Chediak-Higashi Syndrome

Anitha Ajitkumar; Marco Zeppieri

Chediak-Higashi Syndrome

Author: Anitha Ajitkumar Editor: Marco Zeppieri Updated: 3/29/2026 11:02:19 PM

Introduction

Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive, multisystem condition that was identified in the 1940s and marked by partial oculocutaneous albinism, immunodeficiency, bleeding diathesis, and progressive neurological decline. (Please see StatPearls' companion reference, "Lymphoproliferative Disorders," for further information.) Beguez-Cesar initially described the syndrome in 1943.[1] Subsequent work by Chediak in 1952 and Higashi in 1954 identified abnormal distribution of myeloperoxidase within neutrophil granules.[2][3]

A defining feature includes the presence of giant cytoplasmic granules in granulocytes, other cell types, and bone marrow. The disorder results primarily from mutations in the lysosomal trafficking regulator (LYST), also known as CHS1, which encodes a cytoplasmic protein essential for vesicular trafficking and lysosomal function.[4] CHS is categorized as a syndromic primary immunodeficiency and is frequently likened to illnesses associated with analogous lysosomal abnormalities, such as Griscelli and Hermansky-Pudlak syndromes, which need to be considered in the differential diagnosis.[5][6] The natural history usually entails an initial stable phase featuring mild to moderate immune and pigmentation abnormalities. In rare cases, complications can occur and develop into a life-threatening accelerated phase defined by hemophagocytic lymphohistiocytosis (HLH), frequently the primary cause of mortality in these patients.[7] The disease affects multiple organ systems, including the integumentary system, hair follicles, ocular structures, the immune response, the hematopoietic system, and the central nervous system.[8] Phenotypic manifestations vary and include severe childhood-onset typical CHS and milder adult-onset variants characterized by major neurological symptoms and less pronounced immunological dysfunction.[9] Although rare, with fewer than 500 cases documented worldwide, CHS provides essential insights into key biological mechanisms, including lysosomal biogenesis, immunological synapse function, and organelle trafficking.[10] At the cellular level, CHS is characterized by impaired lysosome-related organelles,[11] such as melanosomes, platelet dense granules, lytic granules in cytotoxic T cells and natural killer cells, and late endosomes.[12] Malfunction of these organelles results in characteristic clinical manifestations, including atypical pigmentation, impaired cytotoxicity, aberrant hemostasis, and compromised antigen presentation. The pathophysiological hallmarks are reflected in murine and other animal models, including the Beige mouse,[13] Persian cats,[14] corn snakes,[15] Aleutian mink,[16] and Japanese black cattle,[17] all of which possess mutations in homologs of LYST and exhibit analogous phenotypes, thereby underscoring the conserved function of LYST in vesicle trafficking and lysosomal activity.[4] The disease demonstrates no established regional or ethnic predilection; however, Chediak-Higashi syndrome may occur more frequently in consanguineous populations due to its autosomal recessive inheritance pattern.[10] Diagnosis frequently depends on clinical suspicion supported by distinctive peripheral smear observations and genetic validation of LYST mutations.[18][19] Hematopoietic stem cell transplant is the sole definitive intervention to correct immunologic and hematologic impairments; however, it does not impede neurologic progression. Current research into the molecular and cellular roles of LYST is progressing, providing optimism for prospective disease-modifying therapies.

Etiology

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Etiology

CHS results from pathogenic mutations in the LYST (lysosomal trafficking regulator), also known as CHS1. The LYST gene encodes a substantial cytoplasmic protein (about 430 kDa) that is ubiquitously expressed, with elevated expression in immune cells, melanocytes, and neurons. The protein plays a crucial role in regulating lysosome dimensions, function, synthesis, fusion, and intracellular transport of cytoplasmic granules. Despite LYST's discovery more than 2 decades ago, the exact molecular function of this gene remains incompletely understood.

