The features of Chediak-Higashi syndrome are decreased pigmentation of hair and eyes (partial albinism), photophobia, nystagmus, large eosinophilic, peroxidase-positive inclusion bodies in the myeloblasts and promyelocytes of the bone marrow, neutropenia, abnormal susceptibility to infection, and peculiar malignant ... The features of Chediak-Higashi syndrome are decreased pigmentation of hair and eyes (partial albinism), photophobia, nystagmus, large eosinophilic, peroxidase-positive inclusion bodies in the myeloblasts and promyelocytes of the bone marrow, neutropenia, abnormal susceptibility to infection, and peculiar malignant lymphoma. Death often occurs before the age of 7 years. (See Hermansky-Pudlak syndrome (203300), a similar but distinct entity.) Kritzler et al. (1964) found the karyotype normal in a 16-year-old patient. Glycolipid inclusions were described in histiocytes, renal tubular epithelium, and neurons. Heterozygotes were identifiable by the presence of a granular anomaly of the lymphocytes. The patient died of massive gastrointestinal hemorrhage. Leukemia and lymphoma have been observed (Efrati and Jonas, 1958). Windhorst et al. (1966) found large lysosomal granules in leukocytes and giant melanosomes in melanocytes. For this reason, Leader et al. (1966) referred to the condition as 'hereditary leukomelanopathy.' Hargis and Prieur (1985), who studied CHS in cats, quoted White (1966) as providing evidence that many of the enlarged granules in CHS cells are derived from lysosomes. Sheramata et al. (1971) described 3 brothers, aged 31, 34 and 38, who had this disorder and a neurologic picture resembling spinocerebellar degeneration. Neutrophils are deficient in chemotactic and bactericidal activities. Microtubular abnormalities have been demonstrated (Oliver and Zurier, 1976) and ascorbic acid corrects certain functional abnormalities of the cells (Boxer et al., 1976). Siccardi et al. (1978) described a 4-year-old Italian boy with recurrent infections. Both he and his healthy father had a severe isolated defect in bactericidal activity of circulating neutrophils. The parents of the proband were first cousins once removed. The proband had silvery-blond hair, individual hairs showing silver and blond banding, as well as a slate-gray generalized hyperpigmentation of the skin. Generalized lymph node enlargement and hepatosplenomegaly were present. The boy died at age 4 years and 9 months, following cerebral hemorrhage (probably secondary to thrombocytopenia caused by hypersplenism). No autopsy was performed. Obviously there were similarities to and differences from the Chediak-Higashi syndrome. Inoue et al. (1991) reported the occurrence of sclerosing stromal tumor of the ovary in a 13-year-old girl with CHS. Spritz (1999) stated that about 85 to 90% of CHS patients eventually develop a strange lymphoproliferative syndrome, the so-called 'accelerated phase' of the disorder, characterized by generalized lymphohistiocytic infiltrates, fever, jaundice, hepatosplenomegaly, lymphadenopathy, pancytopenia, and bleeding. Management of this phase is quite difficult (Bejaoui et al., 1989). Most patients ultimately require bone marrow transplantation, without which mean survival is only about 3.1 years, death usually resulting from pyogenic infections or hemorrhage (Blume and Wolff, 1972). Patients who do not develop an accelerated phase tend to have fewer or no infections, but usually develop progressively debilitating neurologic manifestations (Misra et al., 1991; Uyama et al., 1994). Spritz (1999) provided a comprehensive review. Tardieu et al. (2005) reported 3 patients with CHS who underwent successful bone marrow transplantation (BMT) in childhood with sustained mixed chimerism and no subsequent recurrent infections or hemophagocytic syndrome. At the age of 20 to 24 years, each patient developed neurologic symptoms combining difficulty walking, loss of balance, and tremor. Examination revealed cerebellar ataxia and signs of peripheral neuropathy. Electrophysiologic studies showed motor-sensory axonal neuropathy, there was axon loss on peripheral nerve biopsy, and cerebellar atrophy was detected on brain MRI. Tardieu et al. (2005) reviewed the neurologic status of 4 other patients with CHS who had undergone BMT: 1 began having gait abnormality, falls when walking, and decreased cognitive abilities at the age of 21; 3 other patients, aged 17, 14, and 2 years, had borderline low IQ scores but normal neurologic examinations. Tardieu et al. (2005) noted that the neurologic symptoms observed were identical to those in adults with mild CHS who did not undergo BMT, and concluded that the symptoms most likely resulted from steady long-term progression, despite BMT, of the lysosomal defect in neurons and glial cells.
