Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive lysosomal disorder characterized by frequent infections, oculocutaneous albinism (OCA), bleeding diathesis, and progressive neurologic deterioration. In 85% of cases, CHS patients develop the accelerated phase characterized by pancytopenia, high fever, and lymphohistiocytic infiltration of liver, spleen, and lymph nodes. Treatment of accelerated-phase CHS is difficult and the prognosis is poor. All affected individuals, including adolescents and adults with atypical CHS and children with classic CHS who have successfully undergone allogenic hematopoietic stem cell transplantation (HSCT), develop neurologic findings during early adulthood.
Chédiak-Higashi syndrome (CHS) is a rare childhood autosomal recessive disorder that affects multiple systems of the body. Patients with CHS exhibit hypopigmentation of the skin, eyes, and hair; prolonged bleeding times; easy bruisability; recurrent infections; abnormal natural killer cell function; and peripheral neuropathy. Morbidity results from patients succumbing to frequent bacterial infections or to an accelerated-phase lymphoproliferation into the major organs of the body. The accelerated phase of CHS is termed hemophagocytic lymphohistiocytosis (HLH), and it develops in 50-85% of patients; it is fatal if not treated. Most patients who do not undergo bone marrow transplantation die of a lymphoproliferative syndrome, although some patients with CHS have a relatively milder clinical course of the disease. The adult form of CHS has a milder course, with no lymphohistiocytic infiltration. It is characterized by neurological manifestations such as polyneuropathy, parkinsonism, dementia, N-methyl-D-aspartate (NMDA) receptor encephalitis,[1] and ataxia.[2] In young adults, a combination of these defects with oculocutaneous albinism or recurrent infections should bring CHS into consideration. Diagnosis is established by the presence of characteristic eosinophilic peroxidase-positive giant granules in leukocytes.
CHS was first described over 60 years ago by Beguez-Cesar (1943) in three siblings bearing the main clinical features of neutropenia and abnormal granules in leukocytes. Chédiak, a Cuban hematologist, reported another case in 1952, and, in 1954, Higashi, a Japanese pediatrician, described a series of cases characterized by misdistribution of myeloperoxidase in the neutrophilic granules of affected patients.[3, 4, 5]
Chédiak-Higashi syndrome (CHS) is an autosomal recessive immunodeficiency disorder characterized by abnormal intracellular protein transport. The Chédiak-Higashi syndrome gene was characterized in 1996 as the LYST or CHS1 gene and is localized to bands 1q42-43. The CHS protein is expressed in the cytoplasm of cells of a variety of tissues and may represent an abnormality of organellar protein trafficking.[6]
The CHS gene affects the synthesis and/or maintenance of storage/secretory granules in various types of cells. Lysosomes of leukocytes and fibroblasts, dense bodies of platelets, azurophilic granules of neutrophils, and melanosomes of melanocytes are generally larger in size and irregular in morphology, indicating that a common pathway in the synthesis of organelles responsible for storage is affected in patients with CHS.[7] In the early stages of neutrophil maturation, normal azurophil granules fuse to form megagranules, whereas, in the later stage (ie, during myelocyte stage), normal granules are formed. The mature neutrophils contain both populations. A similar phenomenon occurs in monocytes. The impaired function in the polymorphonuclear leukocytes may be related to abnormal microtubular assembly.
The disease is often fatal in childhood as a result of infection or an accelerated lymphomalike phase; therefore, few patients live to adulthood. In these patients, a progressive neurologic dysfunction may be the dominant feature. Neurologic involvement is variable but often includes peripheral neuropathy. The mechanism of peripheral neuropathy in CHS has not been completely elucidated. Both the axonal type and the demyelinating type of peripheral neuropathy associated with CHS have been reported.
Defective melanization of melanosomes occurs in oculocutaneous albinism associated with CHS. In melanocytes, autophagocytosis of melanosomes occurs.
