Chediak-Higashi syndrome

INTRODUCTION — Chediak-Higashi syndrome (CHS; MIM #214500) is a rare, autosomal recessive disorder characterized by recurrent bacterial infections including pyogenic infections, oculocutaneous albinism that is present to a variable extent, progressive neurologic abnormalities, mild coagulation defects, and a high risk of developing hemophagocytic lymphohistiocytosis (HLH; formerly termed the "accelerated phase" of the disease) [1-5].

The diagnosis of CHS is suggested by pathognomonic giant cytoplasmic granules in leukocytes and platelets on a peripheral smear and is confirmed by identification of a pathogenic variant in the CHS1/lysosomal trafficking regulator (LYST) gene. Allogeneic hematopoietic cell transplantation (HCT) is the treatment of choice.

This topic reviews the pathogenesis, clinical manifestations, diagnosis, treatment, and prognosis of CHS. An overview of primary disorders of phagocytic function is presented separately. (See "Primary disorders of phagocyte number and/or function: An overview".)

EPIDEMIOLOGY — CHS is a rare disorder, with an estimated incidence of <1 in 1,000,000. Less than 500 cases have been reported worldwide [6].

GENETICS — The gene responsible for CHS is called Beige in mice because it was first discovered in a mouse model with an altered "beige" coat color [6-9]. This mouse model has been an important source of information on the disease. The mouse gene and the defective human gene, called lysosomal trafficking regulator (CHS1/LYST), are part of the Beige and Chediak-Higashi (BEACH) family of vesicle trafficking regulatory proteins. Studies have also modeled CHS in Drosophila showing that the Drosophila Mauve, a counterpart of LYST, suppresses vesicle fusion events with lipid droplets [10].

PATHOGENESIS — The underlying defect in CHS is abnormal organellar protein trafficking that leads to aberrant fusion of vesicles and failure to transport lysosomes to the appropriate site of action [7]. This defect is due to a mutation in the CHS1/LYST gene at 1q42.1-2 (MIM #214500) [8,9]. Most reported mutations are nonsense or null mutations, resulting in an absent CHS1/LYST protein [1]. A genotype-phenotype relationship appears to exist, with milder forms of CHS associated with missense mutations that probably encode a protein with residual function [1].

The CHS1/LYST protein is widely expressed in the cytosol [7]. CHS is critical for regulating size and trafficking of lysosomes by membrane fusion and fission. Studies have also suggested that the biochemical defect in CHS is due to decreased levels of protein kinase C [11]. Aberrant cortical actin density and granule size are (at least partially) causative for the cytotoxic defect by inhibiting lytic granule release [12]. A study modeled the giant granule formation in myeloid cells, the characteristic cellular defects of CHS, using patient-derived induced pluripotent stem cells (iPSCs) [13].

Altered lysosomes/granules are found in all cell types in CHS and are the hallmark of the disease (picture 1):

●Melanocytes contain enlarged pigment granules (melanosomes) that are not appropriately transferred to keratinocytes or epithelial cells, resulting in a variable degree of oculocutaneous albinism [14,15].

●Neutrophils have giant azurophilic granules [16], and cytotoxic T cells have enlarged mature secretory cytolytic granules [17,18]. These abnormal granules do not appropriately release their contents in the setting of bacterial or viral infections, leading to impaired bactericidal and cytotoxic function. Neutrophils also have impaired chemotaxis [19].

●The number of platelet-dense bodies (serotonin-storage granules) is significantly reduced, resulting in a platelet storage pool deficiency and bleeding diathesis [20,21].

●Plasma membrane repair, which is a lysosome-mediated process, is also impaired [22].

●Data in mice show that the accumulation of phagolysosomes in pigment epithelium of the retina and the induction of oxidative stress cause a reduction of retinal adhesion, potentially explaining some of the ocular disease manifestations [23].

CLINICAL MANIFESTATIONS — Patients are typically identified in infancy or early childhood when they present with partial oculocutaneous albinism type 2 (OCA2) and recurrent pyogenic infections [6]. Less commonly, patients may present with hemophagocytic lymphohistiocytosis (HLH; formerly termed the "accelerated phase" of CHS).

