Chediak-Higashi syndrome …

Douglas J Lanska MD MS MSPH

Neuroimmunology

Updated 05.14.2024
Released 01.28.2000
Expires For CME 05.14.2027

Chediak-Higashi syndrome

Author: Douglas J Lanska MD MS MSPH

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Chediak-Higashi syndrome

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Introduction

Overview

Chediak-Higashi syndrome is a rare autosomal recessive immunological disorder with hypopigmentation, recurrent infections, bleeding, and hematological malignancy. Neurologic manifestations include a parkinsonian syndrome and peripheral neuropathy, which usually occur relatively late in the course of disease. The molecular basis of this disease is due to mutations in the LYST (CHS1) gene. Lysosome trafficking regulator (LYST) is one of the BEACH (Beige and Chediak-Higashi) domain-containing proteins that is involved in protein trafficking and lysosomal functions. An accelerated phase of the disease can be triggered by Epstein-Barr virus infection and by some other viruses. Bone marrow transplantation or hematopoietic stem cell transplantation can provide long-term treatment for many patients. However, progressive neurologic sequelae may not be prevented by this treatment.

Key points

	• Genetic disorders of hypopigmentation include Chediak-Higashi syndrome, which is associated with abnormal recycling of intracellular organelles.
	• The neurologic symptoms and signs in this syndrome include parkinsonism and peripheral neuropathy late in the course of the disease.

Historical note and terminology

Chediak-Higashi syndrome is a rare, inherited, multisystem disorder affecting the immune system, pigmentation, and the nervous system (47). The first description of this disorder is attributed to Cuban pediatrician Antonio Béguez Caesar (1895-1975), but it was not until more detailed descriptions of the disease and histological findings were published that this syndrome was more widely recognized (09; 96; 19; 42). Sato first applied the eponym of “Chediak and Higashi’s disease,” recognizing the likely identity of “a new leucocytal anomaly” by Cuban physician Alejandro Moisés Chédiak (1903-1993) and “congenital gigantism of peroxidase granules” by Japanese pediatrician Otokata Higashi (1883-1981) (87).

Chediak-Higashi syndrome belongs to diseases of the immune system associated with dysfunction of the neutrophil granulocytes and to diseases that cause hypopigmentation. This disease was initially attributed to a dysfunction of leukocytes, but now it is known to cause a general dysfunction in numerous cell types, including melanocytes (causing variable degrees of oculocutaneous albinism), neutrophils and monocytes (causing immune deficiency with susceptibility for pyogenic infections), platelets (causing prolonged bleeding), and Schwann cells (causing peripheral neuropathy). Giant cytoplasmic granular inclusions in leukocytes were described in the early original publications, but later similar large granules were noted in many other cell types (13). Diseases resembling Chediak-Higashi syndrome were discovered in many different species, such as mink, cow, cat, dog, killer whale, and the beige mouse, which is the most extensively studied animal model for Chediak-Higashi disease (50).

Clinical manifestations

Presentation and course

	• Chediak-Higashi syndrome is a rare, inherited, multisystem disorder affecting the immune system, pigmentation, and the nervous system.
	• Individuals with Chediak-Higashi disease typically have light skin, silver-gray hair, photophobia, and solar sensitivity, but these symptoms are not usually recognized before 3 to 4 years of age, when recurrent severe skin and respiratory infections often prompt evaluation and ultimately diagnosis.
	• Neurologic symptoms are infrequent at the early stage of the disease and, if present, are confined to rotatory nystagmus, photophobia, learning disability, and behavioral difficulties.
	• Visual loss and the constriction of visual fields, related to pigmentary degeneration of the peripheral retina, progress with increasing age.
	• In long-term survivors, the most characteristic neurologic abnormality is peripheral, autonomic, and cranial neuropathy.
	• Typically, these patients have slowly progressive weakness, sensory symptoms, clumsy wide-based gait, and diminished deep tendon reflexes.
	• Individuals with Chediak-Higashi syndrome may die at any age from uncontrollable infections.

Chediak-Higashi disease is an autosomal recessive disease resulting from a mutation in the lysosomal trafficking regulator (LYST) gene and characterized by oculocutaneous albinism, easy bruising, dysfunction of natural killer cells, and recurrent pyogenic infections (03).

Patients with Chediak-Higashi disease typically have light skin, silver-gray hair (79), photophobia, and solar sensitivity, but these symptoms are not usually recognized before 3 to 4 years of age, when recurrent severe skin and respiratory infections often prompt evaluation and ultimately diagnosis (45; 47). Pigment defects can be seen in the iris and choroid along with speckled hypopigmentation, typically in sun-exposed areas of the skin. However, some patients do not have oculocutaneous albinism (31). Hepatosplenomegaly can occur after recurrent infections (04). In rare cases, onset is in early adulthood.

The major oral manifestation of with Chediak-Higashi disease is periodontal disease (affecting four of every five affected individuals), although ulceration of the oral mucosa, gingival/labial abscess, and periodontal abscess are also reported (24). There is a large variability of infection-related clinical symptoms such as oropharyngeal infections with gingivitis, periodontitis, or various skin infections caused by either gram-negative or gram-positive organisms. The most frequent infectious agents are Staphylococcus aureus and beta-hemolytic Streptococci (11). Many affected patients are easily bruised and have a prolonged bleeding time due to a functional defect of platelets.

Neurologic symptoms are infrequent at the early stage of the disease and, if present, are usually limited to rotatory nystagmus, photophobia, learning disability, and behavioral difficulties (46).

Visual loss and the constriction of visual fields, related to pigmentary degeneration of the peripheral retina, progress with increasing age (88; 25).

In long-term survivors, the most characteristic neurologic abnormality is peripheral, autonomic, and cranial neuropathy. Typically, these patients have slowly progressive weakness, sensory symptoms, clumsy wide-based gait, and diminished deep tendon reflexes. Two sisters with Chediak-Higashi syndrome presented the same phenotype of slowly progressive motor neuronopathy (with Babinski sign in one of the girls); sural-nerve biopsy showed an abnormal endoneurial accumulation of lipofuscin granules (66). One case has been reported of inflammatory demyelinating neuropathy heralding accelerated Chediak-Higashi syndrome (32).

Mild-to-moderate mental impairment is the most frequently described condition, with seizures, parkinsonism, spasticity, cerebellar deficits, and olivocerebellar atrophy present in some cases (90; 63; 108; 93; 46). Survivors of the childhood-onset disease often have learning disabilities and neuropsychiatric disorders followed by middle-age dementia, but this is not universal, and occasional patients may not develop neuropsychiatric symptoms (116).

Chediak-Higashi disease may present as hereditary spastic paraplegia in adulthood. A Japanese study assessed LYST mutations in 387 hereditary spastic paraplegia patients and found six adult patients with LYST mutations in four families; affected individuals had intellectual disability, cerebellar ataxia, neuropathy, and pyramidal signs (56).