Current data indicate that LYST is essential for the fission of lysosomes and lysosome-related organelles as well as for the regulation of membrane dynamics within the endolysosomal system. The LYST gene is located on the long arm of chromosome 1 [1q42-43]. Numerous different mutations have been discovered.[20][21][22]

Mutations in LYST can be classified as missense, nonsense, frameshift, or splice-site variants, and they are distributed throughout the whole coding area without a unifying mutational hotspot.[4][23] The LYST protein possesses functional domains, including a Pleckstrin homology domain, a Beige and Chediak-Higashi domain, and several WD40 repeats in the C-terminal region, all of which are associated with vesicular trafficking and protein-protein interactions.[24] The N-terminal region includes ARM (armadillo) repeats and HEAT (Huntingtin, elongation factor 3, protein phosphatase 2A, target of rapamycin) repeats. ARM/HEAT-like domains are believed to participate in microtubule-associated transport and membrane docking.[25] A link between genotype and phenotype has been identified. Individuals with biallelic truncating mutations (nonsense or frameshift) typically exhibit more severe clinical symptoms and early-onset disease, including an elevated risk for HLH. Conversely, patients with at least 1 hypomorphic or missense mutation may display an unusual or attenuated phenotype, often manifesting in adolescence or adulthood, frequently characterized by major neurodegenerative symptoms and the absence or delay of HLH. This association is not absolute; exceptions exist, and clinical heterogeneity is affected by supplementary genetic and possibly epigenetic modifiers.[10] Animal models substantiate the function of LYST in lysosomal homeostasis. The Beige mouse possesses a spontaneous LYST mutation, exhibiting enlarged lysosomes, impaired cytotoxic T- and natural killer–cell function, oculocutaneous albinism, and prolonged bleeding tendencies. These findings underscore the critical function of LYST in lysosome fission and trafficking, rather than in degradation itself.

Loss-of-function mutations cause defective vesicle scission following endosome-lysosome fusion, resulting in the development of enlarged, dysfunctional organelles in various cell types, which is a cellular hallmark of CHS.[2][26] The pathogenesis of CHS is based on genetic abnormalities that impair lysosomal dynamics, therefore influencing pigmentation, immunology, hemostasis, and neuronal function. Ongoing research into the molecular biology of LYST and its interacting partners is essential for elucidating disease processes and formulating targeted treatments.

Epidemiology

CHS is an exceedingly rare autosomal recessive condition, with fewer than 500 cases documented worldwide to date.[10] The exact global incidence and prevalence remain unknown due to its rarity. The condition is estimated to affect roughly 1 in 1 million individuals globally.

The disease does not exhibit a noticeable ethnic or regional preference. However, cases have been documented in several communities, including individuals of Middle Eastern, East Asian, European, and Latin American heritage. A heightened prevalence has been noted in populations with elevated consanguinity rates, attributable to autosomal recessive inheritance.[1] CHS exhibits equal sex distribution among men and women, in accordance with its autosomal inheritance pattern. Most cases manifest in early childhood, typically before the age of 5; however, atypical cases with less severe symptoms may remain undiagnosed until adolescence or adulthood. Neonatal or infantile manifestations are more prevalent in the typical, severe variant of CHS, which is often linked to a heightened risk of HLH. In classic instances, the median age of onset of HLH in CHS occurs during the first decade of life, generally between 2 and 5 years.[10][27] A national survey in Japan identified several individuals with CHS, revealing that most exhibited early-onset disease accompanied by severe immunologic problems and neurodegeneration.[28] Findings from this survey emphasize the importance of early diagnosis and hematopoietic stem cell transplant to prevent progression to the accelerated phase. The incidence of CHS is probably underestimated due to misdiagnosis or delayed diagnosis, particularly in atypical adult cases where neurodegeneration or mild pigmentary alterations may predominate in the clinical presentation. Enhanced accessibility to genetic testing and heightened awareness of distinctive peripheral blood smear abnormalities may elevate detection rates. Moreover, improvements in newborn screening and next-generation sequencing panels for primary immunodeficiencies may facilitate the early detection of CHS in areas where the condition was previously overlooked.[20][29]

Pathophysiology

CHS is primarily a lysosomal trafficking and organelle biogenesis disorder caused by biallelic mutations in the LYST or CHS1 gene.[30] The LYST protein regulates the size, quantity, and trafficking of lysosomes and lysosome-related organelles across diverse cell types, including melanocytes, platelets, leukocytes, and neurons.[31] In healthy cells, LYST is thought to promote lysosomal fission following fusion events, thereby preserving a dynamic balance in lysosomal morphology.