Aberrant pigmentation and ocular manifestations — The degree of hypopigmentation varies, but most patients have fair skin and sparse light-blond, gray, or white hair that often has a metallic sheen (picture 2) [24]. Speckled hyperpigmentation and hypopigmentation of sun-exposed areas may be seen in patients with more darkly pigmented skin tones [25]. Pigmentation of the irides and retinae is also reduced [26]. Patients have light-colored, usually blue, eyes. Ocular manifestations include photophobia, decreased visual acuity, nystagmus, and strabismus.

Immunodeficiency with predominantly bacterial infections — Pyogenic infections are frequent, severe, and related to the neutrophil dysfunction characteristic of CHS (see 'Pathogenesis' above). The most common sites of infection are the skin, respiratory tract, and mucous membranes. Cutaneous infections range from superficial pyoderma to deep abscesses and ulcerations [27]. The deeper lesions heal slowly and leave atrophic scars. The most common causative organism is Staphylococcus aureus. Streptococcus pyogenes and Pneumococcus species are other common infectious organisms in CHS.

Coagulation defects — Patients have a mild coagulation defect that results in easy bruising and abnormal bleeding, especially of mucosal tissue [20,21]. Bleeding may become more severe in patients who have developed HLH. Hepatosplenomegaly and lymphadenopathy are common and become more pronounced with HLH. (See 'Hemophagocytic lymphohistiocytosis/accelerated phase' below.)

Other disease manifestations — Gingivitis, oral ulcerations, and periodontal disease are common [28-30]. Defective Toll-like receptor (TLR) expression and function, in particular TLR2/4, may underlie immune dysregulation and influence periodontal disease [31]. Enterocolitis has also been reported [32]. Renal function impairment is reported in animals with the disease [33], and renal giant cytoplasmic inclusion has been reported in ultrastructural studies of human patients [34], although impaired renal function is not a characteristic feature in CHS patients.

Progressive neurologic dysfunction — Approximately 10 to 15 percent of patients who survive early childhood with curative hematopoietic cell transplantation (HCT), despite serious infections, develop severe, debilitating neurologic manifestations in adolescence and early adulthood [35-39]. Both the peripheral and central nervous systems are involved. Neurologic defects include weakness and sensory deficits due to peripheral neuropathy, ataxia, tremors, cranial nerve palsies, progressive intellectual decline, and seizures. Spinocerebellar degeneration, Parkinson disease-like movement disorders, and dementia also occur, especially in the second and third decades of life [40]. HCT does not prevent this neurologic deterioration.

Hemophagocytic lymphohistiocytosis/accelerated phase — Patients who do not die from infection eventually enter the "accelerated phase" of the disease, characterized by HLH disease with massive lymphohistiocytic infiltration of virtually all organ systems and even more profound immunodeficiency, typically occurring in infancy or the first decade of life [41,42]. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Clinical features'.)

Patients with HLH present with fever, increased hepatosplenomegaly and lymphadenopathy, and worsened pancytopenia and bleeding. This phase occurs in more than 80 percent of patients and is usually lethal. As with other genetically determined forms of HLH (primary/familial HLH), onset of disease is typically triggered by viral infections, particularly the Epstein-Barr virus [7,43,44]. The characteristic lack of natural killer (NK) cell function in CHS, but also abnormal surface expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) [45] and reduced cytotoxic T lymphocyte (CTL) and NK cell cytotoxicity [42], predispose to development of HLH with viral infections.

LABORATORY AND IMAGING FINDINGS — Neutropenia is a common laboratory finding and is probably due to intramedullary destruction of neutrophils [46]. Neutrophils and monocytes have decreased chemotactic responses [19]. Intracellular killing of bacteria is also impaired [47]. Natural killer (NK) cells are present, but NK cytotoxicity is nearly absent [48]. Antibody-dependent cellular cytotoxicity is also decreased [17]. B cell function is usually normal [49]. Hypergammaglobulinemia is often seen secondary to frequent infections [50].

Patients with CHS have abnormal platelet aggregation and bleeding time [20,21]. Thrombocytopenia is common in patients with hemophagocytic lymphohistiocytosis (HLH).

Diffuse atrophy of the brain and spinal cord is noted on computed tomography (CT) scan and magnetic resonance imaging (MRI) [51]. There is also markedly delayed nerve conduction time on electromyography (EMG). An electroencephalography (EEG) may reveal seizure activity.

Giant granules are seen in Schwann cells and muscle cells [36,52]. Examination of skin melanocytes reveals giant melanosomes [14]. Light microscopy of hair shafts shows small aggregates of clumped pigmentation that are regularly distributed (picture 3) [53]. Shafts appear bright and polychromatic under polarized light microscopy.