Individuals with Chediak-Higashi syndrome may die at any age from uncontrollable infections (15; 51; 14). The so-called "accelerated phase" of the illness occurs in 85% of individuals and is characterized by the proliferation of lymphocytes and histiocytes in the reticuloendothelial system, leading to lymphadenopathy, hepatosplenomegaly, and pancytopenia, as well as fever and jaundice—hemophagocytic lymphohistiocytosis (12; 94; 47; 49; 62; 14; 01; 85). This lethal stage may be induced by Epstein-Barr virus or other lymphotropic viruses, and sometimes by other viruses (eg, rotavirus) (73), resulting in a lymphoma-like clinical picture with hepatomegaly and lymphadenopathy. The lymphohistiocytic infiltration can involve the central and peripheral nervous systems as well as skeletal muscle. Uncommonly, the accelerated phase is the initial presentation of Chediak-Higashi syndrome. In the accelerated phase, the brain MRI can show enhancing white matter lesions (41). Papilledema can be seen in some patients due to infiltration of the optic nerve by lymphocytic cells. One patient has been reported with an acute transient sixth nerve paresis in the accelerated phase of the disorder (34). One patient was described as suffering from dysautonomia due to a histiocytic infiltration of the para-aortic sympathetic ganglia (98). Death at this stage can occur from sepsis or from massive bleeding into the brain or gastrointestinal tract (76).

Some patients may have milder phenotypes with attenuated hematologic and immunologic presentations and lower risk of developing hemophagocytic lymphohistiocytosis (115). Such individuals may have late diagnoses even into the seventh decade of life (115).

Prognosis and complications

Eighty percent of the deaths occur in the first decade of life (03). Survival of Chediak-Higashi disease patients until later in life depends on the success of antibacterial treatment. About 85% of patients progress to the accelerated phase and death; however, the onset of this second phase is variable, from months to years or even decades. The accelerated phase clinically resembles lymphoma, although the histological markers for malignancy are missing. Therapeutic interventions may change the onset and outcome of the accelerated phase. Neurologic complications (eg, peripheral neuropathy, spinocerebellar ataxia, parkinsonism, and dementia) are more prominent in long-term survivors (78).

Clinical vignette

Case 1. A 3-year-old boy presented with recurrent infections (10). Physical examination revealed silvery-gray hair, nystagmus, hepatosplenomegaly, and cervical lymphadenopathy. Magnified images of the patient’s silver-gray hair showed an irregular distribution of large and small pigment clumps. Giant granules in lymphocytes, monocytes, and granulocytes were seen on a blood smear. A bone-marrow aspirate revealed erythrophagocytosis and numerous giant granules of within myeloid precursors.

Chediak-Higashi syndrome: hair comparison

Comparison of (1) normal dark hair, (2) normal blonde hair, and (3) hair in Chediak-Higashi syndrome with an irregular distribution of large and small pigment clumps. (Source: Beken et al 2014. Creative Commons Attribution License...
Chediak-Higashi syndrome blood smear

Blood smear with giant intracytoplasmic granules in granulocytes and lymphocytes in Chediak-Higashi syndrome (Source: Beken et al 2014. Creative Commons Attribution License.)
Chediak-Higashi syndrome bone marrow aspirate smears

Bone marrow aspirate smears showing giant lysosomal granules within myeloid precursors (red arrows) and hemophagocytosis (black arrow) in Chediak-Higashi syndrome. (Source: Beken et al 2014. Creative Commons Attribution License.)

Case 2. The proband was a 39-year-old Japanese woman who was born to consanguineous parents (108). The parents noted hypopigmentation of the hair, eyes, and skin. Horizontal nystagmus and photophobia occurred later. Her early development was unremarkable, but there was a mild decline in motor function later in childhood, without any history of major infections. The patient completed high school, but at the age of 22 years she developed bilateral tremor and her walking deteriorated, followed by slowing of speech. Two years later she started to have oculogyric crises two to four times a month. At the age of 25 years, neurologic evaluation showed an IQ of 60, horizontal nystagmus, a rest tremor in her hands, mandible, and tongue, cogwheel rigidity of all limbs, muscular atrophy, an unsteady gait, and absent tendon reflexes. An ophthalmological exam revealed partial hypopigmentation in the iris, retina, and choroid. A diagnosis of juvenile parkinsonism was made at this time, and she was treated with amantadine, levodopa, and trihexyphenidyl, which only slightly improved her symptoms. By the age of 33 years she was not ambulatory, and over the next six years she developed decorticate rigidity.

Laboratory examinations revealed that her white cell count was 2510, the erythrocyte sedimentation was 80 mm per hour, and there was decreased natural killer cell activity with normal phagocyte function. A bone marrow aspirate revealed the presence of giant granules in neutrophil granulocytes. MRI showed marked temporal-dominant brain atrophy with ventricular dilation and high-intensity signal in the substantia nigra, as well as diffuse spinal cord atrophy. Genetic testing was not reported.

Biological basis

	• Chediak-Higashi disease is caused by biallelic mutations in the LYST gene named for lysosome trafficking regulator, which is located on chromosome 1q42-43.
	• The main pathological feature of Chediak-Higashi disease is the presence of giant granules in the cytoplasm of many types of cells, such as neutrophil granulocytes, monocytes, melanocytes, and Schwann cells.

Etiology and pathogenesis

Chediak-Higashi disease is caused by biallelic mutations in the LYST gene named for lysosome trafficking regulator (LYST), which is located on chromosome 1q42-43.

LYST gene cytogenetic location

Cytogenetic location of the LYST (lysosomal trafficking regulator) gene (also known as CHS1 for Chediak-Higashi syndrome 1): 1q42.1-q42.2, which is the long (q) arm of chromosome 1 between positions 42.1 and 42.2. (Courtesy...

The LYST gene was first mapped to a 2.4 Mb region of chromosome 13 in the beige mouse model for Chediak-Higashi syndrome (54). The human gene has 86% homology to the mouse gene. The complementary DNA is 11.4 kb, producing a protein of 3801 amino acids with a molecular mass of 429 kd (07; 70). The structure of some domains in the protein (eg, WD40 repeat) suggests that it may participate in protein-protein interactions, whereas other motifs resemble a protein kinase in yeast (112). A novel lipopolysaccharide-inducible protein (Iba) that is involved in polarized-vesicle trafficking interacts with the lysosome trafficking regulator protein (110). The exact function of the lysosome trafficking regulator protein is unknown, but it may act as an adapter protein that juxtaposes proteins that mediate intracellular membrane-fusion reactions (101). In Dictyostelium, mutations in the LYST homolog caused a decrease of fusion-competent lysosomes, suggesting its critical role in the maturation of lysosomes (18). This suggests that lysosome trafficking regulator participates in intracellular protein trafficking or in the transport and fusion of lysosomal vesicles (72). Lysosome trafficking regulator contains BEACH (Beige and Chediak-Higashi), a 280 amino acid residue domain that is a component of nine proteins (BDCPs) associated with several human diseases caused by lysosomal trafficking dysfunction (23). Depending on the function of the particular protein, mutations may affect the size of lysosomes (lysosome trafficking regulator), autophagy, apoptosis, and synapse formation. One of the BDCPs called “neurobeachin” regulates neurotransmitter receptor formation and recycling (71).