In CHS, this mechanism is impaired, leading to the development of oversized, nonfunctional lysosomes and lysosome-related organelles. Mutations in this gene disrupt protein synthesis and affect the storage and secretory functions of lysosomal granules of leukocytes, fibroblasts, dense bodies of platelets, azurophilic granules of neutrophils, and melanosomes of melanocytes.[32] These defects result in enlarged vesicles and nonfunctional lysosomes.[33]

The most constant cellular characteristic of CHS is the presence of abnormally enlarged, fused, azurophilic granules in granulocytes, monocytes, melanocytes, platelets, fibroblasts, Schwann cells, astrocytes, hematopoietic cells, and neurons. In immune cells like neutrophils, these granules hinder chemotaxis, phagolysosomal fusion, and bacterial eradication. These granules result from an abnormal fusion between primary granules (azurophilic) and secondary granules (specific). A diagnosis can be made based on the presence of these granulocytes in the peripheral blood or bone marrow.[1] Defective granule exocytosis in cytotoxic T lymphocytes and natural killer cells results in diminished cytotoxicity, contributing to the vulnerability to HLH, a hyperinflammatory condition induced by inadequate immune regulation.[26]

In melanocytes, the impaired synthesis and transfer of melanosomes to keratinocytes leads to partial oculocutaneous albinism.[34][35] In platelets, the absence or reduction of dense granules leads to an extended bleeding time and mucosal hemorrhage, despite normal platelet count results.[10][36] In neurons, especially in the cerebellum and peripheral nerves, dysfunctional lysosomal recycling and the accumulation of enlarged vesicles are postulated to contribute to the progressive neurodegeneration observed in many patients, particularly those with adult-onset or atypical variants of CHS.[37][38]

Histopathology

The histological characteristic of CHS is the presence of enlarged cytoplasmic granules in multiple cell types, particularly leukocytes. In the peripheral blood smear, neutrophils, eosinophils, and monocytes exhibit pathognomonic granules that manifest as large, azurophilic, peroxidase-positive inclusions. These formations vary in size and number, with some cells harboring a single large granule while others display several smaller granules. These inclusions signify aberrantly merged lysosomes and lysosome-related organelles resulting from impaired regulation of vesicle fission.[39] Comparable results are noted in bone marrow aspirates.[40] Myeloid precursor cells exhibit large granules that stain positively for myeloperoxidase, thereby affirming their lysosomal origin. Erythroid precursors and lymphoid cells may generally be unaffected in terms of inclusion development; nevertheless, natural killer cells and cytotoxic T lymphocytes frequently exhibit aberrant granules when examined by immunohistochemistry or electron microscopy.[41] Ultrastructural evaluation of platelets reveals a significant reduction or total disappearance of dense bodies, which are essential for normal hemostasis and store calcium, adenosine diphosphate, adenosine triphosphate, and serotonin. Skin biopsies in patients with CHS may demonstrate hypopigmented basal keratinocytes with significantly diminished or unevenly distributed melanin. Melanocytes frequently possess larger, irregular melanosomes that are inadequately transferred to adjacent keratinocytes.[42] In neural tissue, especially in postmortem specimens or advanced disease, there may be indications of cytoplasmic inclusions, axonal swelling, and neuronal degeneration. Accumulated autophagic vacuoles and enlarged lysosomal structures have been observed in Purkinje cells of the cerebellum, indicating a neurodegenerative process caused by impaired lysosomal clearance.[43] Electron microscopy is the definitive method for characterizing these anomalies at the ultrastructural level.[44] Electron microscopy investigations reveal enlarged lysosomes, occasionally exceeding 2 to 3 µm in diameter, containing membrane-bound electron-dense material. These inclusions have been identified in granulocytes, fibroblasts, melanocytes, and brain cells.[45] In fibroblasts, the inability to repair the plasma membrane after injury has been shown using electron microscopy, correlating the histological phenotype with functional cellular dysfunction.

History and Physical

Patients present at an early age with symptoms of recurrent infections, partial oculocutaneous albinism, and coagulation defects.[46] Results from studies have shown that disease severity correlates with the molecular phenotype. Generally, mutations that result in loss of function lead to a severe childhood-onset disease.

A missense mutation is associated with a milder adolescent- or adult-onset disease. The severity of the disease is not only associated with the molecular phenotype but also with the cellular phenotype. Results from studies of melanocytes and fibroblasts from patients with different clinical phenotypes showed a range of intracellular granule enlargement in various cell types.

