Clinical manifestations

Presentation and course

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 (78), 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 (87; 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 (89; 63; 106; 92; 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 (114).

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; 93; 47; 49; 62; 14; 01; 84). This lethal stage may be induced by Epstein-Barr virus or other lymphotropic viruses, and sometimes by other viruses (eg, rotavirus) (72), 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 (97). Death at this stage can occur from sepsis or from massive bleeding into the brain or gastrointestinal tract (75).

Some patients may have milder phenotypes with attenuated hematologic and immunologic presentations and lower risk of developing hemophagocytic lymphohistiocytosis (113). Such individuals may have late diagnoses even into the seventh decade of life (113).

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 (77).

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.

Case 2. The proband was a 39-year-old Japanese woman who was born to consanguineous parents (106). 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 2 to 4 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

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.

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; 69). 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 (110). A novel lipopolysaccharide-inducible protein (Iba) that is involved in polarized-vesicle trafficking interacts with the lysosome trafficking regulator protein (108); 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 (99). 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 (71). 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 (70).

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 (88). A LYST-deficient human neuronal model exhibited lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes (88). 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, and all of the mutations have been found to be either nonsense or out-of-frame (69). In a single case, maternal uniparental isodisomy in chromosome 1 was found, and the mutation was a 3 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; 115; 02). Thus, a correlation of the genotype and clinical phenotype can be established in patients (111). However, clinical manifestations may not be the same even in siblings carrying the same mutation (53).

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 (109). 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 (81).

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).

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 (76). 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 (96). 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 (91). 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 (102).

Epidemiology

Chediak-Higashi disease is a rare inherited condition with an estimated incidence of 1 in 1,000,000 births. The 200 cases reported through 1989 occurred in all races worldwide (45). By 2017, approximately 500 cases had been reported, with a mean age of onset of 5 to 6 years (40).

Prevention

Prenatal diagnosis is possible through histological evaluation of amniotic cells and the chorion villus, as lysosomal inclusions are present in both cell types (26; 47). Because the mutations are random and the gene is large, a test for the detection of mutations in affected individuals or carriers is not available commercially. A protein truncation test for the LYST gene appears to be useful for the detection of randomly distributed mutations, and this technique may lead to a form of prenatal genetic testing (16).

The early recognition of Chediak-Higashi syndrome is important to protect against problems related to infections and bleeding. Furthermore, a curative treatment by bone marrow transplantation may be considered.

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 (74; 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 (101; 74; 48; 78; 107). 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; 112).

Elejalde syndrome has similar clinical features to Griscelli syndrome because of the neurocutaneous manifestations (78); 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; 74; 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 (80; 85).

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

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 (82). 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. Long-term correction of the disease has been reported from several institutions (94). 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 (103). However, progressive neurologic symptoms (cerebellar ataxia and peripheral neuropathy) have been reported in a subset of patients receiving bone marrow transplantation 10 years earlier (98).

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; 104; 79; 61; 47; 100; 105; 90). Haploidentical stem cell transplantation (ie, using a half-matched donor, typically a parent) with post-transplant cyclophosphamide is a feasible alternative (83).

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 (73).

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).