mixed chimerism in the bone marrow is higher than in those who undergo traditional conditioning.

2.

Recent studies suggest 20%-30% donor chimerism is likely enough to protect against reactivation [Hartz et al 2016].

3.

For routine monitoring in the setting of hypopigmentation

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. Live vaccines should also be avoided.

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 ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for 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.
  • 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 (Heterozygote) 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 and Preimplantation Genetic Diagnosis

Once the LYST pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

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
    Email: info@hpsnetwork.org
  • International Patient Organisation for Primary Immunodeficiencies (IPOPI)
    Firside
    Main Road
    Downderry Cornwall PL11 3LE
    United Kingdom
    Phone: +44 01503 250 668
    Fax: +44 01503 250 668
    Email: info@ipopi.org
  • 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)
    Email: info@albinism.org
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: esid-registry@uniklinik-freiburg.de

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)

214500CHEDIAK-HIGASHI SYNDROME; CHS
606897LYSOSOMAL TRAFFICKING REGULATOR; LYST

Molecular Genetic Pathogenesis

Gene structure. LYST is a large gene with 53 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 variants. See Table 7. To date, 75 pathogenic variants have been identified throughout the gene. These include missense and nonsense variants, and small deletions and insertions in the coding region.

Table 7.

Selected LYST Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein Change
(Alias 1)
Reference Sequences
c.118dupGp.Ala40GlyfsTer24
(Ala40fsTer63)
NM_000081​.2
NP_000072​.2
c.148C>Tp.Arg50Ter
c.772T>C
(961T>C) 2
p.Cys258Arg
c.925C>Tp.Arg309Ter
c.1467delGp.Glu489AspfsTer78
(Glu489fsTer566)
c.1540C>Tp.Arg514Ter
c.1902dupA
(1897_1898insA)
p.Ala635SerfsTer4
(Lys633fsTer638)
c.2413delGp.Glu805AsnfsTer2
(Glu805fsTer806)
c.2454delAp.Ala819Hisfs5
(Lys818fsTer823)
c.2623delT
(2620delT)
p.Tyr875MetfsTer24
(Phe874fsTer898)
c.3073_3074delAAp.Asn1025GlnfsTer6
(Asn1025fsTer1030)
c.3085C>Tp.Gln1029Ter
c.3310C>Tp.Arg1104Ter
c.3434dupA
(3434_3435insA)
p.His1145GlnfsTer9
(His1145fsTer1153)
c.3622C>Tp.Gln1208Ter
c.3944dupC
(3944_3945insC)
p.Thr1315fsTer1331
c.4052C>Gp.Ser1351Ter
c.4361C>Ap.Ala1454Asp
c.4274delTp.Leu1425TyrfsTer2
(Leu1425fsTer1426)
c.4688G>Ap.Arg1563His
c.5061T>Ap.Tyr1687Ter
c.5317delAp.Arg1773AspfsTer13
(Arg1773fsTer1785)
c.5506C>Tp.Arg1836Ter
c.5541_5542delAAp.Gln1847fsTer1850
c.5996T>Ap.Val1999Asp
c.6078C>Ap.Tyr2026Ter
c.7060_7066delCTATTAGp.Leu2354MetfsTer16
(Leu2354fsTer2369)
c.7555delTp.Tyr2519IlefsTer10
(Tyr2519fsTer2528)
c.7982C>Gp.Ser2661Ter
c.8281A>Tp.Arg2761Ter
c.8428G>Ap.Glu2810Lys
c.8583G>Ap.Trp2861Ter
c.9107_9162del56p.Gly3036GlufsTer16
(Gly3036fsTer3051)
c.9228_9229insTTCTTTCAGTp.Lys3077PhefsTer4
(Lys3077fsTer3080)
c.9590delAp.Tyr3197LeufsTer62
(Tyr3197fsTer3258)
c.9827_9832delATACAAp.Asn3276_Thr3277del
c.9893delTp.Phe3298Serfs7
(Phe3298fsTer3304)
c.10127A>Gp.Asn3376Ser
c.10395delAp.Gly3466AlafsTer2
(Lys3465fsTer3467)
c.11102G>Tp.Glu3668Ter
c.11173G>A
(11362G>A) 2
p.Gly3725Arg

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​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

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].

The precise biologic role of LYST remains unknown. It has been hypothesized that LYST has a role in the regulation of membrane fusion events and lysosomal size [Tanabe et al 2000, Tchernev et al 2002, Möhlig et al 2007, Morimoto et al 2007]. More recently, it was proposed that LYST acts in membrane fusion and fission events as a scaffold protein [Cullinane et al 2013].

Abnormal gene product. CHS occurs through a loss-of-function mechanism.

Many cell types in individuals with CHS manifest enlarged lysosomes or lysosome-related organelles; 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]. A genotype-phenotype correlation has been noted within natural killer cells. Pathogenic variants in the ARM/HEAT domain lead to a reduced number, but markedly enlarged, lytic granules that are capable of migrating to the immunologic synapse but unable to fuse with the plasma membrane. In contrast, pathogenic variants in the BEACH domain lead to normal or slightly enlarged granules that have impaired polarization to the immunologic synapse. In both cases, exocytosis of the lytic granules is impaired with significantly reduced cytotoxicity [Gil-Krzewska et al 2016].

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].

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

References

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Suggested Reading

  • American Academy of Pediatric Dentistry. Antibiotic prophylaxis for dental patients at risk for infection. Recommendations: Best practices. Available online. 2014. Accessed 7-2-18.

Chapter Notes

Author Notes

Dr Toro is a movement-disorder neurologist who works with the National Institutes of Health Undiagnosed Diseases Program.

Dr Nicoli is a pharmacist and a scientist who studies lysosomal storage disorders, pathogenesis and therapy.

Dr Malicdan is a neurologist and a scientist, whose main interest is to study rare diseases.

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.

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

Acknowledgments

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.

Author History

David R Adams, MD, PhD (2009-present)
Gretchen A Golas, RN, MS, CRNP; National Human Genome Research Institute (2009-2018)
Wendy J Introne, MD (2009-present)
May Christine Malicdan, MD, PhD (2018-present)
Elena-Raluca Nicoli, PharmR, PhD (2018-present)
Camilo Toro, MD (2018-present)
Wendy Westbroek, PhD; National Human Genome Research Institute (2009-2018)

Revision History

  • 5 July 2018 (ma) Comprehensive update posted live
  • 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

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "Chediak-Higashi Syndrome" is in the public domain in the United States of America.

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