Clinical Manifestations

Partial oculocutaneous albinism

Partial oculocutaneous albinism is a prominent feature, but the degree of pigment dilution varies and can either be present normally, partially, or absent. Pigmentary changes may involve the skin, hair, and eyes. The hair has a metallic or silvery appearance, as seen in classic forms of the disease.[47][48] The clumping of the pigment within the hair shaft can also be visualized under light microscopy.[8][34]

A decrease in the pigmentation of the iris leads to a decrease in the pigmentation of the retina. Visual acuity may be affected, with patients having either normal visual acuity or some moderate impairment. Other ophthalmologic symptoms include photophobia, an increased red reflex, optic neuropathy, and a horizontal or rotating nystagmus.[35]

Immunodeficiency

Affected individuals have recurrent, often severe infections that typically begin in infancy.[49] Patients are more susceptible to bacterial and fungal infections, with staphylococcal, streptococcal, pneumococcal, and β-hemolytic species being the most prevalent. Cutaneous and upper respiratory tract infections are among the most common. Results from recent studies have shown that periodontitis is an important indicator of immune dysfunction and could help with the correct diagnosis.[50] Patients with atypical disease may not show symptoms of unusual or severe infections.

Bleeding tendency

Symptoms are usually mild and include epistaxis, mucosal or gum bleeding, and easy bruising. Symptoms are subtle and generally do not require any medical intervention.[7] Hemorrhagic symptoms are a prevalent observation and frequently occur before diagnosis.

Although platelet counts often remain within the reference range, patients often experience prolonged bleeding times due to impaired platelet dense granules. Mucosal hemorrhage (eg, gingival hemorrhage, epistaxis), easy bruising, and profuse bleeding with minor trauma or surgical procedures are prevalent. In certain instances, these symptoms require evaluation by a hematologist before additional characteristics of CHS are recognized.[51] Accelerated phase

The accelerated phase occurs in 85% of the individuals affected and can occur at any age. The accelerated phase is associated with a poor prognosis and is the most common cause of mortality.[49] Approximately 90% of patients die within the first 10 years of life.

The accelerated phase is characterized by fever, hepatosplenomegaly, lymphadenopathy, neutropenia, anemia, and sometimes thrombocytopenia. Diffuse lymphohistiocytic infiltration also involves the liver, spleen, bone marrow, lymph nodes, and the central nervous system. The accelerated phase was initially thought to be caused by a malignant neoplasm such as lymphoma, but the disorder is now known to be HLH, which is associated with multiorgan inflammation.[51]

Hemophagocytic syndrome is caused by inappropriate stimulation of macrophages in the bone marrow and lymphoid organs, leading to phagocytosis of blood cells and the production of large numbers of proinflammatory cytokines. The triggers of the accelerated phase remain unclear. Evidence suggests that infections such as the Epstein-Barr virus might hasten its onset, although this association remains unproven.[52] The absence of natural killer cell activity is also believed to play a role in this process.[21]

Neurologic manifestations

Neurological features manifest by early adulthood despite a successful allogeneic hematopoietic stem cell transplant. These changes are due to the long-term progression of the disease and include stroke, coma, ataxia, tremor, motor and sensory neuropathies, and absent deep tendon reflexes. The neurological examination may initially be normal, but neurologic abnormalities often become apparent as the disease progresses.[29]

Classic CHS may exhibit indicators of developmental delay, hypotonia, and diminished deep tendon reflexes during early childhood. During adolescence and adulthood, neurodegeneration progressively presents as spasticity, ataxia, sensorimotor neuropathy, and parkinsonian features, including tremor and rigidity.[53] Behavioral abnormalities, learning difficulties, and cognitive impairments are commonly observed, with neurological symptoms prevailing in certain individuals.[54]

Atypical phenotype

An unknown number of individuals have unrecognized atypical or milder phenotypes of the disease.[55] Features may include the following:

Subtle or absent oculocutaneous albinism
Decreased platelet-dense bodies with subtle bleeding symptoms
Severe infections in childhood become less frequent with age or are insignificant
Progressive neurological symptoms such as intellectual disabilities, tremors, gait disturbances, and parkinsonism
The neurological manifestations are inconsistent and nonspecific. Neurodegeneration may be the predominant symptom, with only subtle alterations in pigmentation, immune functions, and bleeding abnormalities
All individuals with CHS have abnormal granules within leukocytes

Evaluation

The diagnosis of CHS depends on clinical evaluation, peripheral smear analysis, immunological examination, and genetic testing.[34] A heightened index of suspicion is essential in patients with early-onset partial albinism, pigment dilution of the skin, hair, or eyes, recurrent infections, signs of immunodeficiency, congenital or transient neutropenia, bleeding diathesis, and neurological deterioration. The initial diagnostic indication is frequently observed on a peripheral blood smear, which displays characteristic large azurophilic granules in neutrophils, monocytes, and, on occasion, lymphocytes.