Karim et al. (2002) performed mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, they found only functionally null mutant LYST alleles, whereas in patients with ... Karim et al. (2002) performed mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, they found only functionally null mutant LYST alleles, whereas in patients with the adolescent and adult forms of CHS they also found missense mutant alleles that likely encode LYST polypeptides with partial function.
Barbosa et al. (1997) identified novel mutations in the coding region of the LYST gene in 3 CHS patients (606897.0006-606897.0007). Karim et al. (1997) reported 2 homozygous LYST mutations in 2 affected patients (606897.0004-606897.0005).
The diagnosis of Chediak-Higashi syndrome (CHS) is suspected in individuals with any of the following: ...
DiagnosisClinical Diagnosis The diagnosis of Chediak-Higashi syndrome (CHS) is suspected in individuals with any of the following: Partial oculocutaneous albinism (OCA). Pigment dilution of the skin and hair may be appreciated at birth on physical examination. However, complete ophthalmologic examination may be necessary to identify the diagnostic finding of reduced iris pigment manifest as iris transillumination. Associated findings of nystagmus and decreased retinal pigmentation may also be present. Note: OCA was once thought to be a diagnostic criterion for CHS; however, at least one individual with atypical CHS had no evidence of OCA [Author, unpublished data]. In that case a diagnosis was made based on the presence of (1) giant granules in the white blood cells and (2) one frameshift and one missense mutation in LYST. WBC giant inclusions. The finding of giant inclusions in polymorphonuclear neutrophils (PMNs), and to a lesser extent in lymphocytes, is the most reliable diagnostic clinical criterion for CHS, but they may be overlooked in a routinely evaluated CBC unless a peripheral smear is reviewed. Immunodeficiency. A significant history of infections, particularly bacterial infections of the skin and respiratory tract, is characteristic.Mild bleeding tendency. Deficiency of platelet-dense bodies required for the secondary wave of platelet aggregation is characteristic. Neurologic features. Neurologic manifestations are variable but include cognitive impairment, peripheral neuropathy, ataxia, and parkinsonism. Symptoms can appear anytime from childhood to early adulthood.Because the finding of WBC giant inclusions is the most reliable clinical diagnostic criterion, the combination of any other of the above features should prompt review of a peripheral blood smear evaluating for giant inclusions. TestingGiant cell inclusions. Peroxidase-positive giant inclusions can be seen in leukocytes, megakaryocytes, and other bone marrow precursors (Figure 1c-1e). The presence of giant inclusions within white blood cells on the peripheral blood smear is the only clinical diagnostic test currently available.FigureFigure 1 a. Control hair shows pigment that is evenly distributed throughout the shaft. b. Hair of a patient with classic Chediak-Higashi syndrome (CHS) shows an irregular distribution of large and small pigment clumps. c. Normal (more...)Recently, an individual with late-onset CHS with neurologic impairment was found to have on peripheral blood smear eosinophilic granules within polymorphonuclear leukocytes that were larger than normal but smaller than classic CHS granules (Figure 1e) [Westbroek et al 2007]. The presence of abnormal granules in individuals with neurologic disease should alert a clinician to the diagnosis of CHS. Other studies that support the diagnosis of CHS:Natural killer (NK) cells generally in normal numbers but with abnormal (reduced) functionNeutropenia and impaired neutrophil function (particularly chemotaxis and intracellular bactericidal activity). Note: Immunoglobulins, complement, antibody production, and delayed hypersensitivity are all normal.Light microscopy of hair showing pigment clumping (Figure 1a, 1b). Hair analysis is noninvasive and quick. If a blood smear shows enlarged granules, the hair sample should be evaluated for CHS. See Author Notes, Laboratory contact