Clinical characteristics.

Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism (OCA), immunodeficiency, a mild bleeding tendency, and late adolescent- to adult-onset neurologic manifestations (e.g., learning difficulties, peripheral neuropathy, ataxia, and parkinsonism). While present in nearly all individuals with CHS, these clinical findings vary in severity.

Of note, all individuals with CHS are at risk of developing neurologic manifestations and hemophagocytic lymphohistiocytosis (HLH).

Individuals with severe childhood-onset presentations are considered to have "classic" CHS, whereas individuals with milder adolescent- to adult-onset presentations are considered to have "atypical" CHS. Because of the considerable overlap between classic CHS and atypical CHS, the disorder is best understood as a continuum of severe to milder phenotypes, with the universal feature being the pathognomonic giant granules within leukocytes observed on peripheral blood smear.

Diagnosis/testing.

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

Management.

Targeted therapy: The only targeted therapy currently available is hematopoietic stem cell transplantation (HSCT). HSCT can correct the hematologic and immunologic manifestations of CHS but does not appear to protect against the development of neurologic manifestations.

Supportive care: Multidisciplinary care is recommended, including specialists in ophthalmology and low vision services, infectious disease for management and prevention, hematology (to manage the bleeding disorder, HSCT, and treatment of HLH), neurology and physiatry, physical therapy, occupational therapy, and (for children) neuropsychology or developmental pediatrics to address educational and emotional needs or (for adults) neuropsychology.

Surveillance: To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, routinely scheduled follow-up evaluations by the multidisciplinary specialists are recommended.

Agents/circumstances to avoid: Live vaccines given the risk of infection due to immunodeficiency; all nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen) given the risk of exacerbating 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 HLH.

Pregnancy management: Although data are limited, to date females with CHS report uneventful pregnancy, labor, and delivery. However, because of concerns about bleeding during delivery and the postpartum period, developing a plan prior to delivery to address this issue is recommended.

Genetic counseling.

CHS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a LYST pathogenic variant, each sib of an affected individual has at conception 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 the LYST pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

The diagnosis of Chediak-Higashi syndrome (CHS) should be suspected in a proband with any of the following clinical features, supportive laboratory findings, and family history.

Clinical features

• Oculocutaneous albinism (OCA) with residual pigmentation characterized by:
  • Signs and symptoms of low vision typical of OCA
  • Reduced iris pigmentation (manifesting as iris transillumination often only on ophthalmologic examination). Note that irides may be darker than the light blue that is often associated with OCA.
  • Reduced retinal pigmentation
  • Hair that may have a silvery-gray sheen
• A significant history of infections (particularly bacterial) of the skin and respiratory tract; also increased susceptibility to periodontal disease
• Mild bleeding tendency associated with platelet dysfunction such as epistaxis, gum/mucosal bleeding, and easy bruising
• Increased risk for hemophagocytic lymphohistiocytosis (HLH) (previously called "CHS accelerated phase"). Clinical findings and diagnostic criteria are the same as those for familial hemophagocytic lymphohistiocytosis.
• Childhood- to early adult-onset neurologic manifestations, including:
  • Learning difficulties
  • Peripheral neuropathy
  • Ataxia
  • Parkinsonism

Supportive laboratory findings

• White blood cell (WBC) giant granules (also called "inclusions"), peroxidase-positive granules primarily in polymorphonuclear neutrophils (PMNs) and to a lesser extent in lymphocytes (Figure 1c-1e), are the most reliable diagnostic criterion for CHS. Nonetheless, giant granules may be overlooked in a routinely evaluated complete blood count (CBC) unless a peripheral smear is reviewed.
  • Although the giant granules are seen using routine staining techniques, in some individuals with atypical CHS the presence of these giant granules can be less striking and thus missed by routine evaluation.
  • Slide review is optimally conducted by a hematologist or other specialist with experience reviewing blood smears for the presence of abnormal granules.
  • Because the finding of WBC giant granules is the most reliable clinical diagnostic criterion for CHS, the combination of any of the other hematologic findings listed below should prompt review of a peripheral blood smear to evaluate for giant granules.
• Other hematologic findings:
  • Absent or reduced number and/or irregular morphology of platelet-dense bodies (required for the secondary wave of platelet aggregation) on whole-mount electron microscopy (Figure 1a, 1b)
  • Normal or reduced number of natural killer cells with abnormal (reduced) function
  • Neutropenia
  • Normal immunoglobulins, complement, antibody production, and delayed hypersensitivity

Figure 1.