These granules exhibit peroxidase positivity and signify malfunctioning lysosomes and lysosome-related organelles.[56] Microscopy of the hair shaft is an excellent screening tool. Under optical microscopy, hair from patients with CHS often exhibits aggregated melanin granules, in contrast to the evenly distributed melanin observed in healthy individuals.[36]

Testing

A diagnosis can be made based on the presence of abnormally large granules in cells such as melanocytes, leukocytes, and their bone marrow precursors, fibroblasts, the central and peripheral nervous tissue, and hair. Molecular genetic testing can also be performed to detect the biallelic variants in the LYST gene.[57] The definitive diagnostic criterion is genetic testing that verifies biallelic pathogenic mutations in the LYST gene.

Next-generation sequencing panels for primary immunodeficiencies or whole-exome sequencing can detect pathogenic variants, including missense, nonsense, frameshift, and splice-site mutations.[58][59][60] Sequencing techniques may be used to validate specific mutations in families with established harmful alleles when accessible.[61] Immunological testing can indicate compromised natural killer cell and cytotoxic T lymphocyte functionality, frequently characterized by diminished degranulation or cytotoxicity in chromium release assays.[62]

Flow cytometry can reveal reduced expression or atypical mobilization of degranulation markers (eg, CD107a).[63] Standard immunoglobulin levels, lymphocyte subset analysis, and total blood counts with differential may indicate neutropenia and cytopenias, especially during the HLH phase. Once the diagnosis of CHS has been confirmed, the following can be done to assess the extent of the disease:

Assess for the presence of the accelerated phase:
- Splenomegaly
- Any history of recurrent or unexplained fever
- Cytopenias affecting at least 2 cell lines
- Increased serum ferritin concentration
- Increased levels of soluble interleukin-2 receptor levels
- Signs of hemophagocytosis in either the bone marrow or cerebrospinal fluid
- Evidence of liver dysfunction (hypertriglyceridemia or hypofibrinogenemia)[51]
Complete a thorough neurological examination
Screen for signs of lymphoma, as the hemophagocytic lymphohistiocytosis associated with CHS may have a similar clinical appearance
Genetic consultation

Treatment / Management

Treatment of Clinical Symptoms

Hematological and immune deficiency

The only cure for the hematologic and immunologic aspects of the condition is allogeneic hematopoietic stem cell transplantation (HSCT), which should be performed as soon as the diagnosis is established.[40][64]
Outcomes are most favorable when HSCT is performed before the accelerated phase develops. Therefore, clinicians must rule out the accelerated phase or achieve remission before performing HSCT.[7]
Infections, such as those induced by Epstein-Barr virus, require vigorous management, as they might trigger HLH.
If signs of the accelerated phase are evident, then hemophagocytosis should be brought into remission before HSCT.
The guidelines for treating the accelerated phase are the same as those for familial hemophagocytic lymphohistiocytosis and include combination therapy of dexamethasone, cyclosporine A, and etoposide.[65]
Around 75% of individuals achieve remission by 8 weeks. Relapses are not uncommon, and the treatment response declines over time. The 5-year survival rate was reported to be 62%.[66] Success was higher in individuals with human leukocyte antigen-matched donors. Transplant performed during the accelerated phase had a higher rate of mortality. However, those in remission had better outcomes after an HSCT.
Effective medical treatment is essential both prior to and following transplant. Prophylactic antibiotics and antivirals are advised to avert infections in immunocompromised individuals. Platelet transfusions may be necessary during hemorrhagic events, and meticulous dental and surgical planning is recommended due to the danger of bleeding from impaired platelet dense granules.

(B3)

Ocular symptoms

Visual acuity might be improved by correcting refractive errors.
Sunglasses should be worn to protect sensitive eyes against ultraviolet rays.

Hypopigmentation

Individuals must wear sunscreen to prevent skin cancer and sun damage. The degree of protection depends on the severity of hypopigmentation.