LYST plays a key role in maintaining lysosomal homeostasis following autophagy, and the resultant dysregulation during autophagic lysosome reformation is likely associated with the neurodegenerative phenotype of Chediak-Higashi syndrome (89; 99). A LYST-deficient human neuronal model exhibited lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes (89). These results were reproduced in neurons differentiated from induced pluripotent stem cells obtained from Chediak-Higashi syndrome patients. LYST apparently ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation, a necessary step to restore free lysosomes after autophagy.

Randomly distributed, single base-pair mutations have been identified in the LYST gene of Chediak-Higashi patients (70). At least 147 variants in LYST have been identified, including 61 frameshift variants (41%), 44 nonsense variants (30%), 23 missense variants (16%), 13 splice site variants or small genomic deletions for which the coding effect is unknown (9%), five in-frame variants (3%), and one start-loss variant (1%) (69). A genotype-phenotype correlation has been identified, whereby individuals harboring at least one missense or in-frame variant generally had milder disease, whereas those with two nonsense or frameshift variants generally had more severe disease (69).

In a single case, maternal uniparental isodisomy in chromosome 1 was found, and the mutation was a three base-pair deletion leading to a termination codon in the LYST gene (28). Another case with early developmental delay was related to paternal heterodisomy of chromosome 1 (64). In patients with severe childhood Chediak-Higashi syndrome, only functionally null mutant LYST/CHS1 alleles were found, whereas in patients with the adolescent and adult forms of Chediak-Higashi syndrome, missense mutant alleles were identified that likely encode polypeptides with partial function (52; 117; 02). Thus, a correlation of the genotype and clinical phenotype can be established in patients (113). However, clinical manifestations may not be the same even in siblings carrying the same mutation (53).

Individuals with mutations in the ARM/HEAT domain have markedly enlarged granules, but fewer in number, whereas individuals with mutations in the BEACH domain have more numerous granules that are either normal in size or slightly enlarged (99). ARM and HEAT motifs are tandemly repeated sequences of approximately 50 amino acid residues that occur in a wide variety of eukaryotic proteins. The BEACH domain was originally discovered as a conserved region within the protein responsible for the Chediak-Higashi syndrome (CHS). The name BEACH comes from "beige and CHS" domain, where “beige” is another name for Chediak-Higashi disease in mice. The BEACH domain consists of approximately 300 amino acids and is present in proteins involved in vesicle trafficking, membrane dynamics, and receptor signaling. BEACH domains are present in a family of proteins conserved throughout eukaryotes.

The mouse homolog of the lysosome trafficking regulator protein is the Beige protein. Mutagenesis of this gene has led to the development of a mouse model for Chediak-Higashi disease (111). Using N-ethyl-N-nitrosourea mutagenesis in the mouse, investigators found a novel missense mutation in the lysosomal trafficking regulator gene (Lyst(Ing3618) in a highly conserved position of the WD40 protein domain. The Lyst(Ing3618) mouse model shows a predominantly neurodegenerative phenotype with loss of Purkinje cells (82).

The main pathological feature of Chediak-Higashi disease is the presence of giant granules in the cytoplasm of many types of cells, such as neutrophil granulocytes, monocytes, melanocytes, and Schwann cells (35).

Chediak-Higashi syndrome Wright-Giemsa staining

Wright-Giemsa staining of a peripheral blood smear from a patient with Chediak-Higashi syndrome showing polymorphonuclear leukocytes with abundant giant intracytoplasmic granules. (Source: Lozano et al 2014. Creative Commons Attri...

These acidophilic secondary lysosomes are misrouted to the perinuclear region and contain all of the normal lysosomal enzymes (67). Although the lysosome trafficking regulator protein is localized to the microtubular cytoskeletal network, no abnormality is noted in the microtubular network from fibroblasts of Chediak-Higashi patients (77). Study of the transportation of various lysosomal-membrane components gives the strongest evidence that there is a missorting of plasma membrane components between early and late lysosomes (33). Defects in the ability of cells to repair plasma membrane lesions and faulty exocytosis of lysosomes were found in fibroblasts derived from patients and the beige-J mouse (44). In addition, the peptide loading onto major histocompatability complex class II molecules and antigen presentation are severely delayed by a mechanism that involves microtubules. The defect in transporting vesicles likely explains the defects seen in granulocytes, melanocytes, and platelets (27).

In granulocytes, the lysosomal abnormality causes impairment in migration and chemotactic functions, but phagocytosis is apparently normal. Patients with Chediak-Higashi disease have abnormal natural killer cell function, which is in part responsible for the cellular immune defect leading to recurrent infections (36; 35). LYST is involved in regulation of multiple aspects of natural-killer-cell lytic activity, including control of lytic granule size, polarization, and regulated exocytosis (36). An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in these patients (35).

Cytotoxic lymphocytes in culture show that the initial steps of secretory lysosome formation are normal in Chediak-Higashi syndrome, but the organelles subsequently fuse together during cell maturation to form the giant secretory lysosomes (97). Cytotoxic lymphocyte-associated antigen 4 (CTLA-4 or CD152) shows an abnormal accumulation in enlarged vesicles instead of proper cell surface expression, which may have a role in generation of the lymphoproliferative phase of this disease (08).

A defect in the fusion of melanosomes to secondary vesicles in melanocytes results in the aggregation of melanin pigment. Furthermore, the transfer of melanosomes to keratinocytes is disturbed, leading to hypomelanosis. Decreased pigmentation is found in the retina, the choroid, and the ciliary epithelium, which explains the ocular findings.

The defect in platelets is related to the abnormal serotonin, nucleotide, and calcium storage pool in dense granules, which affects the aggregation of platelets. In bovine Chediak-Higashi syndrome, collagen-induced aggregation is deficient, which has been attributed to impaired alpha2-beta1-integrin or rhodocytin-associated pathways (92). The coagulation cascade is normal; however, there is a prolongation of bleeding time in spite of the normal platelet count, which only declines in the accelerated phase of the disease.

The cell membrane lipid (sphingomyelin, phosphatidylcholine, saturated fatty acids) composition of erythrocytes is also altered in Chediak-Higashi disease; however, the clinical significance of this finding is unknown (20).

Neuronal cells also show the presence of giant intracellular aggregates. There are acid phosphatase-positive inclusions in Schwann-cells and muscle cells. In nerve biopsy specimens, axonopathy of myelinated fibers has been observed (60; 68). Other neuropathological changes have been associated with a lymphohistiocytic infiltration of the central and peripheral nervous system (63). Although the serotonin uptake in the platelets is abnormal, there is no defect in the synaptic serotonin uptake in the brain (58). Neuronal heterotopias in the cerebellum and hippocampus have been described in the beige mouse, but no similar report has been made in humans suffering from Chediak-Higashi disease (38). In a Drosophila model for this disease, with mutations in the Drosophila blue cheese (bchs) gene, there is progressive brain degeneration and a shortened life span; blue-cheese protein is homologous with the lysosome trafficking regulator protein and is known to interact with a lysosomal transport pathway (59). Late-onset degeneration of cerebellar Purkinje cells was observed in the DBA-2J mouse with a Lyst mutation, and it was attributed to oxidative damage to lipid membranes (104).

Differential diagnosis

Chediak-Higashi disease must be distinguished from “gray hair syndromes” and generalized hypopigmentary hair and skin defect syndromes, including forms of oculocutaneous albinism (75; 48; 37).