Most patients also undergo an accelerated phase or accelerated reaction, which is a nonmalignant lymphohistiocytic lymphomalike infiltration of multiple organs that occurs in more than 80% of patients. This lymphomalike stage is precipitated by viruses, particularly by infection by the Epstein-Barr virus. It is associated with anemia, bleeding episodes, and overwhelming infections leading to death. Infections most commonly involve the skin, the lungs, and the respiratory tract and are usually due to Staphylococcus aureus, Streptococcus pyogenes, and Pneumococcus species.
Chédiak-Higashi syndrome (CHS) is inherited in an autosomal recessive pattern. Parental consanguinity is often reported. The genetic hallmark of CHS is mutations in the CHS1/LYST gene located on band 1q42-43. Mutations of this gene result in a defect in granule morphogenesis in multiple tissues. The gene encodes a protein called the lysosomal trafficking regulator, which regulates the synthesis, transport, and fusion of cytoplasmic vesicles. The abnormalities observed in these vesicles result in grossly enlarged and nonfunctional lysosomes, which are identified during cytology as giant, coalesced, azurophilic granules present mostly in granulocytes and monocytes, but also in fibroblasts, melanocytes, astrocytes, Schwann cells, and hematopoietic cells. These granules are specific to CHS, and their presence in granulocytes from peripheral blood and bone marrow is the basis of diagnosis. Clinical CHS phenotypes correlate with molecular genotypes. CHS patients with deletions in the LYST gene usually present with a fulminant accelerated phase early in life, whereas, those with missense mutations have a better prognosis, characterized by the absence of an accelerated phase and no neurological involvement.[5, 8, 9] Although defects in cytotoxic T-cell lytic secretory granule secretion and neutrophil phagocytosis are suggested to contribute to the immunodeficiency in CHS, the underlying molecular mechanisms are unknown.
Patients with CHS exhibit alterations in neutrophils. These alterations include neutropenia, which may be profound; decreased deformability, resulting in impaired chemotaxis; and delayed phagolysosomal fusion, resulting in impaired bactericidal activity.
Clinical features resulting from LYST mutations in CHS have much in common with immunodeficiencies caused by Toll-like receptor (TLR) signaling defects, such as conditions caused by autosomal recessive mutations in TLR adapters, IRAK-4 and MyD88 (OMIM# 610799, 607676, 612260). Like mutations in LYST, reduced function of IRAK-4 and MyD88 results in selective impairment of cell responsiveness to TLRs other than TLR-3, and limited presence of interleukin 6 protein when exposed to TLR agonists. These conditions feature noninvasive pyogenic bacterial infections affecting skin and the upper respiratory tract, with occasional periodontal disease. However, patients with MyD-88 and IRAK-4 deficiency show no impaired defense against viral infections, owing to their normal functional natural killer cells and their retained ability to signal through TLR-3/-7/-9 and other non-TLR viral receptors. In contrast, patients with the classic CHS phenotype develop life-threatening hemophagocytic lymphohistiocytosis following infections with viruses, which may result from dysfunctional natural killer cells lacking cytotoxic activities as well as defective trafficking in TLR-3/-7/-9 signaling. Loss of expression or proper localization of TLR-2 and TLR-4, together with the lack of response of cell production of proinflammatory cytokines, leads to exacerbated bacterial burden and delayed clearance.[10]
Chédiak-Higashi syndrome (CHS) is rare, with fewer than 500 cases published worldwide over the last 20 years.[11, 8] In a nationwide survey in Japan, 15 patients were diagnosed during a period of 11 years (2000-2010), indicating that one or two patients with CHS were diagnosed each year.[5] The exact prevalence is difficult to determine as some individuals are reported in the literature more than once. In addition, the phenotypic variability that has more recently been appreciated suggests that many mildly affected individuals may be unrecognized or unreported.
