Chediak Higashi syndrome (CHS) is a rare autosomal recessive condition that was initially described by Beguez-Cesar in1943. Chediak in 1952 and Higashi in 1954 then discovered the maldistribution of myeloperoxidases in the granules of the neutrophils in affected patients.
It is characterized by oculocutaneous albinism, easy bruising, abnormal functions of the natural killer cells, and recurrent pyogenic infections and is a result of a mutation in the lysosomal trafficking regulator (LYST) gene. Individuals also may develop neurological symptoms such as ataxia and neuropathies which could be a predominant feature in the atypical forms of the disease.
The presence of abnormally large intracytoplasmic granules, especially in white blood cells and bone marrow, are diagnostic.
Morbidity is a result of recurrent infections or the development of accelerated phase where there is lymphoproliferation into major organs. Eighty percent of the deaths occur in the first decade of life, and those who survive into adulthood develop progressive neurological symptoms.
Treatment is with an allogeneic hematopoietic stem cell transplantation. This, however, only cures the hematological and immune dysfunction; it does not stop the progressive neurological impairment.
The underlying defect is a mutation in the LYST or the CHS1 gene. This gene is responsible for the regulation of lysosomal trafficking and the synthesis, fusion, and transport of cytoplasmic granules. It is located on the long arm of chromosome 1 [1q42-43]. Around 40 different mutations have been discovered, including nonsense and missense mutations and deletions and insertions.
The exact prevalence is unknown. There have been fewer than 500 cases worldwide that have been reported in the literature. It is difficult to determine the prevalence, as some patients were reported more than once. Also, due to the phenotypic variability, mildly affected individuals are largely unrecognized or unreported.
There is no race predilection. All age groups can be affected. However, the onset of the disease is typically after birth and under the age of five.
The mutation of the lysosomal trafficking regulator (LYST) gene or Chediak-Higashi syndrome (CHS1) gene disrupts the protein synthesis and affects the storage and secretory functions of lysosomal granules of leukocytes, fibroblasts, dense bodies of platelets, azurophilic granules of neutrophils, and melanosomes of melanocytes. The defects result in enlarged vesicles and non-functional lysosomes.
On cytology, large, fused, azurophilic granules can be seen mainly in the granulocytes and monocytes but also can be noted in the fibroblasts, Schwann cells, astrocytes, melanocytes, and hematopoietic cells. These granules are made up of an abnormal fusion between the primary granules (azurophilic) and the secondary granules (specific).
Lymphocytes containing these large granules function poorly in the antibody-dependent, cell-mediated cytolysis. Patients also exhibit alterations in the neutrophils, leading to neutropenia, impaired chemotaxis, and delayed phagolysosomal fusion which, in turn, leads to an impaired bactericidal activity. It also was seen that the functions of the natural killer cells also were reduced. A deficiency of serotonin and adenosine phosphate-containing granules in platelets led to the impairment of platelet aggregation as well as a prolonged bleeding time.
A diagnosis can be made based on the presence of these granulocytes in the peripheral blood or bone marrow.
Patients present at an early age with symptoms of recurrent infections, partial oculo-cutaneous albinism, and coagulation defects. It has been observed that the severity of the disease correlates with the molecular phenotype. Generally, mutations resulting in a loss of function leads to a severe childhood-onset of the disease. Whereas, a missense mutation is associated with a more milder adolescent or adult-onset disease. However, exceptions to this have been reported in two cases.
The severity of the disease is not only associated with molecular phenotype but also with the cellular phenotype. A range of intracellular granule enlargement in different cell types was observed from the studies of melanocytes and fibroblasts from patients with different clinical phenotype.
(a) Partial oculo-cutaneous albinism: This is a prominent feature but the degree of pigment dilution varies and can either be present normally, partially, or could be absent. It can include the skin, hair, and eyes. There is a metallic or "silvery" appearance of the hair that can be seen in the classic forms of the disease.
The clumping of the pigment within the hair shaft also can be visualized under a light microscope
A decrease in the pigmentation of the iris leads to a decrease in the pigmentation of the retina. The visual acuity might be affected and patients could either have a normal acuity or have some moderate impairment. Other ophthalmologic symptoms include photophobia, increasing red reflex, and a horizontal or rotating nystagmus.
(b) Immunodeficiency: Affected individuals have recurrent infections that are often severe and typically begin in infancy. Patients are more susceptible to bacterial and fungal infections with staphylococcal, streptococcal, pneumococcal, and beta-hemolytic species being the most predominant. Skin infections and upper respiratory tract infections are some of the most common infections. Recently, periodontitis has been identified as an important indicator of immune dysfunction and could help lead to the correct diagnosis.
Patients with the atypical disease may not show symptoms of unusual or severe infections.
(c) Bleeding tendency: Symptoms are usually mild and include epistaxis, mucosal or gum bleeding, and easy bruising. Symptoms are subtle and generally do not require any medical intervention.