The term “gray hair syndrome” encompasses a heterogeneous group of rare autosomal recessive disorders with the clinical hallmark of inborn silvery gray hairs (17; 37). In addition to Chediak-Higashi syndrome, this group includes Griscelli syndrome, Elejalde syndrome, Hermansky-Pudlak syndrome, and oculocerebral hypopigmentation syndrome of the Cross type.

Griscelli syndrome is characterized by hypopigmentation localized to the hair, humoral immunodeficiency, an accelerated phase, and progressive neurologic symptoms such as seizures, cerebellar ataxia, and hypotonia (103; 75; 48; 79; 109). However, in contrast to Chediak-Higashi syndrome, there is no peripheral neuropathy, and neutrophil granulocytes do not have giant cytoplasmic inclusions (55). At least three disease-causing genes have since been identified: RAB7A and MYO5A (both on chromosome 15q21), and MLPH (on chromosome 2q37.3) (65; 114).

Elejalde syndrome has similar clinical features to Griscelli syndrome because of the neurocutaneous manifestations (79); however, immunodeficiency is not present. Nevertheless, these have been proposed to represent different presentations of the same disorder. The main clinical features include silver-gray hair and photosensitivity with prominent and progressive neurologic involvement. Most cases have been reported in children with mental retardation, seizures, muscular hypotonia, and premature death (29).

Hermansky-Pudlak syndrome resembles Chediak-Higashi syndrome with oculocutaneous albinism and a bleeding diathesis; however, there is no immunodeficiency and no accelerated phase (43; 75; 48). Ceroid lipofuscin accumulates in different organs leading to pulmonary fibrosis and hepatomegaly, but no significant neurologic involvement is seen. This disease is associated with mutations in various genes coding for “biogenesis of lysosome-related organelles complex-1” (BLOC-1), which is associated with phosphatidylinositol 4-kinase type II, an integral component of the lysosomal membrane (81; 86).

Oculocerebral hypopigmentation syndrome of the Cross type is a rare congenital syndrome characterized by cutaneous and ocular hypopigmentation, various ocular anomalies (including corneal and lens opacity, spastic ectropium, and/or nystagmus), growth deficiency, intellectual deficit and other progressive neurologic anomalies such as spastic tetraplegia, hyperreflexia, and athetoid movements (22; 21). Other associated anomalies include urinary tract abnormalities, Dandy-Walker malformations, and bilateral inguinal hernia.

Diagnostic workup

	• The presence of giant, irregular granules in leukocytes seen in Wright-stained blood smears is still the best diagnostic marker of Chediak-Higashi syndrome.
	• Molecular testing for Chediak-Higashi disease is difficult and time-consuming due to the large size of the gene and the random nature of mutations.

Although the genetic basis for Chediak-Higashi disease is known, the presence of giant, irregular granules in leukocytes seen in Wright-stained blood smears is still the best diagnostic marker (83). Similar large cytoplasmic granules can be seen occasionally in chronic myelogenic leukemia and acute promyelocytic leukemia.

Nerve conduction tests and neuroimaging are helpful to assess neurologic involvement (68; 06). Electrophysiological studies may reveal prolonged conduction velocities and axonal loss (68). Neuroradiologic examinations (CT or MRI) may show nonspecific diffuse cerebral atrophy and periventricular white matter changes (06) and possibly developmental structural abnormalities of the cerebellum and posterior fossa (46).

Molecular testing for Chediak-Higashi disease is difficult and time-consuming due to the large size of the gene and the random nature of mutations. Protein truncation analysis is a possible alternative to demonstrate a defect in the lysosome trafficking regulator protein but it is not routinely available.

Genetic confirmation is established by the detection of pathogenic variants in LYST in combination with clinical evidence of disease. Conventional molecular genetic testing of LYST by genomic DNA (gDNA) Sanger sequencing detects most pathogenic variants, but a significant minority remain undiagnosed.

cDNA Sanger sequencing as a complementary method to identify variant alleles that are undetected by gDNA Sanger sequencing increases the molecular diagnostic yield (57).

Heterozygotes are completely symptom-free, and no histological or biochemical abnormalities have been detected (45).

Management

	• Bone marrow transplantation may provide curative treatment.
	• Allogenic hematopoietic stem cell or cord-blood transplantation from HLA-matched donors (mainly relatives) has been used with a more than 50% survival over 5 years.
	• Routine immunizations are strongly encouraged.
	• Antibiotic management of infections is crucial in the early phase; however, no benefit is experienced from antibiotic prophylaxis.
	• High-dose glucocorticoids, chemotherapy, intravenous immunoglobulins, and splenectomy are of some benefit in patients during the accelerated phase.
	• The therapeutic outlook for patients with Chediak-Higashi syndrome has improved significantly over the past 30 years, with improved quality of life and survival.

Bone marrow transplantation may provide curative treatment. Long-term correction of the disease has been reported from several institutions (95). Out of 10 children receiving bone marrow transplantation, seven had a favorable outcome for the 2 to 13 years of observation. Two patients died after progressing into the accelerated phase and one died from infectious complications (39). The presence of a small percentage of donor neutrophils (hematopoietic chimerism) in a patient resulted in normal development and no increase in incidence of infections (105). However, progressive neurologic symptoms (cerebellar ataxia and peripheral neuropathy) have been reported in a subset of patients receiving bone marrow transplantation 10 years earlier (100).

Allogenic hematopoietic stem cell or cord-blood transplantation from HLA-matched donors (mainly relatives) has been used with a more than 50% survival over 5 years (30; 106; 80; 61; 47; 102; 107; 91). Haploidentical stem cell transplantation (ie, using a half-matched donor, typically a parent) with post-transplant cyclophosphamide is a feasible alternative (84).

Other therapeutic modalities available in Chediak-Higashi disease are supportive. Routine immunizations are strongly encouraged. Antibiotic management of infections is crucial in the early phase; however, no benefit is experienced from antibiotic prophylaxis. Intravenous DDAVP is used prior to invasive procedures to help control bleeding, and platelet transfusions are given as needed for serious bleeding; nonsteroidal antiinflammatory drugs should generally be avoided because they can exacerbate the bleeding tendency (47). Corrective lenses are used to improve visual acuity. Results from ascorbic acid administration are contradictory. In some reports there was a benefit from ascorbate supplementation for the bactericidal function of granulocytes in vitro; however, several studies showed no effect in patients (45). The treatment of neurologic symptoms remains symptomatic.

High-dose glucocorticoids, chemotherapy, intravenous immunoglobulins, and splenectomy are of some benefit in patients during the accelerated phase (11; 05). A combined treatment with rituximab and cyclosporine may produce remission before bone marrow transplantation (74).

Ongoing surveillance should include yearly ophthalmologic examinations, and for atypical or adolescent/adult-onset disease the following are recommended: abdominal ultrasound (for hepatosplenomegaly), complete blood count (for cytopenias), liver-function tests, serum ferritin concentration, and serum soluble interleukin-2 receptor concentration (47).