Examples of granules in polymorphonuclear neutrophils, platelet-dense bodies, and pigment in hair shafts for controls, classic Chediak-Higashi syndrome (CHS), and atypical CHS a. Whole-mount electron microscopy (EM) of control platelets shows several (more...)

Other. Pigment clumping on polarized light microscopy hair analysis (Figure 1f, 1g)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. Note: When evaluating sibs of a proband for the purpose of the family history, clinicians should have a high level of suspicion for all findings that may be associated with CHS, since presenting manifestations may vary in sibs with the same biallelic LYST pathogenic variants.

Establishing the Diagnosis

The clinical diagnosis of CHS is established in a proband by identification of the pathognomonic giant granules within leukocytes on peripheral blood smear (see Suggestive Findings). The molecular diagnosis of CHS is established in a proband by the identification of biallelic pathogenic (or likely pathogenic) variants in LYST on molecular genetic testing [Sharma et al 2020, Morimoto et al 2023] (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variant" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic LYST variants of uncertain significance (or of one known LYST pathogenic variant and one LYST variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (Option 1), whereas comprehensive genomic testing does not (Option 2).

Clinical Description

Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism (OCA), immunodeficiency, and a mild bleeding tendency. These features are present in nearly all individuals with CHS but to a very variable degree. Affected individuals with severe presentations (i.e., OCA; early-onset, recurrent, severe infections; and a bleeding diathesis) are considered to have "classic" CHS. Individuals with milder phenotypes (e.g., later-onset, milder pigmentary, immunologic, and hematologic features) are considered to have "atypical" CHS (also referred to as "mild" or "adolescent" CHS). Both groups of individuals are at risk of developing hemophagocytic lymphohistiocytosis (HLH), previously called "the accelerated phase," with the highest risk of HLH (~85%) in individuals with classic CHS.

Over time, it has become apparent that the classification of CHS into "classic" vs "atypical" phenotypes is arbitrary, as the considerable overlap of the two groups means that this disorder is best understood as a continuum of severe to milder phenotypes, with the universal feature being the pathognomonic giant granules within leukocytes observed on peripheral blood smear.

Although the proportion of individuals with atypical CHS is unknown [Karim et al 2002, Westbroek et al 2007], it is likely underrecognized. In some individuals with atypical CHS, the neurologic findings may be the predominant manifestation. Additionally, some individuals may not be diagnosed until the third decade of life or later [Weisfeld-Adams et al 2013, Yarnell et al 2020].

Partial oculocutaneous albinism (OCA). Pigment dilution, which can involve eyes, hair, and skin, is highly variable.

Reduced iris pigmentation and iris transillumination may be subtle. Affected individuals may have decreased retinal pigmentation and nystagmus. Visual acuity varies from normal to moderately reduced.

The hair has a "silvery" or metallic appearance. Pigment clumping within the shaft of the hair is generally observed by light microscopy (Figure 1g) [Smith et al 2005].

Skin pigment dilution may not be appreciated unless compared to the pigmentation of family members. Individuals with darker skin tone may observe areas with scattered hyper- and hypopigmentation.

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

Immunodeficiency. Frequent infections usually begin in infancy and are often severe in classic CHS. Individuals with atypical CHS may not have a noticeable increase in severity or frequency of infections.

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.

Periodontitis, an important manifestation of immunologic dysfunction [Thumbigere Math et al 2018, de Arruda et al 2023], can be the clinical finding that leads to the correct diagnosis [Bailleul-Forestier et al 2008].

Neutropenia may be present and, in some individuals, cycles between normal absolute neutrophil counts and neutropenia (also called "cyclic neutropenia").

Bleeding tendency. The bleeding diathesis in CHS, a result of absent or severely reduced platelet-dense granules, is present in both classic and atypical CHS. Clinical manifestations are generally mild and include epistaxis, gum/mucosal bleeding, and easy bruising. The bleeding diathesis may also be subtle (i.e., generally not requiring medical intervention) and thus may not be identified as a health concern by affected persons. However, with trauma or invasive procedures, bleeding may be more severe and prolonged.