DIAGNOSIS — The diagnosis of CHS is typically suspected in patients with partial oculocutaneous albinism and recurrent pyogenic infections and is made by examining a peripheral blood smear for the classic giant azurophilic granules in neutrophils, eosinophils, and other granulocytes (picture 1 and picture 4). These large granules are found in all granule-containing cells, including peripheral blood and bone marrow cells, melanocytes, peripheral and central nerve tissue, renal tubular epithelium, fibroblasts, and gastric mucosa [54,55].

Definitive diagnosis is based upon genetic testing for mutations in the CHS1/LYST gene. The gene is large, and most mutations are unique. Thus, identifying the exact mutation and differentiating true disease-causing mutations from benign genetic variants can be a challenge.

The diagnostic criteria for CHS in patients who present with hemophagocytic lymphohistiocytosis (HLH) are the same as for HLH due to other primary genetic defects and include five out of the following eight criteria: fever; splenomegaly; cytopenia in at least two lineages in peripheral blood; hypertriglyceridemia and/or hypofibrinogenemia; hemophagocytosis in bone marrow, spleen, or lymph nodes; low or absent natural killer (NK) cell activity; hyperferritinemia; and high levels of soluble interleukin (IL) 2 receptor [56]. The diagnosis of HLH is reviewed in greater detail separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Diagnosis'.)

As for other genetic diseases, prenatal diagnosis is possible and is commonly performed by capillary sequencing of the CHS1/LYST gene.

DIFFERENTIAL DIAGNOSIS — There are several other rare disorders combining both partial albinism and immunodeficiency that are in the differential diagnosis. These include Griscelli syndrome and Hermansky-Pudlak syndromes (HPS). Several features including neurologic symptoms prior to hemophagocytic lymphohistiocytosis (HLH) onset (particularly peripheral neuropathy) and giant intracellular granules in leukocytes are characteristic of CHS but are not seen in these other conditions. However, genetic testing is strongly recommended to differentiate these rare disorders since they have partial phenotypic overlap and treatment is not identical.

●Griscelli syndrome – Griscelli syndrome is a rare, autosomal recessive disorder characterized by partial oculocutaneous albinism and immunodeficiency [57]. This disorder is due to a mutation in one of three intracellular trafficking genes. Griscelli syndrome may also be distinguished from CHS by examination of hair shafts [53]. Larger, irregular clumps of melanin granules are distributed mainly near the medulla of the hair shaft. The shaft appears uniformly white under polarized light microscopy. (See "Syndromic immunodeficiencies", section on 'Griscelli syndrome' and 'Laboratory and imaging findings' above.)

●Hermansky-Pudlak syndromes – HPS denote a group of rare, autosomal recessive disorders characterized by partial oculocutaneous albinism and a platelet storage pool deficiency [58]. Mutations in 10 different genes are associated with HPS. These mutations lead to defects in cytoplasmic organelles involved in protein sorting and trafficking. Three of these types of HPS also have an associated immunodeficiency. These include HPS-2 caused by an autosomal recessive mutation in the adaptor-related protein complex 3 beta 1 subunit (AP3B1) gene [59-63], HPS-9 caused by an autosomal recessive mutation in the biogenesis of lysosomal organelles complex 1 subunit 6 (BLOC1S6) gene [64], and HPS-10 caused by an autosomal-recessive mutation in the adaptor-related protein complex 3 delta 1 subunit (AP3D1) gene [65]. Other types of HPS have associated pulmonary fibrosis and colitis [66,67]. (See "Inherited platelet function disorders (IPFDs)".)

●Other conditions combining partial albinism and immunodeficiency – Another condition in the differential diagnosis is deficiency of the endosomal adaptor protein (mitogen-activated protein binding protein interacting protein [MAPBPIP]) encoded by the late endosomal/lysosomal adaptor, MAPK and mTOR activator 2 (LAMTOR2) gene [68]. Features in this disorder not seen in CHS include short stature and coarse facial features.

The differential diagnosis in patients who present with HLH (accelerated phase) includes a number of common conditions that cause fever, pancytopenia, hepatic abnormalities, or neurologic findings. Cytopenias, a very high ferritin level, and liver function abnormalities are helpful in distinguishing HLH from these other conditions. The differential diagnosis of HLH is reviewed in greater detail separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Differential diagnosis'.)