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References

01: AlAhmari A, Khogeer H. Successful use of emapalumab in refractory hemophagocytic lymphohistiocytosis in a child with Chédiak-Higashi syndrome: a case report. J Med Case Rep 2023;17(1):113. PMID 36978158
02: Al-Tamemi S, Al-Zadjali S, Al-Ghafri F, Dennison D. Chediak-Higashi syndrome: novel mutation of the CHS1/LYST gene in 3 Omani patients. J Pediatr Hematol Oncol 2014;36(4):e248-50. PMID 24072239
03: Ajitkumar A, Yarrarapu SNS, Ramphul K. Chediak Higashi syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, 2022. PMID 29939658
04: Antunes H, Pereira A, Cunha I. Chediak-Higashi syndrome: pathognomonic feature. Lancet 2013;382(9903):1514. PMID 23541537
05: Aslan Y, Erduran E, Gedik Y, Mocan H, Yildiran A. The role of high dose methylprednisone and splenectomy in the accelerated phase of Chediak-Higashi syndrome. Acta Haematol 1996;96:105-7. PMID 8701696
06: Ballard R, Tien RD, Nohria V, Juel V. The Chediak-Higashi syndrome: CT and MRI findings. Pediatr Radiol 1994;24:266-7. PMID 7800448
07: Barbosa MD, Nguyen QA, Tchernev VT, et al. Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature 1996;382:262-5. PMID 8717042
08: Barrat FJ, Le Deist F, Benkerrou M, et al. Defective CTLA-4 cycling pathway in Chediak-Higashi syndrome: a possible mechanism for deregulation of T lymphocyte activation. Proc Natl Acad Sci U S A 1999;96:8645-50. PMID 10411929
09: Beguez-Cesar BA. Neutropenia cronica maligna familial con granulaciones atipicas de los leucocitos. Bol Soc Cubana Pediat 1943;15:900-22.
10: Beken B, Unal S, Gümrük F. Lysosomal vesicles, giant granules, and erythrophagocytosis in chédiak-higashi syndrome. Turk J Haematol 2014;31(2):209-10. PMID 25035688
11: Blume RS, Wolff SM. The Chediak-Higashi syndrome: studies in four patients and a review of the literature. Medicine 1972;51:247-80. PMID 5064229
12: Bouatay A, Hizem S, Tej A, Moatamri W, Boughamoura L, Kortas M. Chediak-Higashi syndrome presented as accelerated phase: case report and review of the literature. Indian J Hematol Blood Transfus 2014;30(Suppl 1):223-6. PMID 25332584
13: Boxer LA. Qualitative abnormalities of neutrophils. In: Williams WJ, Beutler E, Erslev AJ, Lichtman MA, editors. Hematology. New York: McGraw-Hill Co, 1990:821-34.
14: Carneiro IM, Rodrigues A, Pinho L, et al. Chediak-Higashi syndrome: lessons from a single-centre case series. Allergol Immunopathol (Madr) 2019;47(6):598-603. PMID 31477396
15: Carnide EM, Jacob CM, Pastorino AC, Bellinati-Pires R, Costa MB, Grumach AS. Chediak-Higashi syndrome: presentation of seven cases. Rev Paul Med 1998;116:1873-8. PMID 10349196
16: Certain S, Barrat F, Pastural E, et al. Protein truncation test of LYST reveals heterogenous mutations in patients with Chediak-Higashi syndrome. Blood 2000;95:979-83. PMID 10648412
17: Chandravathi PL, Karani HD, Siddaiahgari SR, Lingappa L. Light microscopy and polarized microscopy: a dermatological tool to diagnose gray hair syndromes. Int J Trichology 2017;9(1):38-41. PMID 28761265
18: Charette SJ, Cosson P. A LYST/beige homolog is involved in biogenesis of Dictyostelium secretory lysosomes. J Cell Sci 2007;120(Pt 14):2338-43. PMID 17606989
19: Chediak MM. [New leukocyte anomaly of constitutional and familial character.] Rev Hematol 1952;7:362-7. PMID 13004553
20: Chico Y, Lafita M, Ramirez-Duque P, Merino F, Ochoa B. Alterations in erythrocyte membrane lipid and fatty acid composition in Chediak-Higashi syndrome. Biochim Biophys Acta 2000;1502:380-90. PMID 11068180
21: Courtens W, Broeckx W, Ledoux M, Vamosa E. Oculocerebral hypopigmentation syndrome (Cross syndrome) in a Gipsy child. Acta Paediatr Scand 1989;78(5):806-10. PMID 2596292
22: Cross HE, McKusick VA, Breen W. A new oculocerebral syndrome with hypopigmentation. J Pediatr 1967;70(3):398-406. PMID 4959856
23: Cullinane AR, Schäffer AA, Huizing M. The BEACH is hot: a LYST of emerging roles for BEACH-domain containing proteins in human disease. Traffic 2013;14(7):749-66. PMID 23521701
24: de Arruda JAA, Sousa-Neto SS, Abreu LG, et al. Oral manifestations of Chediak-Higashi syndrome: a systematic review. Dis Mon 2023;69(1):101356. PMID 35414415
25: Dessinioti C, Stratigos AJ, Rigopoulos D, Katsambas AD. A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytes. Exp Dermatol 2009;18(9):741-9. PMID 19555431
26: Diukman R, Tanigawara S, Cowan MJ, Golbus MS. Prenatal diagnosis of Chediak-Higashi syndrome. Prenat Diagn 1992;12:877-85. PMID 1494540
27: Dotta L, Parolini S, Prandini A, et al. Clinical, laboratory and molecular signs of immunodeficiency in patients with partial oculo-cutaneous albinism. Orphanet J Rare Dis 2013;8:168. PMID 24134793
28: Dufourcq-Lagelouse R, Lambert N, Duval M, et al. Chediak-Higashi syndrome associated with maternal uniparental isodisomy of chromosome 1. Eur J Hum Genet 1999;7:633-7. PMID 10482950
29: Duran-McKinster C, Rodriguez-Jurado R, Ridaura C, de la Luz Orozco-Covarrubias M, Tamayo L, Ruiz-Maldonando R. Elejalde syndrome--a melanolysosomal neurocutaneous syndrome: clinical and morphological findings in 7 patients. Arch Dermatol 1999;135:182-6. PMID 10052404
30: Eapen M, DeLaat CA, Baker KS, et al. Hematopoietic cell transplantation for Chediak-Higashi syndrome. Bone Marrow Transplant 2007;39(7):411-5. PMID 17293882
31: Elevli M, Hatipoğlu HU, Çivilibal M, Selçuk Duru N, Celkan T. Chediak-Higashi syndrome: a case report of a girl without silvery hair and oculocutaneous albinism presenting with hemophagocytic lymphohistiocytosis. Turk J Haematol 2014;31(4):426-7. PMID 25541665
32: Faber IV, Prota JRM, Martinez ARM, Nucci A, Lopes-Cendes I, Júnior MCF. Inflammatory demyelinating neuropathy heralding accelerated Chediak-Higashi syndrome. Muscle Nerve 2017;55(5):756-60. PMID 27669550
33: Faigle W, Raposo G, Tenza D, et al. Deficient peptide loading and MHC class II endosomal sorting in a human genetic immunodeficiency disease: the Chediak-Higashi syndrome. J Cell Biol 1998;141:1121-34. PMID 9606205
34: Feizi M, Rajavi Z, Khorshidifar M, Torkian P, Rahimi F. Acute transient sixth nerve palsy in Chediak-Higashi syndrome. J Pediatr Ophthalmol Strabismus 2018;55:e22-5. PMID 30180240
35: Gil-Krzewska A, Saeed MB, Oszmiana A, et al. An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak-Higashi syndrome. J Allergy Clin Immunol 2018;142(3):914-27. PMID 29241728
36: Gil-Krzewska A, Wood SM, Murakami Y, et al. Chediak-Higashi syndrome: Lysosomal trafficking regulator domains regulate exocytosis of lytic granules but not cytokine secretion by natural killer cells. J Allergy Clin Immunol 2016;137(4):1165-77. PMID 26478006
37: Gironi LC, Zottarelli F, Savoldi G, et al. Congenital hypopigmentary disorders with multiorgan impairment: a case report and an overview on gray hair syndromes. Medicina (Kaunas) 2019;55(3). PMID 30934652
38: Guo H, Sekiguchi M, Shimai K. Cytoarchitectonic abnormalities in cerebellum and hippocampal formation of beige mutant mouse. Tokai J Exp Clin Med 1992;17:53-61. PMID 1523694
39: Haddad E, Le Deist F, Blanche S, et al. Treatment of Chediak-Higashi syndrome by allogenic bone marrow transplantation: report of 10 cases. Blood 1995;85:3328-33. PMID 7756666