information.Absent or reduced number and irregular morphology of platelet-dense bodies on whole mount electron microscopy (Figure 1f, 1g). Platelet-dense bodies, which contain calcium, ADP, ATP, and serotonin, are important for the secondary wave of platelet aggregation [Introne et al 1999].Molecular Genetic Testing Gene. LYST, briefly referred to as CHS1, is the only gene known to be associated with CHS.Evidence for locus heterogeneity. Mutations in other genes are not known to result in CHS. Although it had been previously reported that a lower mutation detection rate suggested the possibility of locus heterogeneity [Karim et al 2002]; the detection method in use was single-strand conformational polymorphism (SSCP) analysis, which has a lower rate of detection than sequencing of the entire open reading frame [Zarzour et al 2005]. However, because the function of the lysosomal trafficking regulator protein encoded by LYST is largely unknown, it is possible that mutations in other genes whose products interact with LYST could also result in CHS.Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Chediak-Higashi SyndromeView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityLYSTSequence analysis Sequence variants 2~90%Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband. If an individual’s clinical history is suggestive of CHS the following evaluations are indicated:Evaluation of a blood smear to determine whether abnormal white blood cell granules are present (Figure 1)Evaluation by an ophthalmologist to confirm OCAConsideration of platelet aggregation studiesConsideration of Hermansky Pudlak syndrome Molecular genetic testing of LYSTCarrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No other conditions are known to be caused by mutations in LYST.
Chediak-Higashi syndrome (CHS) is characterized by OCA, immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop the accelerated phase, a lymphoproliferative infiltration of the bone marrow and reticuloendothelial system. Adolescents and adults with atypical CHS and children with classic CHS who have successfully undergone allogenic hematopoietic stem cell transplantation develop neurologic findings. ...
Natural History Chediak-Higashi syndrome (CHS) is characterized by OCA, immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop the accelerated phase, a lymphoproliferative infiltration of the bone marrow and reticuloendothelial system. Adolescents and adults with atypical CHS and children with classic CHS who have successfully undergone allogenic hematopoietic stem cell transplantation develop neurologic findings. Partial OCA. Pigment dilution is highly variable, but can involve hair, skin, and eyes. In classic forms of CHS, the hair has a “silvery” or metallic appearance. Skin pigment dilution may not be appreciated unless compared to that of more darkly pigmented family members. Reduced iris pigmentation is associated with decreased retinal pigmentation and nystagmus. Visual acuity varies from normal to moderate impairment. Quantitative data are not available and are difficult to obtain given the young age of individuals with the classic presentation.Pigment clumping within the shaft of the hair is generally observed under the light microscope (Figure 1b) [Smith et al 2005]. Immunodeficiency. Frequent infections usually begin in infancy and are often severe. Bacterial infections are most common, with Staphylococcus and Streptococcus species predominating; viral and fungal infections can also occur [Introne et al 1999]. Infections of the skin and upper respiratory tract are the most common. More recently, case reports have identified periodontitis as an important manifestation of immunologic dysfunction [Hart & Atkinson 2007, Khocht et al 2010]. In some instances periodontitis can be the clinical finding leading to correct diagnosis [Bailleul-Forestier et al 2008]. Individuals with atypical CHS may not have a history of unusual or severe infections.Bleeding tendency. Clinical manifestations are generally mild and include epistaxis, gum/mucosal bleeding, and easy bruising. The bleeding diathesis in CHS may also be subtle, i.e., generally not requiring