CHS affects all races. Al-Khenaizan suggests that CHS may be underreported in persons of darker-skinned races.[12]
Symptoms of CHS usually appear soon after birth or in children younger than 5 years. The mean age of onset is 5.85 years; however, most patients die before age 10 years.[5]
Chédiak-Higashi syndrome (CHS) usually leads to early death from infection or, less commonly, hemorrhage. Intractable respiratory and cutaneous infections usually prove fatal before a child with CHS reaches age 10 years. Longer survival is possible, but the lymph nodes, spleen, and liver become enlarged and a malignant lymphoma develops. A few patients have survived to age 20 years.
In CHS patients who survive beyond childhood, neurological problems persist and/or increase in magnitude. Approximately 50-85% of patients develop a fatal accelerated phase, namely hemophagocytic lymphohistiocytosis (HLH), characterized by pancytopenia, high fever, hemophagocytosis, and marked infiltration of organs by lymphocytes, leading to multiorgan dysfunction. Treatment of HLH is difficult, and the prognosis is poor. CHS patients with deletions in the LYST gene usually present with a fulminant accelerated phase early in life, whereas those with missense mutations have a better prognosis, characterized by the absence of HLH and no neurological involvement.[5]
Price et al report a patient with CHS whose pregnancy, labor, and delivery were not affected. The infant and placenta were normal.[13]
Measures to prevent routine infections include education of the child and caregivers regarding effective hygiene and meticulous attention to oral and dental care. Skin protection and sunglasses should be used to prevent sunburn and to protect sensitive eyes from ultraviolet light. While these patients can safely receive all killed or inactivated vaccines, live vaccines are contraindicated.[14]
Infants born with Chédiak-Higashi syndrome (CHS) have nonpigmented skin (similar to albinos but in patchy distribution), blonde hair, and blue eyes. Signs and symptoms that usually appear soon after birth include the following:
The clinical features of Chédiak-Higashi syndrome (CHS) include partial albinism, photosensitivity, severe recurrent bacterial infections, bleeding diatheses, and late-onset neurological manifestations (central and peripheral neuropathies, sensory loss, muscle weakness, parkinsonism, cerebellar ataxia, and cognitive impairment).[5]
Most patients are diagnosed during the first decade of life, and, while the disease affects multiple organs and systems, death often occurs early because of infection, bleeding, or development of hemophagocytic lymphohistiocytosis (HLH). The accelerated phase is the most life-threatening clinical feature of CHS, affecting about 85% of CHS patients within the first decade. This manifestation defines the characteristic childhood form of the disease and is characterized by massive HLH. It often occurs following initial exposure to Epstein-Barr virus (EBV), when it may resemble lymphoma. HLH manifests as fever, lymphadenopathy, and hepatosplenomegaly with signs of liver dysfunction, cytopenia, and bleeding. Massive lymphohistiocytic infiltration of virtually all organ systems may also be observed. Most patients with a history suggestive of CHS undergo a variable period of recurrent infections before entering the accelerated phase, but primary presentation in the accelerated phase has also been reported.[14, 15]
About 10-15% of patients follow a less severe clinical course of CHS—the adolescent and adult forms. These children present with mostly subtle hypopigmentation; a lower frequency of infections during childhood, adolescence, and adulthood; and mild bleeding manifestations. They survive until adulthood without experiencing an accelerated phase. Nonetheless, during adolescence or adulthood, they develop progressive neurologic symptoms, including intellectual deficit, dementia, peripheral neuropathy, parkinsonism, balance abnormalities, and tremor.[14]
Oculocutaneous albinism (OCA) is prominent, and, together with photophobia and silvery hair, it is helpful in early diagnosis.[16] Pigment dilution of the skin and hair may be appreciated at birth on physical examination. The skin is fair, the retinae are pale, and the irides are translucent. The hair is light blonde or silvery gray and may be sparse. Iris hypopigmentation may be associated with decreased retinal pigmentation, and ocular manifestations include photophobia, decreased visual acuity, nystagmus, and strabismus.[14] The degree of hypopigmentation varies and typically affects skin, hair, and eyes. A speckled hyperpigmentation or dark skin may uncommonly be seen in more pigmented races, leading to the suspicion of other diseases with a consequent delay in diagnosis.