40: Helmi MM, Saleh M, Yacop B, ElSawy D. Chédiak-Higashi syndrome with novel gene mutation. BMJ Case Rep 2017;2017. PMID 28183707
41: Herman TE, Lee BC. Accelerated phase of Chediak-Higashi syndrome diffuse white matter-enhancing lesions. Pediatr Radiol 1999;29:527-9. PMID 10398790
42: Higashi O. Congenital gigantism of peroxidase granules: the first case ever reported of qualitative abnormality of peroxidase. Tohuku J Exp Med 1954;59:315-32. PMID 13169161
43: Huizing M, Anikster Y, Gahl WA. Hermansky-Pudlak syndrome and Chediak-Higashi syndrome: disorders of vesicle formation and trafficking. Thromb Haemost 2001;86(1):233-45. PMID 11487012
44: Huynh C, Roth D, Ward DM, Kaplan J, Andrews NW. Defective lysosomal exocytosis and plasma membrane repair in Chediak-Higashi/beige cells. Proc Natl Acad Sci U S A 2004;101(48):16795-800. PMID 15557559
45: Introne W, Boissy RE, Gahl WA. Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome. Mol Genet Metab 1999;68(2):283-303. PMID 10527680
46: Introne WJ, Westbroek W, Cullinane AR, et al. Neurologic involvement in patients with atypical Chediak-Higashi disease. Neurology 2016;86(14):1320-8. PMID 26944273
47: Introne WJ, Westbroek W, Golas GA, Adams D. Chediak-Higashi syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. Seattle (WA): University of Washington, Seattle; 1993-2016. GeneReviews® [Internet] 2015. PMID 20301751
48: Ishaq M, Niazi MK, Khan MS, Nadeem Y. Partial oculocutaneous albinism: two siblings with features of both Hermansky Pudlak and Waardenburg's syndrome. J Coll Physicians Surg Pak 2015;25(11):S43-4. PMID 25933462
49: Jaiswal P, Yadav YK, Bhasker N, Kushwaha R. Accelerated phase of Chediak-Higashi syndrome at initial presentation: a case report of an uncommon occurrence in a rare disorder. J Clin Diagn Res 2015;9(12):ED13-4. PMID 26816903
50: Kahraman MM, Prieur DJ. Chediak-Higashi syndrome in the cat: prenatal diagnosis by evaluation of amniotic fluid cells. Am J Med Genet 1990;36:321-7. PMID 2363432
51: Kaplan J, De Domenico I, Ward DM. Chediak-Higashi syndrome. Curr Opin Hematol 2008;15(1):22-9. PMID 18043242
52: Karim MA, Suzuki K, Fukai K, et al. Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome. Am J Med Genet 2002;108(1):16-22. PMID 11857544
53: Kaya Z, Ehl S, Albayrak M, Maul-Pavicic A, et al. A novel single point mutation of the LYST gene in two siblings with different phenotypic features of Chediak Higashi syndrome. Pediatr Blood Cancer 2011;56(7):1136-9. PMID 21488161
54: Kingsmore SF, Barbosa MD, Nguyen QA, et al. Physical mapping of the beige critical region on mouse chromosome 13. Mamm Genome 1996;7:773-5. PMID 8854868
55: Klein C, Philippe N, Le Deist F, et al. Partial albinism with immunodeficiency (Griscelli syndrome). J Pediatr 1994;125:886-95. PMID 7996360
56: Koh K, Tsuchiya M, Ishiura H, et al. Chédiak-Higashi syndrome presenting as a hereditary spastic paraplegia. J Hum Genet 2022;67(2):119-21. PMID 34483340
57: Kuptanon C, Morimoto M, Nicoli ER, et al. cDNA sequencing increases the molecular diagnostic yield in Chediak-Higashi syndrome. Front Genet 2023;14:1072784. PMID 36968585
58: Lampugnani MG, Buczko W, Ceci A, Mennini A, de Gaetano G. Normal serotonin uptake by blood platelets and brain synaptosomes but selective impairment of platelet serotonin storage in mice with Chediak-Higashi syndrome. Life Sci 1986;16:2193-8. PMID 3713444
59: Lim A, Kraut R. The Drosophila BEACH family protein, blue cheese, links lysosomal axon transport with motor neuron degeneration. J Neurosci 2009;29(4):951-63. PMID 19176804
60: Lockman LA, Kennedy WR, White JG. The Chediak-Higashi syndrome: electrophysiological and electron microscopic observation on the peripheral neuropathy. J Pediatr 1967;70:942-51. PMID 4290695
61: Lozano ML, Rivera J, Sánchez-Guiu I, Vicente V. Towards the targeted management of Chediak-Higashi syndrome. Orphanet J Rare Dis 2014;9:132. PMID 25129365
62: Maaloul I, Talmoudi J, Chabchoub I, Ayadi L, Kamoun TH, Boudawara T, Kallel CH, Hachicha M. Chediak-Higashi syndrome presenting in accelerated phase: A case report and literature review. Hematol Oncol Stem Cell Ther 2016;9(2):71-5. PMID 26254864
63: Maeda K, Sueishi K, Lida M. A case report of Chediak Higashi syndrome complicated with systemic amyloidosis and olivo-cerebellar degeneration. Pathol Res Pract 1989;185:231-7. PMID 2798223
64: Manoli I, Golas G, Westbroek W, et al. Chediak-Higashi syndrome with early developmental delay resulting from paternal heterodisomy of chromosome 1. Am J Med Genet A 2010;152A(6):1474-83. PMID 20503323
65: Masri A, Bakri FG, Al-Hussaini M, et al. Griscelli syndrome type 2: a rare and lethal disorder. J Child Neurol 2008;23(8):964-7. PMID 18403584
66: Mathis S, Cintas P, de Saint-Basile G, Magy L, Funalot B, Vallat JM. Motor neuronopathy in Chediak-Higashi syndrome. J Neurol Sci 2014;344(1-2):203-7. PMID 25043664
67: Miller AI, Stein R, Sundsmo M, Yeh RY. Characterization of lysosomes and lysosomal enzymes from Chediak-Higashi syndrome cultured fibroblasts. Biochem J 1986;238(2):589-95. PMID 3099770
68: Misra VP, King RH, Harding AE, Muddle JR, Thomas PK. Peripheral neuropathy in the Chediak-Higashi syndrome. Acta Neuropathol (Berl) 1991;81:354-8. PMID 2058369
69: Morimoto M, Nicoli ER, Kuptanon C, et al. Spectrum of LYST mutations in Chediak-Higashi syndrome: a report of novel variants and a comprehensive review of the literature. J Med Genet 2024;61(3):212-23. PMID 37788905
70: Nagle DL, Karim MA, Woolf EA, et al. Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nat Genet 1996;14:307-11. PMID 8896560
71: Nair R, Lauks J, Jung S, et al. Neurobeachin regulates neurotransmitter receptor trafficking to synapses. J Cell Biol 2013;200(1):61-80. PMID 23277425
72: Navarro RE, Ramos-Balderas JL, Guerrero I, Pelcastre V, Maldonado E. Pigment dilution mutants from fish models with connection to lysosome-related organelles and vesicular traffic genes. Zebrafish 2008;5(4):309-18. PMID 19133829
73: Nielsen C, Agergaard CN, Jakobsen MA, Møller MB, Fisker N, Barington T. Infantile hemophagocytic lymphohistiocytosis in a case of Chediak-Higashi syndrome caused by a mutation in the LYST/CHS1 gene presenting with delayed umbilical cord detachment and diarrhea. J Pediatr Hematol Oncol 2015;37(2):e73-9. PMID 25551669
74: Ogimi C, Tanaka R, Arai T, Kikuchi A, Hanada R, Oh-Ishi T. Rituximab and cyclosporine therapy for accelerated phase Chediak-Higashi syndrome. Pediatr Blood Cancer 2011;57(4):677-80. PMID 21681939
75: Otreba M, Buszman E, Miliński M, Wrześniok D. Hypomelanoses transmitted from generation to generation [Article in Polish]. Postepy Hig Med Dosw (Online) 2014;68:1081-90. PMID 25228517
76: Page AR, Berrendes H, Warner J, Good RA. The Chediak-Higashi syndrome. Blood 1962;20:330-6. PMID 14483147
77: Perou CM, Leslie JD, Green W, Li L, Ward DM, Kaplan J. The Beige/Chediak-Higashi syndrome gene encodes a widely expressed cytosolic protein. J Biol Chem 1997;272:29790-4. PMID 9368050
78: Pettit RE, Berdal KG. Chediak-Higashi syndrome. Neurologic appearance. Arch Neurol 1984;41:1001-2. PMID 6477224