medical intervention. Bleeding problems may not be listed as a health concern by affected persons. Accelerated phase. The accelerated phase, occurring in 85% of individuals with CHS [Blume & Wolff 1972], can occur at any age. Clinical manifestations include fever, lymphadenopathy, hepatosplenomegaly, anemia, neutropenia, and sometimes thrombocytopenia. Originally thought to be a malignancy resembling lymphoma, the accelerated phase is now known to be a hemophagocytic lymphohistiocytosis characterized by multiorgan inflammation. The accelerated phase and its complications are the most common cause of mortality in individuals with CHS [Eapen et al 2007].Triggers of the accelerated phase remain unclear. Infection with Epstein-Barr virus is thought to hasten development of the accelerated phase, although this relationship has never been proven. Absence of NK cell function is also believed to contribute to development of the accelerated phase.Neurologic disease. Despite successful hematologic and immunologic outcomes with allogenic hematopoietic stem cell transplantation (HSCT), neurologic disease still manifests by early adulthood. Findings are similar to those described in individuals with atypical or adolescent forms of the disease. Tardieu et al [2005] reported on the neurologic outcomes of 11 children at their center who had received successful transplants. All 11 exhibited neurologic manifestations primarily consisting of low cognitive abilities, balance abnormalities and ataxia, tremor, absent deep-tendon reflexes, and motor and sensory neuropathies. The authors concluded that the neurologic changes were a result of long-term progression of the disease rather than neurotoxic effects of the transplant-conditioning regimen or the accelerated phase.Atypical phenotypes. An unknown fraction of individuals with CHS have atypical or milder phenotypes [Karim et al 2002, Westbroek et al 2007], which are likely under-recognized. Atypical phenotypes are characterized by the following:OCA that is generally subtle or absentInsignificant infections or severe infections during childhood that become much less frequent later in life Reduced platelet-dense bodies with subtle bleeding manifestations Progressive neurologic findings that can include intellectual disabilities, peripheral neuropathy, balance abnormalities, and tremor. The scope of neurologic manifestations is poorly defined because many individuals may be undiagnosed.
The diagnosis of Chediak-Higashi syndrome (CHS) should be considered in individuals with pigment dilution defects of the hair, skin, or eyes; congenital or transient neutropenia; immunodeficiency; and otherwise unexplained neurologic abnormalities or neurodegeneration. Each of these findings may be variably represented in affected individuals; therefore, heightened suspicion is needed to pursue an accurate diagnosis....
Differential DiagnosisThe diagnosis of Chediak-Higashi syndrome (CHS) should be considered in individuals with pigment dilution defects of the hair, skin, or eyes; congenital or transient neutropenia; immunodeficiency; and otherwise unexplained neurologic abnormalities or neurodegeneration. Each of these findings may be variably represented in affected individuals; therefore, heightened suspicion is needed to pursue an accurate diagnosis.Oculocutaneous albinism. The four types of oculocutaneous albinism (OCA1, OCA2, OCA4, and XLOA) all feature visual impairment and varying degrees of iris/retinal depigmentation. Except in individuals with XLOA, in whom skin and hair pigment is normal, the characteristic skin and hair findings vary from complete absence of pigment to reduced pigment. Neither an infectious history resulting from neutropenia nor neurologic abnormalities accompany the OCA types. OCA is common enough (~1:18,000) that it may coexist with other conditions, including primary immunodeficiencies.Hermansky Pudlak syndrome (HPS). Like CHS, HPS is characterized by OCA and a bleeding diathesis secondary to absent platelet-dense bodies. Of the at least eight subtypes of HPS, HPS2 (caused by mutations in AP3B1) most closely resembles CHS.HPS2 is currently described with molecular analysis in