In CHS, patients are affected by frequent and severe pyogenic infections secondary to abnormal functioning of polymorphonuclear leukocytes, which is associated with albinism and a bleeding tendency. Recurrent skin infections occur frequently and range from superficial pyoderma to deep subcutaneous abscesses and ulcers that heal slowly and result in atrophic scars. Staphylococcus aureus is the most common causative agent. Deep ulcerations resembling pyoderma gangrenosum have also been described.
The complete syndrome includes oculocutaneous albinism with photophobia, neurologic features, recurrent infections, and enterocolitis.
Severe gingivitis and oral mucosal ulceration are common. Oral ulcerations and periodontal disease also occur.[17, 18]
CHS may present with neurologic dysfunction and should be considered in the differential diagnosis of children and young adults first seen with symptoms of spinocerebellar degeneration or movement disorders. Common physical findings include abnormal gait, clumsiness, seizures, paresthesia, mental retardation, ataxia, parkinsonism, and peripheral neuropathy. In many persons with CHS, neurologic changes appear in the lymphoproliferative lymphomalike phase. Progressive neurologic deterioration is common in patients who survive early childhood. Generally, such patients eventually enter an accelerated phase of the disease with widespread infiltration by lymphocytes and histiocytes, causing rapid enlargement of the liver, the spleen, and the lymph nodes, and with concurrent severe leukopenia and thrombocytopenia, resulting in death from infection or bleeding.
The thrombocytopenia and depletion of coagulation factors lead to petechiae, bruising, and gingival bleeding. Renal function may be impaired because of the involvement of the renal tubular epithelium. The progressive visual loss and the constriction of visual field can occur.
Chédiak-Higashi syndrome (CHS) patients are affected by frequent and severe pyogenic infections secondary to the abnormal functions of polymorphonuclear leukocytes. Most children with CHS receive early attention because of troublesome recurrent bacterial infections. The most common sites of infection are the skin, respiratory tract, and mucous membranes. Staphylococcus and Streptococcus are the species most frequently isolated from these sites. Periodontal disease and bone loss of dental alveoli associated with various microorganisms are common.
CHS may present with neurologic dysfunction and should be considered in the differential diagnosis of children and young adults first seen with symptoms of spinocerebellar degeneration or movement disorders. Common physical findings include motor and sensory neuropathies, ataxia, tremors, cranial nerve palsies, low cognitive abilities, learning disabilities, and seizures. Patients who survive to the second or third decade may exhibit neurologic deterioration, including parkinsonism and dementia, and are often confined to a wheelchair.[14]
Diagnosis of Chédiak-Higashi syndrome (CHS) is made by recognition of the characteristic giant granules in neutrophils, eosinophils, and granulocytes by using light microscopy of a routine blood smear. Laboratory findings include neutropenia and hypergammaglobulinemia.
Bone marrow smears reveal giant inclusion bodies in leukocyte precursor cells. The granules are peroxidase positive and contain lysosomal enzymes, suggesting that they are giant lysosomes, or in the case of melanocytes, that they are giant melanosomes. The diagnostic hallmark is the occurrence of giant inclusion bodies in the peripheral leukocytes and their bone marrow precursors.[20]
In addition to the characteristic leukocytic dysfunctions, fluorescence cytometric analysis of cellular granularity and surface molecules offer useful diagnostic information.
Microscopic examination of the hair can also reveal clumped melanin granules, larger than those seen in normal hairs, and examination of the skin shows giant melanosomes both in keratinocytes and melanocytes, which can be us.
Definite diagnosis is based on the molecular genetic testing of CHS1.[14]
Molecular testing approaches can include the following:
Oral radiographs reveal extensive loss of alveolar bone, leading to tooth exfoliation in most cases. CT scans and MRIs demonstrate diffuse brain and spinal cord atrophy.