79: Raghuveer C, Murthy SC, Mithuna MN, Suresh T. Silvery hair with speckled dyspigmentation: Chediak-Higashi syndrome in three Indian siblings. Int J Trichology 2015;7(3):133-5. PMID 26622160
80: Rihani R, Barbar M, Faqih N, et al. Unrelated cord blood transplantation can restore hematologic and immunologic functions in patients with Chediak-Higashi síndrome. Pediatr Transplant 2012;16(4):E99-E105. PMID 21450011
81: Rodriguez-Fernandez IA, Dell'angelica EC. A data-mining approach to rank candidate protein-binding partners-The case of biogenesis of lysosome-related organelles complex-1 (BLOC-1). J Inherit Metab Dis 2009;32(2):190-203. PMID 19083121
82: Rudelius M, Osanger A, Kohlmann S, et al. A missense mutation in the WD40 domain of murine Lyst is linked to severe progressive Purkinje cell degeneration. Acta Neuropathol 2006;112(3):267-76. PMID 16791600
83: Rudramurthy P, Lokanatha H. Chediak-Higashi syndrome: a case series from Karnataka, India. Indian J Dermatol 2015;60(5):524. PMID 26538743
84: Sachdev M, Bansal M, Chakraborty S, Hamal S, Bhargava R, Dua V. Haploidentical stem cell transplant with post-transplant cyclophosphamide for Chediak-Higashi syndrome: a very rare case report. J Pediatr Hematol Oncol 2021;43(7):e1030-2. PMID 33093354
85: Safavi M, Parvaneh N. Chediak Higashi syndrome with hemophagocytic lymphohistiocytosis. Fetal Pediatr Pathol 2023;42(2):259-62. PMID 35608383
86: Salazar G, Zlatic S, Craige B, Peden AA, Pohl J, Faundez V. Hermansky-Pudlak Syndrome Protein Complexes Associate with Phosphatidylinositol 4-Kinase Type II {alpha} in Neuronal and Non-neuronal Cells. J Biol Chem 2009;284(3):1790-802. PMID 19010779
87: Sato A. Chediak and Higashi's disease: probable identity of a new leucocytal anomaly (Chediak) and congenital gigantism of peroxidase granules (Higashi). Tohoku J Exp Med 1955;61(2-3):201-10. PMID 14396888
88: Sayanagi K, Fujikado T, Onodera T, Tano Y. Chediak-Higashi syndrome with progressive visual loss. Jpn J Ophthalmol 2003;47(3):304-6. PMID 12782169
89: Serra-Vinardell J, Sandler MB, De Pace R, et al. LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size. Cell Mol Life Sci 2023;80(2):53. Erratum in: Cell Mol Life Sci 2023;80(3):81. PMID 36707427
90: Sheramata W, Kott HS, Cyr DP. The Chediak-Higashi-Steinbrinck syndrome: presentation of three cases with features resembling spinocerebellar degeneration. Arch Neurol 1971;25:289-94. PMID 5156632
91: Shimizu K, Hayashi M, Ito N, et al. Oral management of a haematopoietic stem cell transplant recipient with Chédiak-Higashi syndrome. Case Rep Dent 2021;2021:9918199. PMID 34589239
92: Shiraishi M, Ogawa H, Ikeda M, Kawashima S, Ito K. Platelet dysfunction in Chediak-Higashi syndrome-affected cattle. J Vet Med Sci 2002;64(9):751-60. PMID 12399597
93: Silveira-Moriyama L, Moriyama TS, Gabbi TV, Ranvaud R, Barbosa ER. Chediak-Higashi syndrome with parkinsonism. Mov Disord 2004;19(4):472-5. PMID 15077248
94: Sood S, Biswas B, Kaushal V, Mandal T. Chediak-higashi syndrome in accelerated phase: a rare case report with review of literature. Indian J Hematol Blood Transfus 2014;30(Suppl 1):195-8. PMID 25332576
95: Sparber-Sauer M, Hönig M, Schulz AS, et al. Patients with early relapse of primary hemophagocytic syndromes or with persistent CNS involvement may benefit from immediate hematopoietic stem cell transplantation. Bone Marrow Transplant 2009;44(6):333-8. PMID 19252534
96: Steinbrinck E. Uber eine neue granulationanomalie der luokocyten. Deut Arch Klin Med 1948;193:577-81.
97: Stinchcombe JC, Page LJ, Griffiths GM. Secretory lysosome biogenesis in cytotoxic T lymphocytes from normal and Chediak Higashi syndrome patients. Traffic 2000;1(5):435-44. PMID 11208129
98: Sung JH, Meyers JP, Standlan EM, Cowen D, Wolf A. Neuropathological changes in Chediak-Higashi disease. J Neuropathol Exp Neurol 1968;28:86-118. PMID 5656570
99: Talbert ML, Malicdan MCV, Introne WJ. Chediak-Higashi syndrome. Curr Opin Hematol 2023;30(4):144-51. PMID 37254856
100: Tardieu M, Lacroix C, Neven B, et al. Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak-Higashi syndrome. Blood 2005;106(1):40-2. PMID 15790783
101: Tchernev VT, Mansfield TA, Giot L, et al. The Chediak-Higashi protein interacts with SNARE complex and signal transduction proteins. Mol Med 2002;8(1):56-64. PMID 11984006
102: Thakor A, Geng B, Liebhaber M, Moore T, Wang K, Roberts RL. Successful stem cell transplantation in Chediak-Higashi syndrome. J Allergy Clin Immunol Pract 2015;3(2):271-2. PMID 25609327
103: Tomita Y, Suzuki T. Genetics of pigmentary disorders. Am J Med Genet C Semin Med Genet 2004;131C(1):75-81. PMID 15452859
104: Trantow CM, Hedberg-Buenz A, Iwashita S, Moore SA, Anderson MG. Elevated oxidative membrane damage associated with genetic modifiers of Lyst-mutant phenotypes. PLoS Genet 2010;6(7):e1001008. PMID 20617205
105: Trigg ME, Schugar R. Chediak-Higashi syndrome: hematopoietic chimerism corrects genetic defect. Bone Marrow Transplant 2001;27(11):1211-3. PMID 11551033
106: Trottestam H, Beutel K, Meeths M, et al. Treatment of the X-linked lymphoproliferative, Griscelli and Chédiak-Higashi syndromes by HLH directed therapy. Pediatr Blood Cancer 2009;52(2):268-72. PMID 18937330
107: Umeda K, Adachi S, Horikoshi Y, et al. Allogeneic hematopoietic stem cell transplantation for Chediak-Higashi syndrome. Pediatr Transplant 2016;20(2):271-5. PMID 26511512
108: Uyama E, Hirano T, Ito K, et al. Adult Chediak-Higashi syndrome presenting as parkinsonism and dementia. Acta Neurol Scand 1994;89:175-83. PMID 8030398
109: Verma N, Kumar A, Kushwaha R. Severe anemia due to parvovirus B19 in a silver haired boy. Indian J Pathol Microbiol 2016;59(1):110-2. PMID 26960654
110: Wang JW, Howson J, Haller E, Kerr WG. Identification of a novel lipopolysaccharide-inducible gene with key features of both A kinase anchor proteins and chs1/beige proteins. J Immunol 2001;166(7):4586-95. PMID 11254716
111: Ward DM, Shiflett SL, Huynh D, Vaughn MB, Prestwich G, Kaplan J. Use of expression constructs to dissect the functional domains of the CHS/beige protein: identification of multiple phenotypes. Traffic 2003;4(6):403-15. PMID 12753649
112: Ward DM, Shiflett SL, Kaplan J. Chediak-Higashi syndrome: a clinical and molecular view of a rare lysosomal storage disorder. Curr Mol Med 2002;2(5):469-77. PMID 12125812
113: Westbroek W, Adams D, Huizing M, et al. Cellular defects in Chediak-Higashi syndrome correlate with the molecular genotype and clinical phenotype. J Invest Dermatol 2007;127(11):2674-7. PMID 17554367
114: Westbroek W, Tuchman M, Tinloy B, et al. A novel missense mutation (G43S) in the switch I region of Rab27A causing Griscelli syndrome. Mol Genet Metab 2008;94(2):248-54. PMID 18397837
115: Yarnell DS, Roney JC, Teixeira C, et al. Diagnosis of Chediak Higashi disease in a 67-year old woman. Am J Med Genet A 2020;182(12):3007-13. PMID 32990340
116: Yliranta A, Mäkinen J. Chediak-Higashi syndrome: neurocognitive and behavioral data from infancy to adulthood after bone marrow transplantation. Neurocase 2021;27(1):1-7. PMID 33295840
117: Zarzour W, Kleta R, Frangoul H, et al. Two novel CHS1 (LYST) mutations: clinical correlations in an infant with Chediak-Higashi syndrome. Mol Genet Metab 2005;85(2):125-32. PMID 15896657