Neurological manifestations

Since the symptoms are progressive, rehabilitation should be started as early as possible for older patients with the disease. Neurological problems are addressed symptomatically, as HSCT can not prevent or reverse neurodegeneration. Physical therapy, occupational therapy, and the use of assistive technology can enhance quality of life. In patients exhibiting parkinsonism or motor symptoms, levodopa and carbidopa may provide transient relief.[67]

Prevention of Secondary Complications

Protect against exposure to infectious agents as much as possible.
Nonsteroidal anti-inflammatory drugs should also be avoided as they can exacerbate bleeding tendencies.
Prompt, aggressive use of antibiotics is recommended for bacterial infections.
The use of widespread antibiotic prophylaxis before dental or invasive procedures is controversial. However, clinicians should consider prophylaxis for patients with a compromised immune system and neutropenia.
Immunizations should be administered.
Before any invasive procedures, intravenous desmopressin should be given for 30 minutes to help control bleeding. Platelet transfusion might be necessary for those with serious trauma or extensive bleeding.

Monitoring

Classic CHS

Guidelines for disease surveillance do not exist.
The current standard is to evaluate for HSCT as soon as possible once the diagnosis is established.
An ophthalmologic examination is also necessary.

Atypical or adult-onset form of the disease

Annual screening that should include the following:

Ultrasonography of the abdomen to detect the presence of hepatosplenomegaly
A complete blood count to evaluate for cytopenias
Signs of liver disease include hypofibrinogenemia and hypertriglyceridemia
Check levels of serum ferritin
Monitor levels of interleukin-2 receptor
A bone marrow biopsy or a lumbar puncture if there is suspicion of central nervous system involvement or symptoms of accelerated phase
Ophthalmologic exam

Treatment in Pregnancy

Treatment of CHS during pregnancy is difficult because the data are limited.[68] However, available reports indicate no impact on pregnancy or labor. These findings suggest that the course of the disease does not affect pregnant women.

Differential Diagnosis

The differential diagnosis should include other genetic conditions with oculocutaneous albinism.

Hermansky-Pudlak Syndrome and Griscelli Syndrome

Griscelli syndrome is a rare disorder with features similar to CHS, including partial oculocutaneous albinism, pancytopenia, hemophagocytosis, and humoral and cell-mediated immune deficiency.[26]
Hermansky-Pudlak syndrome is characterized by ocular and cutaneous albinism, bleeding disorders, and deposits of ceroid lipofuscin in various organs.[69]
A key differentiating feature is the absence of abnormal granules in neutrophils, a hallmark of CHS.
Molecular testing can identify mutations in one of several genes associated with Hermansky-Pudlak syndrome (eg, Hermansky-Pudlak syndrome 1 [HPS1], Hermansky-Pudlak syndrome 3 [HPS3]), thereby further differentiating it from CHS.
Giant granules resembling those seen in Chediak-Higashi might also be present in acute and chronic myeloid leukemia, a condition known as the pseudo-Chediak-Higashi anomaly.[70]

Other Conditions to Consider

Cross syndrome is characterized by hypopigmentation, central nervous system involvement such as developmental delay, and ocular defects.[71]
Oculocutaneous albinism subtypes can present with similar pigmentary changes but lack the systemic immune and neurologic features.[72]
Deficiency of the endosomal adaptor p14, identified in 2007, includes short stature, partial albinism, congenital neutropenia, and lymphoid deficiency.[73] The neutrophils demonstrate azurophilic granules and abnormal microbicidal phagosome functions, in contrast to the giant inclusions seen in neutrophils in CHS.
Familial hemophagocytic lymphohistiocytosis is an autosomal recessive disorder caused by a mutation of 1 of the 5 familial hemophagocytic lymphohistiocytosis (FHL1-FHL5) genes, which correspond to the 5 disease subtypes.[74] Symptoms include prolonged fever, hepatosplenomegaly, neurologic abnormalities, including ataxia, coma, hemiplegia, convulsions, and increased cranial pressure. The onset is within the first few months of life or in utero. The symptoms can also appear later in adulthood or childhood.
Primary immunodeficiencies such as chronic granulomatous disease and severe combined immunodeficiency should also be considered in patients presenting with recurrent infections, especially if pigmentation changes are subtle. Unlike CHS, these disorders typically lack bleeding diathesis and hypopigmentation. Patients with chronic granulomatous disease show defective oxidative burst in neutrophils, which is not a feature of CHS. In severe combined immunodeficiency, lymphopenia and early-onset severe infections predominate without the hallmark granule anomalies of CHS.[75][76]
Ataxia-telangiectasia, mitochondrial disorders, and neurodegenerative lysosomal storage diseases may mimic the neurologic features of CHS but are usually distinguishable through neuroimaging, biochemical tests, or genetic studies.[77][78][79]