Neurologic involvement. Despite successful hematologic and immunologic outcomes with allogenic hematopoietic stem cell transplantation (HSCT) to treat hematologic findings, neurologic involvement nonetheless manifests by early adulthood.

Neurologic features are similar across the CHS phenotypic spectrum; thus, individuals with classic and atypical CHS cannot be distinguished neurologically [Introne et al 2017]. Due to the wide range of neurologic features that can occur, findings among affected individuals are variable and nonspecific. Likewise, age of onset and disease progression also vary. While learning difficulties may be present in childhood and can be considered developmental in nature, other neurologic signs and symptoms are generally not observed until late adolescence or early adulthood and are progressive. Neurologic findings can include:

• Learning difficulties in childhood [Introne et al 2017, Shirazi et al 2019]
• Sensory neuropathy. Onset in late adolescence or early third decade and slowly progresses to sensorimotor neuropathies and/or diffuse motor neuronopathy [Lehky et al 2017]
• Cerebellar dysfunction. Onset in late adolescence or early adulthood [Introne et al 2017]
• Optic neuropathy. Onset in late adolescence or early adulthood [Desai et al 2016]
• Spastic paraplegia. Onset in early to middle adulthood [Shimazaki et al 2014, Koh et al 2022]
• Tremor, which can include kinetic and postural tremor
• Parkinsonism, including L-dopa-responsive parkinsonism, may occur as early as the second or third decade [Bhambhani et al 2013, Weisfeld-Adams et al 2013]
• Progressive cognitive decline late in the disease course

Hemophagocytic lymphohistiocytosis (HLH; also known as the "accelerated phase") occurs in the majority of individuals with CHS who have not undergone HSCT [Lozano et al 2014] and can occur at any age. Although individuals with atypical CHS are thought to be at lower risk of HLH than individuals with classic CHS, the frequency of occurrence in atypical CHS is unknown.

Originally thought to be a malignancy resembling lymphoma, the "accelerated phase" is now known to be HLH characterized by multiorgan inflammation. Manifestations include fever, lymphadenopathy, hepatosplenomegaly, anemia, neutropenia, and thrombocytopenia.

Triggers of HLH remain unclear. Although infection with Epstein-Barr virus is thought to hasten development of HLH, this relationship has never been proven. Abnormal function of NK cells and cytolytic T cells is also believed to contribute to development of HLH [Jessen et al 2011, Gil-Krzewska et al 2016].

Prognosis. HLH and its complications are the most common cause of mortality in individuals with CHS [Lozano et al 2014].

Genotype-Phenotype Correlations

Clinical phenotypes of CHS have been correlated with classes of LYST pathogenic variants [Karim et al 2002, Zarzour et al 2005, Westbroek et al 2007, Morimoto et al 2023].

• Loss-of-function LYST pathogenic variants (e.g., nonsense, frameshift, canonical splice site, single- or multiexon deletions) are typically associated with classic CHS.
• Missense pathogenic variants and in-frame deletions of LYST are associated with atypical CHS; however, individuals with biallelic missense pathogenic variants with classic CHS and HLH have been reported [Sánchez-Guiu et al 2014].

Prevalence

Fewer than 500 individuals with CHS have been reported [Morimoto et al 2023, Talbert et al 2023].

Exact prevalence is difficult to determine, as some individuals have been reported in the literature more than once. In addition, the broad phenotypic spectrum that has become evident since the early descriptions of CHS suggests that many mildly affected individuals may be underrecognized or underreported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Chediak-Higashi syndrome (CHS), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for Chediak-Higashi syndrome.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 6 are recommended.

Agents/Circumstances to Avoid

Avoid the following:

• Live vaccines given the risk of infection due to immunodeficiency
• All nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen) given the risk of exacerbating the bleeding tendency

Evaluation of Relatives at Risk

For early diagnosis and treatment. 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 HLH. Evaluations include:

• Molecular genetic testing if the LYST pathogenic variants in the family are known;
• Examination of peripheral blood for the presence of giant granules in white blood cells if the LYST pathogenic variants in the family are not known. (Note: Although the giant granules are seen using routine staining techniques, in some individuals with atypical CHS 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.)