TREATMENT — The initial treatment of CHS includes prophylactic antibiotics and aggressive therapy for acute bacterial infections (see "Inborn errors of immunity (primary immunodeficiencies): Overview of management"). Other pretransplant therapies include granulocyte colony stimulating factor (G-CSF) to correct neutropenia and decrease infection [69] and interferon gamma, which may partially restore function of natural killer (NK) cells. Allogeneic hematopoietic cell transplantation (HCT), including cord blood transplant, is the treatment of choice to correct the immunologic and hematologic manifestations of CHS, although it does not prevent the progressive neurologic deterioration or the oculocutaneous albinism [51,70,71].

A deficiency or deterioration of cytotoxic T cell function may predispose to hemophagocytic lymphohistiocytosis (HLH) and is of use in determining the need for early HCT [42]. HLH treatment in patients with CHS follows the same clinical protocols for familial/primary HLH, such as the HLH2004 protocol. Although systematic data are lacking, it is assumed that the outcome of HCT depends upon prior infections and whether HLH has developed in an individual patient. Thus, early, preemptive HCT is preferred, in particular when a matched sibling or unrelated donor is available. Successful HCT with donor immune reconstitution will normalize the risk of infection-triggered HLH. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

Transplantation appears to be most successful if a human leukocyte antigen (HLA) identical donor is used and if the transplantation is performed prior to the onset of HLH or during remission. However, even patients with HLH may benefit from transplantation [72]. Successfully transplanted patients have improved NK cell function, no significant infections, and do not progress to or have a recurrence of HLH. In a 2013 report from Japan, five of six patients with CHS survived transplantation [73]. HCT was performed prior to the development of HLH in all six patients. Three additional children with CHS successfully underwent HCT with umbilical cord blood [74]. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

High-dose glucocorticoids and splenectomy have been used with some success to induce a transient remission in the accelerated phase/HLH [75]. Intravenous immune globulin, antivirals (eg, acyclovir), and chemotherapy (eg, etoposide, methotrexate, vincristine) have also been used to induce transient remission of HLH [76]. However, treatment with these agents is not curative, and HLH usually recurs in a more aggressive and difficult-to-manage form.

Given the skin hypopigmentation, patients with CHS should avoid significant levels of ultraviolet (UV) irradiation (eg, sunlight exposure) and wear sunscreen for protection.

PROGNOSIS — Most patients with CHS die from pyogenic infection before seven years of age if not transplanted. Hemorrhage is a less common cause of death. The five-year probability of survival posttransplantation was 62 percent in a review of 35 children with CHS [70]. However, most transplanted patients and those few patients who survive childhood without transplantation develop neurologic deficits by the time they reach their early 20s [51]. These deficits include cerebellar ataxia, with difficulty walking and loss of balance, tremor, peripheral neuropathy, and low cognitive abilities. These neurologic sequelae can be quite debilitating. (See 'Progressive neurologic dysfunction' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by recurrent pyogenic infections, partial oculocutaneous albinism, progressive neurologic abnormalities, mild coagulation defects, and hemophagocytic histiocytosis (HLH; formerly termed the "accelerated phase" of the disease). (See 'Introduction' above and 'Clinical manifestations' above.)

●Genetics and pathogenesis – The defective gene, called lysosomal trafficking regulator (CHS1/LYST), is part of the BEACH family of vesicle trafficking regulatory proteins. (See 'Genetics' above and 'Pathogenesis' above.)

●Diagnosis – The diagnosis is made by examination of a peripheral smear for pathognomonic giant cytoplasmic granules in leukocytes and platelets and molecular analysis of the CHS1/LYST gene. (See 'Diagnosis' above.)

●Outcome – Patients who do not die from infection eventually develop HLH, characterized by massive lymphohistiocytic infiltration of virtually all organ systems. (See 'Hemophagocytic lymphohistiocytosis/accelerated phase' above.)

●Hematopoietic cell transplantation – Hematopoietic cell transplantation (HCT) is the treatment of choice to correct the immunologic and hematologic manifestations of CHS. Treatment with HCT prevents infections and development of HLH, but patients still develop neurologic deficits, and the oculocutaneous albinism is not corrected. (See 'Treatment' above and 'Prognosis' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Robert L Roberts, MD, PhD and Kevin Yeh-Sheng Wang, MD, LAc, who contributed as authors to earlier versions of this topic review.

The editorial staff at UpToDate also acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.