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Douglas J Lanska MD MS MSPH

Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
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Former Authors

Gyula Acsadi MD PhD

Patient Profile

Age range of presentation: 0 month to 5 years
Sex preponderance: male=female
Heredity: autosomal recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Chediak-Higashi syndrome: E70.3
ICD-11: Oculocutaneous albinism: EC23.20
OMIM: Chediak-Higashi syndrome: #214500

Elejalde disease: # 256710

Griscelli syndrome, type 1: # 214450

Griscelli syndrome, type 2: # 607624

Griscelli syndrome, type 3: # 609227

Hermansky-Pudlak syndrome, type 1: # 203300

Hermansky-Pudlak syndrome, type 2: # 608233

Hermansky-Pudlak syndrome, type 3: # 614072

Hermansky-Pudlak syndrome, type 4: # 614073

Hermansky-Pudlak syndrome, type 5: # 614074

Hermansky-Pudlak syndrome, type 6: # 614075

Hermansky-Pudlak syndrome, type 7: # 614076

Hermansky-Pudlak syndrome, type 8: # 614077

Hermansky-Pudlak syndrome, type 9: # 614171

Hermansky-Pudlak syndrome, type 10: # 617050

Oculocerebral syndrome with hypopigmentation (Cross syndrome): %257800

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Chediak-Higashi syndrome

Associated Disorders

Albinism
Bleeding disorders
Neutrophil disorders
Peripheral neuropathy
Spinocerebellar degeneration

Differential Diagnosis

gray hair syndrome
other forms of oculocutaneous albinism
Griscelli syndrome
Elejalde syndrome
Hermansky-Pudlak syndrome
- oculocerebral hypopigmentation syndrome of the Cross type
- Wiscott-Aldrich syndrome

Chediak-Higashi syndrome …

Chediak-Higashi syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Media

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Bowel dysfunction in neurologic disorders

Anti-IgLON5 disease

Coma due to primary brainstem and diencephalic lesions

Anti-LGI1 encephalitis

Giant cell arteritis

Transient visual loss

Hyperventilation syndrome

Myositis and cancer

	• Prenatal diagnosis is possible.
	• Early recognition of Chediak-Higashi syndrome is important to protect against problems related to infections and bleeding.
	• Curative treatment by bone marrow transplantation may be considered.

Chediak-Higashi syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Media

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Bowel dysfunction in neurologic disorders

Anti-IgLON5 disease

Coma due to primary brainstem and diencephalic lesions

Anti-LGI1 encephalitis

Giant cell arteritis

Transient visual loss

Hyperventilation syndrome

Myositis and cancer

This is an article preview.
Start a Free Account
to access the full version.