For hematopoietic stem cell donation. Any relative considering stem cell donation should undergo molecular genetic testing to clarify their genetic status so that informed risk vs benefit discussions for both recipient and donor can be incorporated into transplant donor-option decision making. Whenever possible, related donors who do not have a familial LYST pathogenic variant are preferred.

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

Pregnancy Management

Based on the limited number of pregnancies in females with CHS reported in the literature to date, pregnancy, labor, and delivery were uneventful [Price et al 1992, Weisfeld-Adams et al 2013]. The infants were healthy.

Bleeding during delivery and the postpartum period are a concern; thus, prior to delivery developing a plan to deal with possible bleeding is recommended.

Therapies Under Investigation

A natural history study at the NIH (Study of Chediak-Higashi Syndrome, NCT00005917) is currently enrolling individuals for longitudinal studies but not offering new therapy.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• The parents of an affected individual are usually heterozygous for a LYST pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a LYST pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Two individuals with CHS caused by uniparental disomy of chromosome 1 have been reported [Dufourcq-Lagelouse et al 1999, Manoli et al 2010].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a LYST pathogenic variant, each sib of an affected individual has at conception 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.
• Sibs who inherit the same biallelic LYST pathogenic variants as the proband may present with discrepant phenotypes [Morimoto et al 2023].
• 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 of a LYST pathogenic variant.

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 and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the LYST pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

LYST encodes the cytoplasmic protein lysosomal-trafficking regulator (LYST), also called CHS1. 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]. Studies in Drosophila have suggested that LYST plays a role in regulating lysosome-related organelle (LRO) formation and in facilitating centrosome maturation and positioning [Lattao et al 2021]. Another study suggested LYST involvement in autophagosome lysosome reformation facilitates fission of autolysosome tubules for lysosomal homeostasis [Serra-Vinardell et al 2023]. However, the precise biologic role of LYST remains unknown.

Mechanism of disease causation. Loss of function

Variants of uncertain significance (VUS). As the use of broader genomic sequencing increases, identification of VUS is also rising. For individuals identified to have VUS in LYST, it is important to correlate the genetic findings with the clinical features following a comprehensive evaluation, specifically taking into consideration the finding of giant granules within leukocytes on the peripheral blood smear (see Suggestive Findings). If a blood smear is unavailable, light microscopy of the hair showing the characteristic pigment clumping throughout the hair shaft may aid in interpretation of VUS.

Author Notes

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

Dr Morimoto is a scientist who performs translational research in the National Institutes of Health Undiagnosed Diseases Program.

Dr Malicdan is a neurologist and a scientist whose main interest is the study of rare diseases. She performs basic and translational research on rare diseases in the National Institutes of Health Undiagnosed Diseases Program.

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

Dr Introne (vog.hin@enortniw) is a pediatrician and medical and biochemical geneticist who performs clinical research on rare diseases at the National Institutes of Health. Dr Introne is actively involved in clinical research regarding Chediak-Higashi syndrome and Hermansky-Pudlak syndrome. She would be happy to communicate with persons who have questions regarding the diagnosis of these disorders or other considerations.

Acknowledgments

The authors would like to gratefully acknowledge the patients with Chediak-Higashi syndrome and their families for contributing to our understanding of CHS over the years. Special thanks to the Chediak-Higashi Syndrome Association and the Hermansky-Pudlak Syndrome Network for their long-standing dedication to research and patient advocacy.

The authors would like to respectfully acknowledge the authors of the Familial Hemophagocytic Lymphohistiocytosis GeneReview for allowing us to link to their GeneReview and providing expert information on the clinical presentation, diagnosis, and management of HLH.

This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

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)
Marie Morimoto, PhD (2023-present)
Elena-Raluca Nicoli, PharmR, PhD; National Human Genome Research Institute (2018-2023)
Camilo Toro, MD (2018-present)
Wendy Westbroek, PhD; National Human Genome Research Institute (2009-2018)

Revision History

• 21 December 2023 (bp) Comprehensive update posted live
• 5 July 2018 (ma) Comprehensive update posted live
• 15 January 2015 (me) Comprehensive update posted live
• 16 February 2012 (me) Comprehensive update posted live
• 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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