Ultimately, light microscopy of peripheral blood smears, hair shaft analysis, and genetic confirmation of LYST mutations remain the most definitive tools for differentiating CHS from related syndromes. Clinicians should pursue these studies early in patients with unexplained albinism, recurrent infections, and neurologic decline to prevent delays in diagnosis and timely HSCT.[8]

Prognosis

The prognosis of CHS is guarded, with outcomes significantly influenced by the time of diagnosis, the commencement of the accelerated phase, and the accessibility of curative treatments. In the absence of intervention, the median survival generally extends only through the initial decade of life, predominantly due to lethal infections or complications arising from the accelerated phase.[80] The accelerated phase markedly worsens the prognosis owing to its swift and severe progression.

Patients who fail to get prompt HSCT frequently experience multiorgan failure and may die within months of onset. HSCT, when conducted promptly, ideally before the emergence of neurological symptoms, constitutes the sole therapeutic intervention, rectifying immunodeficiency and averting repeated infections and accelerated phase relapses.[81] Nonetheless, HSCT exhibits restricted effectiveness in preventing or correcting neurological decline, which continues to be a significant contributor to long-term morbidity. Neurological involvement, especially increasing neurodegeneration, significantly influences quality of life and long-term survival. Despite progress in transplantation and supportive treatment, numerous patients experience lasting neurological abnormalities, including ataxia, peripheral neuropathy, and cognitive impairment, which profoundly affect their functionality and autonomy.[54] Bleeding problems and systemic symptoms such as oculocutaneous albinism, although not immediately life-threatening, increase morbidity and necessitate supportive care. The prognosis is most favorable for individuals diagnosed early, managed assertively to avert or address the accelerated phase, and who have HSCT before the onset of significant neurological symptoms.

Complications

Chediak-Higashi syndrome clinical manifestations emerge from atypical lysosomal granules in several cell types, especially immunological cells, resulting in multisystem involvement. A significant complication of CHS is immunodeficiency, which predisposes patients to recurrent and severe infections. Deficient neutrophil chemotaxis and compromised cytotoxic function of natural killer cells and cytotoxic T lymphocytes hinder the body's capacity to eliminate bacterial and viral infections effectively.[1]

Patients often experience infections of the skin, respiratory tract, and mucous membranes, leading to increased morbidity and mortality. Neurologic complications in CHS are progressive and devastating, typically emerging in late childhood or adolescence. These include peripheral neuropathy, cerebellar ataxia, and cognitive deterioration attributable to the accumulation of giant lysosomal granules in neurons and glia, leading to neurodegeneration.[4]

In addition to immunological and neurological involvement, patients with CHS display oculocutaneous albinism and bleeding diathesis resulting from platelet dense granule abnormalities, which cause easy bruising and extended bleeding durations. Skeletal deformities and dental disorders have also been documented, but to a lesser extent. These problems collectively highlight the multisystem characteristics of CHS and the necessity for interdisciplinary care.

A significant consequence is the emergence of the HLH-like accelerated phase, an aggressive lymphoproliferative illness marked by unregulated activation of macrophages and T cells.[49] Infections frequently initiate this phase and may be fatal if not addressed. Clinical manifestations include fever, hepatosplenomegaly, pancytopenia, and coagulopathy, indicative of a systemic hyperinflammatory condition. Timely identification and swift commencement of immunosuppressive treatment and HSCT are essential for survival.[82]

Deterrence and Patient Education

Genetic Counseling

CHS is an autosomal recessive disease; therefore, parents of affected individuals are heterozygotes (ie, carriers of one abnormal LYST gene). Molecular genetic testing is needed to determine the parents' carrier status.[83] If the parents are heterozygotes, each sibling of an affected individual has a 25% chance of developing the disease, a 50% chance of being a carrier, and a 25% chance of not developing the disease or being a carrier.

Evaluation of relatives

Clinicians should assess siblings of affected individuals early. Early assessment helps allow HSCT before complications such as the accelerated phase develop.

Molecular testing can be performed to assess genetic status when family-specific pathogenic variants are known.
If the variants are unknown, an examination of peripheral blood can be performed to detect inclusions in white blood cells.