(d) Accelerated phase: This arises in 85% of the individuals affected and can occur at any age. It is associated with a poor prognosis and is the most common cause of mortality. The accelerated phase is characterized by fever, hepatosplenomegaly, lymphadenopathy, neutropenia, anemia, and sometimes thrombocytopenia. There is also a diffuse lymphohistiocytic infiltration of the liver, spleen, bone marrow, lymph nodes, and the central nervous system.
The accelerated phase was initially thought to be caused by a malignancy such as lymphoma but is now known to be hemophagocytic lymphohistiocytosis that is associated with multi-organ inflammation.
The hemophagocytic syndrome is caused by the inappropriate stimulation of the macrophages in the bone marrow and the lymphoid organs that leads to phagocytosis of blood cells and production of a large number of pro-inflammatory cytokines. The triggers of the accelerated phase remain unclear. It is believed that infections such as the Epstein-Barr virus might hasten the development, although it is yet unproven. The absence of natural killer (NK) cells also is believed to play a role in the development.
Approximately 90% of patients die within the first 10 years of life.
(e) Neurologic manifestations: Neurological features manifest by early adulthood despite successful allogeneic hematopoietic stem cell transplantation. These changes are due to the long-term progression of the disease and include stroke, coma, ataxia, tremor, motor and sensory neuropathies, and absent deep-tendon reflexes.
(f) Atypical phenotype: An unknown number of individuals have atypical or milder phenotypes of the disease that are unrecognized. Features may include the following:
Clinically, a diagnosis should be considered in individuals that exhibit signs of immunodeficiency; pigment dilution of the skin, hair, or eyes; congenital or transient neutropenia; and signs of unexplained neurologic symptoms or neurodegeneration.
A diagnosis can be made based on the presence of abnormally large granules in cells such as melanocytes, leukocytes and their bone marrow precursors, fibroblasts, the central and peripheral nervous tissue, and hair.
Molecular genetic testing also can be done to detect the biallelic variants in the LYST gene.
Once the diagnosis of Chediak Higashi has been confirmed, the following can be done to assess the extent of the disease:
(a) Assess the presence of accelerated phase
(b) Complete a thorough neurological examination
(c) Screen for signs of lymphoma as the hemophagocytic lymphohistiocytosis that is associated with Chediak Higashi may have a similar clinical appearance.
(d) Genetic consultation
Treatment of Clinical Symptoms
(a) Hematological and immune deficiency
(b) Ocular symptoms
(c) Hypopigmentation: Individuals must wear sunscreen to prevent skin cancers and sun damage. The degree of protection depends on the severity of hypopigmentation.
(d) Neurological manifestation: since the symptoms are progressive in nature, rehabilitation should be started for older patients as early as possible during the course of the disease.
Prevention of Secondary Complications
(a) Classical Chediak Higashi
(b) Atypical or adult-onset form of disease
Annual screening that should include the following:
Management in Pregnancy
There is limited data that is available for individuals with Chediak Higashi. However, it is reported that there is no impact on pregnancy or labor. The course of the disease also had no effect in mothers diagnosed with the disease.
This is an autosomal recessive disease and therefore, parents of the affected individuals are heterozygotes for the disease (i.e., they are carriers of one abnormal LYST gene). Molecular genetic testing needs to be carried out to check the carrier status of the parents.
If the parents are heterozygotes, each sibling of an affected individual has a 25% chance of developing the disease, 50% chance of being a carrier and 25% chance of not developing the disease nor being a carrier.
Evaluation of At-risk Relatives:
It is necessary to assess siblings of affected individuals early. This will help in undergoing an HSCT before complications such as accelerated phase develop.
The best time for determining genetic risk as well as carrier status is before pregnancy. Genetic counseling including risks and complications should be offered to adults who are carriers or are at risk of being carriers or are already affected. A preimplantation genetic diagnosis is also an option for those where the pathogenic LYST genes have been identified.
DNA banking possibilities also should be offered to affected individuals where the DNA that is extracted, typically the white blood cells are stored for future use. There is a possibility that testing and understanding genes will improve in the future.
The differential diagnosis should include other genetic conditions with oculocutaneous albinism.
Hermansky-Pudlak syndrome and Griscelli Syndrome
Other Conditions to Consider
The most common cause of death in patients with Chediak Higashi syndrome results from recurrent infections or the development of accelerated phase where there is lymphoproliferation into major organs. 80% of deaths occur in the first decade of life, and those who survive into adulthood develop progressive neurological symptoms.
CHS is a rare genetic disorder with a very high mortality rate. The disorder is best managed by an interprofessional team that includes a geneticist, neurologist, ophthalmologist, infectious disease expert, hematologist and laboratory specialist. The primary care giver and the nurse practitioner should educate the caregiver on prevention of complications by encouraging hand washing, avoiding NSAIDs, remaining compliant with medications and undergoing all the recommended immunizations.
Unfortunately, the disorder has no cure and more than 80% of patient are dead before the first decade of life. Survivors tend to have many physiological deficits and lead a poor quality of life.
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