only nine individuals [Gahl 2010]. In addition to the albinism and bleeding diathesis, individuals with HPS2 also have congenital neutropenia, a recurrent pattern of severe bacterial infections, and neurologic features including developmental delay, balance abnormalities, and tremor. The distinction between CHS and HPS2 depends on identifying giant intracellular granules within the neutrophils of those individuals with CHS. Griscelli syndrome (GS). Mild skin hypopigmentation and silvery gray hair are present, but platelet function is normal. Griscelli syndrome may be caused by mutations in:MYO5A (GSI), characterized by severe neurologic involvement [Pastural et al 1997];RAB27A (GSII), leading to immunodeficiency and lymphohistiocytosis [Menasche et al 2000];MLPH (GSIII), with hypopigmentation as its only clinical characteristic [Menasche et al 2003]. Cross syndrome. Cross syndrome is manifested by hypopigmentation, ocular defects, and severe developmental delay reflecting extensive central nervous system (CNS) involvement. An infectious component is absent from this diagnosis.Deficiency of endosomal adaptor p14. In 2007, this novel immunodeficiency syndrome was identified in four members of a Mennonite pedigree [Bohn et al 2007]. Clinical features include partial albinism, short stature, congenital neutropenia, and lymphoid deficiency. Neutrophils show altered azurophilic granule ultrastructure and less than normal microbicidal function of phagosomes, in contrast to the giant inclusions seen in neutrophils in CHS. Neurologic dysfunction was not described in members of this pedigree. Familial hemophagocytic lymphohistiocytosis (FLH) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes. Acute illness with prolonged fever and hepatosplenomegaly are seen. Onset is typically within the first few months of life and on occasion in utero, although adult onset has been reported. Neurologic abnormalities that may be present initially or may develop later may include increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Rash and lymphadenopathy are less common. Other findings include cytopenias (anemia, thrombocytopenia, and neutropenia), liver dysfunction, and bone marrow hemophagocytosis. Median survival of children with typical FLH, without treatment, is less than two months; progression of FLH and infection account for the majority of deaths in untreated children. Familial LH, inherited in an autosomal recessive manner, is caused by biallelic mutation in one of five genes, corresponding to five disease subtypes (FHL1 – FLH5).Vici syndrome. A small number of individuals with cutaneous hypopigmentation, combined immunodeficiency, agenesis of the corpus callosum, bilateral cataracts, and cleft lip and palate have been described. Cognitive impairment, seizures, and severe respiratory infections were observed [Vici et al 1988, del Campo et al 1999, Chiyonobu et al 2002, Miyata et al 2007].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Chediak-Higashi syndrome (CHS), the following are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Chediak-Higashi syndrome (CHS), the following are recommended:Assessment for evidence of the accelerated phase including [Filipovich 2006]:History of unexplained, persistent, or recurrent feverSplenomegalyCytopenia of at least two cell linesSigns of liver dysfunction including hypertriglyceridemia and/or hypofibrinogenemiaElevated serum ferritin concentrationElevated soluble interleukin-2 receptor levelEvidence of hemophagocytosis in bone marrow and/or cerebrospinal fluidComprehensive neurologic examinationScreening for a history of frequent or unusual infectionsScreening for clinical signs of lymphoma. The hemophagocytic lymphohistiocytosis associated with CHS may have this clinical appearance.Treatment of ManifestationsHematologic and Immunologic defectsThe only treatment that cures the hematologic and immunologic defects is allogenic HSCT. A conditioning regimen, described in detail by Haddad et al [1995], generally includes a combination of etoposide, busulfan, and cyclophosphamide. 