Light and electron microscopic examinations of biopsy specimens of periodontal tissues reveal massive bacterial invasion of epithelial tissue, epithelial cells, and connective tissue.
Ultrastructural observations of periodontal polymorphonuclear leukocytes reveal defective granulation, with abnormal granules not discharging their lysosomal content against the engulfed bacteria. Viable dividing bacteria are found in the cytoplasm.
Prenatal diagnosis can be made by examination of hair from fetal scalp biopsy specimens and of leukocytes from fetal blood samples.
A skin biopsy specimen usually appears entirely normal but may show melanin macroglobules and perhaps sparse dermal melanin. Ultrastructural examination reveals large abnormal type stage IV melanosomes that are transferred to keratinocytes with difficulty and are degraded rapidly.
Allogeneic transplantation from an HLA-matched sibling or from an unrelated donor or cord blood transplantation is the treatment of choice to correct the immunologic and hematologic manifestations of early-onset Chédiak-Higashi syndrome (CHS). Transplantation appears to be most successful when performed prior to the accelerated phase. Therefore, it would be of great value to differentiate patients who present with the childhood form of the disease from those who exhibit clinical phenotypes of adolescent and adult CHS, so as to prematurely enroll only the former ones in to a transplantation protocol.[14]
Early treatment of children with Chédiak-Higashi syndrome (CHS) is of paramount importance.
Treatment of manifestations includes the following:
The only treatment that cures the hematologic and immunologic defects is allogenic HSCT, but this therapy does not prevent the progressive neurological dysfunction frequently observed during long-term follow up.[8, 21] The current standard of care is HSCT as soon as the diagnosis is confirmed and the accelerated phase has either been ruled out or is in remission. The most favorable outcome is achieved when HSCT is performed prior to development of the accelerated phase. If signs of the accelerated phase are present, hemophagocytosis must be brought into clinical remission before HSCT can be performed. Guidelines for treatment of the accelerated phase are the same as those for familial hemophagocytic lymphocytic lymphohistiocytosis. Combination therapy consists of etoposide, dexamethasone, and cyclosporine A. Remission is achieved in 75% of individuals within 8 weeks; however, relapses are common and response to treatment declines over time. Once remission occurs, prompt HSCT is recommended.
Prevention of secondary complications includes the following:
In patients with CHS and Epstein-Barr virus (EBV)–associated hemophagocytic lymphohistiocytosis (HLH), the addition of rituximab has been reported to be a valuable adjunct to therapy, although in contrast to normal EBV infection, in HLH patients, the virus is also present in T cells. Other treatment options include the anti-CD52 monoclonal antibody alemtuzumab as a second-line therapy for pretransplantation treatment of HLH refractory to etoposide-based treatments.[5]
A conditioning regimen generally includes a combination of etoposide, busulfan, and cyclophosphamide.[22]
The duration of antimicrobial therapy to treat common infections should ideally be two to three times longer than standard recommendations. Granulocyte colony-stimulating factor (G-CSF) can be used to improve or correct neutropenia and decrease infections.
Careful dental hygiene can minimize gingival bleeding, and treatment with desmopressin and/or antifibrinolytic agents is effective in preventing bleeding after dental extraction or minor surgery in patients with storage pool disease or mild bleeding disorders. Platelet transfusions are particularly indicated in cases of severe uncontrolled bleeding, when prior treatments have been unsuccessful and/or in the presence of, or anticipation of, excessive traumatic or surgical bleeding.[14]
A subset of CHS patients presenting with the adult form of the disorder have a muted pigmentary or hematologic presentation while their neurologic symptoms dominate the disease. Patients with this pattern of manifestations might benefit, at least in the short term, from L-dopa, selegiline, trihexyphenidyl, biperiden, or amantadine treatment.[14, 23]
Surveillance is as follows:
Agents/circumstances to avoid include nonsteroidal anti-inflammatory drugs, which can exacerbate the bleeding tendency.[23]
Increased awareness and the early identification of patients with the potentially lethal form of Chédiak-Higashi syndrome (CHS) convey unique therapeutic and prognostic implications that may improve outcomes. With a high degree of clinical suspicion, these patients should be immediately referred to a tertiary care center and treated by multidisciplinary teams including hematologists, pediatricians, dermatologists, biologists, neurologists, clinical immunologists, and social workers.
