Chediak-Higashi Syndrome

A number sign (#) is used with this entry because Chediak-Higashi syndrome (CHS) is caused by homozygous or compound heterozygous mutation in the lysosomal trafficking regulator gene (LYST; 606897) on chromosome 1q42.

Clinical Features

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.

Clinical Variability

Shimazaki et al. (2014) reported 2 brothers, born of consanguineous Japanese parents, who presented with gait abnormalities due to spastic paraplegia, cerebellar ataxia, and peripheral neuropathy at ages 48 and 58 years, respectively. Brain MRI showed cerebellar atrophy. Neither patient had pigmentary abnormalities of the skin or eyes, clinical features of immunodeficiency, or a bleeding tendency. Peripheral blood showed giant granules in granulocytes and reduced NK cell activity. Linkage analysis combined with exome sequencing identified a homozygous missense mutation in the LYST gene (c.4189T-G, F1397V); functional studies of the variant were not performed. The report expanded the phenotypic spectrum of CHS to include a late-onset, slowly progressive, mainly neurologic disorder.

Clinical Management

In a girl with Chediak-Higashi syndrome, Aslan et al. (1996) reported on the temporary success (11 months) of high-dose methylprednisolone during the 'accelerated phase' of her condition after unsuccessful treatment with vincristine, prednisolone, ascorbic acid, and antibiotics (ceftriaxone, netilmicin, and co-trimoxazole). After a second trial of high-dose methylprednisolone was unsuccessful, splenectomy continued the child's survival for an additional 29 months. The patient died of neutropenic septicemia. Atypically, this child had pulmonary involvement and no evidence of lymphohistiocytic infiltration in the rectum and sigmoid colon with biopsy proven intestinal polyposis.

Biochemical Features

Ganz et al. (1988) demonstrated deficiency of cathepsin G (116830) and elastase (130130) in all 3 patients with CHS whom they studied. Cathepsin G is a constituent of the azurophil granule; defensins, which are also constituents, were normal or only mildly decreased in the CHS patients. Elastase has an ancillary microbicidal/cytotoxic action. In another disorder with frequent and severe bacterial infections, namely, specific granule deficiency (SGD; 245480), Ganz et al. (1988) found almost complete deficiency of defensins.

In cells from patients with the Chediak-Higashi syndrome, Faigle et al. (1998) found that peptide loading onto major histocompatibility complex class II molecules and antigen presentation were strongly delayed. Results of other studies suggested that the product of the LYST gene (606897) is required for sorting endosomal resident proteins into late multivesicular endosomes by a mechanism involving microtubules.

Cytotoxic T-lymphocyte-associated antigen-4 (CTLA4; 123890) plays a major role in the regulation of T-cell activation. Its membrane expression is highly regulated by endocytosis and trafficking through the secretory lysosome pathway. Chediak-Higashi syndrome is caused by mutations in the lysosomal trafficking regulator gene LYST. It results in defective membrane targeting of the proteins present in secretory lysosomes, and it is associated with a variety of features, including a lymphoproliferative syndrome with hemophagocytosis in the human. 'Beige' mice, the murine equivalent of CHS, present similar characteristics but do not develop the lymphoproliferative syndrome. Barrat et al. (1999) showed that intracellular trafficking of CTLA4 is impaired in the T cells of CHS patients and results in defective cell surface expression of this molecule. In contrast, little is defective in CTLA4 trafficking in 'beige' mouse T cells, and membrane expression of CTLA4 is normal. They proposed that the defective surface expression of CTLA4 by CHS T cells is involved in the generation of lymphoproliferative disease.

Inheritance

Dufourcq-Lagelouse et al. (1999) reported the case of a unique patient with CHS, who was homozygous for a stop codon in the LYST gene and who had a normal 46,XY karyotype. The mother was found to be a carrier of the mutation, whereas the father had 2 normal LYST alleles. Nonpaternity was excluded by analysis of microsatellite markers from different chromosomes. The results of 13 informative microsatellite markers spanning the entire chromosome 1 revealed that the proband had a maternal isodisomy of chromosome 1 encompassing the LYST mutation. The proband's clinical presentation also confirmed the absence of imprinted genes on chromosome 1. No clinical abnormalities other than those related to the LYST mutation were found.

Manoli et al. (2010) reported an 8-month-old boy with severe Chediak-Higashi syndrome and early developmental delay who was homozygous for a truncating mutation in the LYST gene, resulting from paternal isodisomy of chromosome 1. The patient's fibroblasts expressed no detectable protein. In addition to classic features of CHS, the patient had hypotonia and developmental delay. However, both parents also had cognitive delay, and comparative genomic hybridization showed that the patient had an interstitial duplication of chromosome 6q14 inherited from his father, which likely contributed to the additional features and/or more severe phenotype.