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, revised in 2004 [Henter et al 2007], are the same as those for familial hemophagocytic lymphohistiocytosis (HLH-2004). Combination therapy consists of etoposide, dexamethasone, and cyclosporine A. Select individuals may also receive intrathecal methotrexate and prednisilone. Remission is achieved in 75% of individuals within eight weeks [Filipovich 2006]; however, relapses are common and response to treatment declines over time. Once remission occurs, prompt HSCT is recommended. The overall five-year survival rate in 35 children with CHS who underwent HSCT was 62% [Eapen et al 2007]. Success was highest with HLA-matched siblings or unrelated donors; transplantation during the accelerated phase had a higher mortality rate. Individuals in remission following symptoms of the accelerated phase can have successful outcomes following HSCT [Eapen et al 2007]. Ocular abnormalitiesCorrection of refractive errors may improve visual acuity.Sunglasses should be used to protect sensitive eyes from UV light.Neurologic abnormalities. Because of the progressive nature of the neurologic symptoms, older patients should engage rehabilitation specialists early in the course of the disease.Prevention of Secondary ComplicationsProtection from infectious exposures should be employed as much as is practical. Antibiotics and antiviral agents should be used promptly and aggressively to treat bacterial and viral illnesses. A study by Wolff et al [1972] did not find antibiotic prophylaxis to be beneficial; however, in situations of recurrent bacterial infections, it should be considered. Antibiotic prophylaxis should be given prior to dental or invasive procedures. Immunizations are generally well tolerated and should be administered.Intravenous DDAVP (0.2-0.4 µg/kg/dose over 15 to 30 minutes) can be given 30 minutes prior to invasive procedures to help control bleeding. For serious trauma or extensive bleeding, platelet transfusion may be necessary.Skin protection varies depending on the degree of hypopigmentation. Regardless, all individuals should use sunscreen to prevent sun damage and skin cancer.SurveillanceNo guidelines for surveillance of classic CHS exist. For atypical or adolescent- or adult-onset CHS, annual screening should include:Abdominal ultrasound examination to monitor for hepatosplenomegalyCBC to evaluate for cytopeniasEvaluation for signs of liver dysfunction including hypertriglyceridemia and/or hypofibrinogenemiaMeasurement of serum ferritin concentration Soluble interleukin-2 receptor measurementConsideration of bone marrow biopsy and/or lumbar puncture if history or physical examination suggests CNS involvement or other manifestations of the accelerated phaseIf clinical status changes, the above tests should be repeated.For both classic and atypical CHS, annual ophthalmologic examination is appropriate.Agents/Circumstances to AvoidAll nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen) are to be avoided as they can exacerbate the bleeding tendency.Evaluation of Relatives at RiskAt-risk sibs may have peripheral blood examined for the presence of giant inclusions within white blood cells. When the family-specific mutations are known, molecular genetic testing may be performed. Early diagnosis may provide the opportunity to perform HSCT prior to the development of the accelerated phase.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementThere is only one case report in the literature of pregnancy in a female individual with CHS [Price et al 1992]. In this case, presence of the disease had no impact on the pregnancy, labor, or delivery. The infant was normal. The pregnancy also did not appear to affect the course of disease in the affected mother.