A neurologist should be consulted. Neurologic involvement, such as loss of deep tendon reflexes due to peripheral neuropathy, cerebellar ataxia, intellectual impairment, nystagmus, and the Babinski sign, is often observed in the course of CHS.
Hematologist consultation is necessary because the accelerated phase resembles lymphoma. Allogenic bone marrow or stem cell transplantation is the treatment of choice to correct the hematologic manifestation of the disease.
Ophthalmologists should be aware that progressive visual loss and the constriction of visual field can occur in patients with CHS as they grow older.[24]
Some activity limitations are advised because of the bruising problem and the bleeding tendency.
Chédiak-Higashi syndrome (CHS) patients may exhibit an increased bleeding tendency owing to platelet dysfunction caused by delta storage pool deficiency. Preventative measures include avoidance of drugs that interfere with platelet functions such as aspirin, other nonsteroidal anti-inflammatory agents, or serotonin reuptake inhibitors. Intramuscular injections are prohibited, but subcutaneous injections are authorized.[14]
Hygiene should be meticulous to avoid bacterial infections. The skin should be washed 2 times a day with disinfectant soap to prevent skin infections. Cutting the fingernails to a short length helps to reduce autoinoculation.
Excessive operative blood loss should be anticipated during the operation secondary to quantitative and qualitative defects in platelet function, and certain techniques (eg, epidural anesthesia, intramuscular injections) should be avoided.
Even though there are no general recommendations for clinical follow-up of patients with adult-onset Chédiak-Higashi syndrome (CHS), regular screening might include physical examination and/or abdominal ultrasound to monitor for hepatosplenomegaly, blood cell counts to evaluate cytopenias, biochemical tests to assess for signs of liver dysfunction, including serum ferritin levels, hypertriglyceridemia, and/or hypofibrinogenemia.[14, 23]
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Clinical Context: Acyclovir inhibits the activity of both HSV-1 and HSV-2. It has affinity for viral thymidine kinase and, once phosphorylated, causes DNA chain termination when acted on by DNA polymerase.
Use as suggested, and dosing below is not for antiviral properties but for cellular antimitotic activity at high doses for the accelerated phase.
These agents inhibit DNA synthesis and viral replication. Nucleoside analogs are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit HSV polymerase with 30-50 times the potency of human alpha-DNA polymerase.
Use as suggested and dosing below is not for antiviral properties but for cellular antimitotic activity at high doses for the accelerated phase.
Clinical Context: Intravenous immune globulin neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks the complement cascade; promotes remyelination; and may increase CSF IgG (10%).
Clinical Context: Interferon alfa-2a and -2b are protein products manufactured by recombinant DNA technology. Their mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.
Clinical Context: Vincristine's mechanism of action is uncertain. It may involve a decrease in reticuloendothelial cell function or an increase in platelet production. Reduce the dose by 50% if the direct bilirubin level is greater than 3 mg/100 mL.
Clinical Context: Vinblastine inhibits microtubule formation, which, in turn, disrupts the formation of the mitotic spindle, causing cell proliferation to arrest at metaphase. Use hematologic parameters as a guide. If the direct bilirubin level is greater than 3, reduce the dose by 50%.
Local injection of hyaluronidase and application of moderate heat to the area of extravasation help disperse drug and are thought to minimize discomfort and the possibility of cellulitis.
These agents inhibit cell growth and proliferation. Useful in the accelerated phase of the disease.
Clinical Context: Colchicine decreases leukocyte motility and phagocytosis in inflammatory responses.