Other Features

Penner and Prieur (1987) found close morphologic similarities of the CHS fibroblasts from humans, cats, mink, and cattle. Mice homozygous for the 'beige' (bg) gene have a selective deficiency of NK (natural killer) lymphocytes and an increased susceptibility to transplanted tumors. Patients with the homologous Chediak-Higashi syndrome appear to have the same defect of NK cells (Roder et al., 1980). Perou et al. (1997) showed that the mutation in the bg allele is the result of a LINE-1 (see 151626) retrotransposition. Penner and Prieur (1987) found a lack of complementation when human CHS fibroblasts were fused with cat CHS fibroblasts, and also when human CHS fibroblasts were fused with mink CHS fibroblasts. This suggested that the disease has the same cause in these 3 species. NK cells are thought to have an important role in surveillance against tumor development. Virelizier and Griscelli (1980) simultaneously demonstrated the defect in NK cells. They could not modify the NK activity of CHS leukocytes by prolonged in vitro incubation with interferon, or by in vivo administration of interferon. Bone marrow transplantation, however, restored NK activity. Both spontaneous levels of NK activity and its in vitro activation by interferon were restored. Neutrophils kill their targets by means of 2 distinct classes of effector substances: reactive oxygen intermediates (ROI) and microbicidal/cytotoxic proteins. Myeloperoxidase deficiency (254600) and chronic granulomatous disease (306400) are examples of deficient ROI production by polymorphonuclear leukocytes.

Mapping

In the mouse, the analog of CHS (beige) is linked to the TCRG locus (see 186970) on mouse chromosome 13 (Holcombe et al., 1987). The 2 loci show a frequency of recombination of 0.025. However, Holcombe et al. (1987) found nonlinkage in man between TCRG and the Chediak-Higashi syndrome; lod scores were negative through a full range of recombination values and were less than -2.0 at theta = 0.20 and lower. Jenkins et al. (1991) predicted that the CHS1 gene may reside on distal 1q because in the mouse the homologous condition to Chediak-Higashi syndrome shows linkage to the nidogen gene (131390) which is located on human 1q.

Fukai et al. (1996) carried out homozygosity mapping in 4 inbred probands with classic childhood CHS using markers derived from the human chromosome segment 1q42-q44. The lod score between markers in this region (e.g., D1S235, D1S1594, and D1S204) and CHS in the inbred kindreds was 4.82. Fukai et al. (1996) also studied several inbred patients with the atypical adult form of CHS. None of these individuals were homozygous for markers in distal 1q. This finding suggested to the authors that at least some cases of CHS may represent a genetic entity with a different map location.

Barrat et al. (1996) mapped the CHS locus by linkage analysis to a 5-cM interval on chromosome 1q42.1-q42.2. The highest lod score (5.38 at theta = 0) was obtained with the marker D1S235. They used haplotype analysis to define D1S2680 as the telomeric flanking marker and D1S163 as the centromeric flanking marker. The 9 families used in this study were from 7 different countries. There was consanguinity in 5 of the families. Barrat et al. (1996) identified 3 YAC clones which covered the entire region in a contig.

Kunieda et al. (2000) demonstrated linkage between the CHS locus and marker loci on the proximal end of bovine chromosome 28.

Molecular Genetics

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).

Genotype/Phenotype Correlations

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.

Animal Model

Man, mouse, cattle, mink, and killer whale are known to be affected. Kahraman and Prieur (1990) stated that this disorder has been identified in 10 species, including humans. Kahraman and Prieur (1990) succeeded in prenatal diagnosis of the disorder in cats by demonstrating abnormally large lysosomes (stained for acid phosphatase) in cultured amniotic fluid cells. In mink and cattle, the disorder is autosomal recessive (Padgett et al., 1964).

Chediak-Higashi syndrome in Japanese black cattle is a hereditary disease with prolonged bleeding time and partial albinism. Kunieda et al. (2000) demonstrated linkage between the CHS locus and marker loci on the proximal end of bovine chromosome 28. They also showed that the bovine LYST gene is on chromosome 28 using a bovine/murine somatic cell hybrid panel.

History

This disorder was first reported by Beguez-Cesar (1943), a Cuban pediatrician. Chediak (1952) and Higashi (1954) gave further descriptions. Sato (1955) reported 'Chediak and Higashi's disease,' the probable identity of 'a new leucocyte anomaly (Chediak)' and 'congenital gigantism of peroxidase granules (Higashi)'. Donohue and Bain (1957) used the specific designation Chediak-Higashi syndrome.