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Chediak-Higashi Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDLYST1q42.3Lysosomal-trafficking regulatorAlbinism Database Mutations of the Chediak-Higashi Syndrome gene Resource of Asian Primary Immunodeficiency Diseases (RAPID) Retina International Mutations of the Chediak Higashi Syndrome LYST homepage - Mendelian genesLYSTData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Chediak-Higashi Syndrome (View All in OMIM) View in own window 214500CHEDIAK-HIGASHI SYNDROME; CHS 606897LYSOSOMAL TRAFFICKING REGULATOR; LYSTMolecular Genetic Pathogenesis Interestingly, the neurologic findings of adult-onset Chediak-Higashi syndrome (CHS) resemble those of the recently described ENU-induced homozygous LYSTIng3618 mouse, which manifests age-dependent neurologic impairment and Purkinje cell degeneration [Rudelius et al 2006]. Normal allelic variants. LYST is a large gene with 55 exons. The 13.5-kb gene transcript produces a protein of 3,801 amino acids with a molecular weight of 430 kd. Pathologic allelic variants. See Table 2. To date, 40 mutations have been identified throughout the gene. These include missense and nonsense mutations, and small deletions and insertions in the coding region. Table 2. Selected LYST Pathologic Allelic Variants View in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid Change (Alias 1)Reference Sequencesc.118_119insGp.Ala40Glyfs*24 (Ala40fs*63)NM_000081.2 NP_000072.2c.148C>Tp.Arg50*c.1467delGp.Glu489Aspfs*78 (Glu489fs*566)c.1540C>Tp.Arg514*c.1902dupA (1897_1898insA)p.Ala635Serfs*4 (Lys633fs*638)c.2413delGp.Glu805Asnfs*2 (Glu805fs*806)c.2454delAp.Ala819Hisfs5 Lys818fs*823c.2623delT (2620delT)p.Tyr875Metfs*24 (Phe874fs*898)c.3073_3074delAAp.Asn1025Glnfs*6 (Asn1025fs*1030)c.3085C>Tp.Gln1029*c.3310C>Tp.Arg1104*c.3434dupA (3434_3435insA)p.His1145Glnfs*9 (His1145fs*1153)c.4052C>Gp.Ser1351*c.4361C>Ap.Ala1454Aspc.4274delTp.Leu1425Tyrfs*2 (Leu1425fs*1426)c.4688G>Ap.Arg1563Hisc.5061T>Ap.Tyr1687*c.5317delAp.Arg1773Aspfs*13 (Arg1773fs*1785c.5996T>Ap.Val1999Aspc.6078C>Ap.Tyr2026*c.7060_7066delCTATTAGp.Leu2354Metfs*16 (Leu2354fs*2369)c.7555delTp.Tyr2519Ilefs*10 (Tyr2519fs*2528)c.8428G>Ap.Glu2810Lysc.8583G>Ap.Trp2861*c.9107_9162del56p.Gly3036Glufs*16 (Gly3036fs*3051)c.9228_9229insTTCTTTCAGTp.Lys3077Phefs*4 (Lys3077fs*3080)c.9590delAp.Tyr3197Leufs*62 (Tyr3197fs*3258)c.9893delTp.Phe3298Serfs7 (Phe3298fs*3304)c.10127A>Gp.Asn3376Serc.10395delAp.Gly3466Alafs*2 (Lys3465fs*3467)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. LYST encodes a 430-kd cytoplasmic protein with unknown biologic function called LYST (lysosomal-trafficking regulator) or CHS1. LYST is a member of the BEACH (beige and Chediak-Higashi) family of proteins, which are defined by the presence of a BEACH motif. The LYST N terminus has several ARM/HEAT repeats known to play a role in membrane interaction [Kaplan et al 2008], whereas the C-terminal BEACH motif consists of a WIDL-enriched sequence followed by several WD-40 domains known to serve as a platform for protein-protein interaction [Jogl et al 2002, De Lozanne 2003, Kaplan et al 2008]. Abnormal gene product. Many cell types in individuals with CHS manifest enlarged lysosomes or lysosome-related organelles (LROs); this is the main cellular characteristic of CHS [Introne et al 1999, Ward et al 2002, Clark & Griffiths 2003, Westbroek et al 2007]. In fibroblasts, enlarged lysosomes show a perinuclear distribution, and fusion with the plasma membrane in the wound healing process is inhibited [Huynh et al 2004]. In epidermal melanocytes of individuals with CHS, oversized melanosomes accumulate in the perinuclear area and are not transferred to surrounding keratinocytes, which could explain the skin hypomelanosis observed in CHS [Westbroek et al 2007]. Enlarged mature lytic granules in CHS cytotoxic T-lymphocytes (CTLs) are unable to mediate targeted cell killing [Stinchcombe et al 2000], and peptide loading onto MHC class II molecules and antigen presentation are delayed [Faigle et al 1998]. Most CHS platelets show absent dense bodies; a few platelets harbor enlarged and irregularly shaped dense bodies (Figure 1f, 1g) [White 2003, Zarzour et al 2005, Westbroek et al 2007].Although the precise biologic role of CHS1 remains unknown, interactions with other proteins, including v-SNAREs and t-SNAREs, signaling protein 14-3-3, casein kinase II, and Hrs, suggests a role in membrane fusion events [Tchernev et al 2002]. It has been proposed that alterations in protein kinase C levels in CHS cells cause the formation of enlarged lysosomes and LROs, but reports remain inconclusive [Tanabe et al 2000, Möhlig et al 2007, Morimoto et al 2007].