The best time to determine genetic risk and carrier status is before pregnancy.[84] Genetic counseling, including risks and complications, should be offered to adults who are carriers, at risk of being carriers, or are already affected. Preimplantation genetic diagnosis is also an option for those in whom the pathogenic LYST genes have been identified. DNA banking should also be offered to affected individuals, in which DNA extracted from white blood cells is stored for future use. Future advances may improve testing and understanding of genes.

Preventing infections is crucial given CHS's inherent immunodeficiency. Patients and caregivers must be informed of stringent hygiene protocols, the need to avoid contact with ill individuals, and the importance of seeking immediate medical care for fever or signs of infection. Immunization against prevalent diseases, such as influenza and pneumococcus, is advised; however, live vaccines may be contraindicated in immunosuppressed individuals.

Consistent surveillance for initial indications of infection and timely antibiotic intervention are essential elements of preventive care. Patient education must highlight the signs and symptoms of the accelerated phase of HLH, including persistent fever, atypical bleeding, or neurological manifestations, necessitating rapid evaluation.[85] Families must recognize the imperative nature of HSCT referral when warranted because it is the sole curative treatment for the immunological problems of CHS.

Nutritional support and physical therapy are crucial for alleviating neurological decline and enhancing quality of life. Patients must be apprised of the potential hazards of bleeding and the necessary precautions to prevent trauma or invasive procedures in the absence of appropriate prophylaxis. Psychological assistance is essential due to the chronic and progressive characteristics of CHS, aiding patients and families in managing disease burden and enhancing treatment adherence. Comprehensive patient education encompasses medical, psychological, and preventive elements to diminish morbidity and improve patient outcomes.[86]

Pearls and Other Issues

Numerous clinical insights and challenges are crucial for the effective recognition and management of CHS. The distinctive large granules found in leukocyte peripheral blood smears serve as a vital diagnostic indicator, frequently prompting early diagnosis of CHS.[18] Nonetheless, these granules may be inconsistently present, necessitating molecular genetic testing for LYST mutations to achieve a clear diagnosis. A significant drawback in the management of CHS is the delayed identification of the accelerated phase, which can rapidly progress to lethal multiorgan failure if not addressed.

Clinicians must maintain heightened suspicion in patients with established CHS who exhibit systemic inflammatory manifestations. Misdiagnosis as infectious or other hematologic illnesses can postpone the initiation of suitable immunosuppressive treatment and referral for transplant. Preventive therapies encompass early HSCT before the emergence of neurological symptoms, because transplant can rectify immunodeficiency but has a restricted effect on progressing dementia. Moreover, ethical considerations of genetic counseling for families impacted by CHS and the difficulties of addressing increasing neurodegeneration with few therapeutic alternatives highlight the necessity of comprehensive, patient-centered therapy.

Enhancing Healthcare Team Outcomes

Effective management of CHS necessitates a coordinated, interdisciplinary health care team approach to enhance patient-centered treatment and outcomes.[87] Clinicians, including hematologists, geneticists, neurologists, ophthalmologists, infectious disease experts, laboratory specialists, and immunologists, are accountable for diagnostic and therapeutic decision-making and for coordinating HSCT.[88] These clinicians must equilibrate immunosuppressive therapies with infection prophylaxis and address complications such as HLH and neurodegeneration.

Advanced practice clinicians are essential for patient monitoring, education, and the early identification of problems. Nurses deliver primary care by administering medications, conducting assessments, and instructing patients and families on home care protocols. Their responsibility is to observe for indications of infection or hemorrhage and maintain compliance with guidelines, which is essential for patient safety. Pharmacists enhance antibacterial regimens, oversee drug interactions in immunosuppressive therapy, and provide counsel on supportive care drugs. They also educate the team and patients on drug adherence and potential adverse effects. Effective interdisciplinary communication and care coordination are crucial, incorporating neurologists for progressive neurological symptoms, physical therapists for mobility and rehabilitation, nutritionists for nutritional support, and social workers for psychosocial care. Regular interdisciplinary meetings improve collaborative decision-making and guarantee thorough care plans. Ethical considerations encompass genetic counseling for families, informed consent for HSCT, and addressing quality-of-life concerns. Ongoing education and training of the health care team regarding CHS advancements ensure evidence-based, patient-centered methodologies.

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