Continuing Education Activity

Chediak Higashi syndrome (CHS) is an autosomal recessive disorder that is characterized by easy bruising, oculocutaneous albinism and recurrent pyogenic infections. The defect is caused by a mutation in the lysosomal trafficking regulator protein that leads to decreased phagocytosis and predisposition to recurrent bacterial infection. This activity reviews the evaluation and management of Chediak Higashi syndrome and explains the role of the interprofessional team in managing patients with this condition.

Objectives:

• Identify the mutations in LYST or CHS1 gene as the underlying defect in the etiology of Chediak Higashi syndrome.
• Describe the pathophysiology of Chediak Higashi syndrome.
• Summarize the use of allogeneic hematopoietic stem cell transplantation (HSCT) as the only cure of Chediak Higashi syndrome.
• Review the importance of improving care coordination among the interprofessional team members to educate the caregiver on methods to prevent complications, remain compliant with medications and undergo the recommended immunizations to enhance the delivery of care for patients affected by Chediak Higashi syndrome.

Introduction

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.[1][2][3]

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, is diagnostic. 

Morbidity is a result of recurrent infections or the development of an 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.

Etiology

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.[4][5]

Epidemiology

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.

Pathophysiology

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.[6][7][8]

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 prolonged bleeding time.

 A diagnosis can be made based on the presence of these granulocytes in the peripheral blood or bone marrow.

History and Physical

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 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 phenotypes.

Clinical Manifestations

(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 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 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 a 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 lead to phagocytosis of blood cells and the 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:

• Subtle or absent oculocutaneous albinism
• Decreased platelet-dense bodies with subtle bleeding symptoms
• Severe infections in childhood that become less frequent with age or infections that are insignificant.
• Progressive neurological symptoms such as intellectual disabilities, tremors, gait disturbances, parkinsonism.
• The neurological manifestations are inconsistent and nonspecific. Neurodegeneration may be the predominant symptom with only subtle alterations in the pigmentation, immune functions, and bleeding abnormalities.
• All individuals, however, have abnormal granules within the leukocyte.

Evaluation

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.

Testing

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

• Splenomegaly
• Any history of recurrent fever or unexplained fever
• Cytopenia affecting at least two cell lines
• Increased serum ferritin concentration
• Increased levels of soluble interleukin-2 receptor levels
• Signs of hemophagocytosis in either the bone marrow or cerebrospinal fluid
• Evidence of liver dysfunction (hypertriglyceridemia or hypofibrinogenemia)

(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 / Management

 Treatment of Clinical Symptoms

(a) Hematological and immune deficiency

• The only cure is an allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, HSCT should be done as soon as the diagnosis is established.
• Outcomes are most favorable when the HSCT is done before the development of the accelerated phase. Hence, the accelerated phase must be ruled out or in remission before HSCT can be conducted.
• If signs of accelerated phase are evident, then hemophagocytosis should be brought into a stage of remission before HSCT.
• The guidelines for the treatment of the accelerated phase are the same as that for familial hemophagocytic lymphohistiocytosis and include combination therapy of dexamethasone, cyclosporine A, and etoposide. Around 75% of individuals achieve remission by eight weeks. Relapses are not uncommon, and the treatment response declines over time.
• The 5-year survival rate was reported to be 62%. It was seen that success was more prevalent in individuals with HLA-matched donors. Transplantation that took place during the accelerated phase had a higher rate of mortality. However, those in remission had better outcomes after an HSCT.

(b) Ocular symptoms

• Visual acuity might be improved by correcting refractive errors.
• Sunglasses should be worn for protecting sensitive eyes against UV rays.

(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

• Protect against exposure to infectious agents as much as possible.
• NSAIDs should also be avoided as they can exacerbate bleeding tendencies.
• Prompt and aggressive use of antibiotics to treat bacterial illnesses.
• The use of widespread antibiotic prophylaxis prior to dental or invasive procedures is controversial. However, it should be considered in those with a compromised immune system and neutropenia.
• Immunizations should be administered.
• Prior to any invasive procedures, intravenous desmopressin should be given for 30 minutes to help control bleeding. Platelet transfusion might be necessary for those with serious trauma or extensive bleeding.

Monitoring

(a) Classical Chediak Higashi

• There are no specific guidelines for surveillance. 
• The current standard is to evaluate for HSCT as soon as possible once the diagnosis is established. 
• An ophthalmologic examination is also necessary

(b) Atypical or adult-onset form of the disease

Annual screening that should include the following:

• Ultrasound of the abdomen to detect the presence of hepatosplenomegaly
• A complete blood count to check for signs of cytopenias
• Signs of liver disease including hypofibrinogenemia and hypertriglyceridemia.
• Check levels of serum ferritin concentration
• Monitor levels of interleukin-2 receptor
• A bone marrow biopsy or a lumbar puncture if there is suspicion of CNS involvement or symptoms of accelerated phase
• Ophthalmologic exam

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 on mothers diagnosed with the disease.

Differential Diagnosis

The differential diagnosis should include other genetic conditions with oculocutaneous albinism.

Hermansky-Pudlak syndrome and Griscelli Syndrome

• Griscelli syndrome is a rare disorder with features similar to Chediak Higashi, including partial oculocutaneous albinism, pancytopenia, hemophagocytosis, and humoral and cell-mediated immune deficiency. 
• Hermansky-Pudlak syndrome is characterized by ocular and cutaneous albinism, bleeding disorders, and deposits of ceroid lipofuscin in various organs
• The differentiating factor is that these syndromes lack the presence of abnormal granules in the neutrophils which is the hallmark for Chediak Higashi.
• Giant granules might also be seen in acute and chronic myeloid leukemia resembling those seen in Chediak Higashi. This is referred to as the Pseudo-Chediak-Higashi anomaly.

Other Conditions to Consider

• Cross syndrome which is characterized by hypopigmentation, CNS involvement such as developmental delay, and ocular defects.
• Deficiency of endosomal adaptor p14, a syndrome identified in 2007, includes short stature, partial albinism, congenital neutropenia, and lymphoid deficiency. The neutrophils demonstrate azurophilic granules and abnormal microbicidal phagosome functions. This is in contrast to the giant inclusions that are seen in neutrophils in Chediak Higashi.
• Familial hemophagocytic lymphohistiocytosis is an autosomal recessive disorder that is caused by mutation of one of the five [FHL1-FHL5] gene which corresponds to the five disease subtypes. Symptoms include prolonged fever, hepatosplenomegaly, neurologic abnormalities including ataxia, coma, hemiplegia, convulsions, and increased cranial pressure. The onset is within the first few months or in utero. The symptoms can also appear later in adulthood or childhood.

Prognosis

The most common cause of death in patients with Chediak Higashi syndrome results from recurrent infections or the development of an 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.

Deterrence and Patient Education

Genetic Counseling

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.

• Molecular testing can be done to assess the genetic status if family-specific pathogen variants are known.
• If the variants are unknown, then an examination of peripheral blood can be done to detect the presence of inclusions in the white blood cells.

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. 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 of genes will improve in the future.

Enhancing Healthcare Team Outcomes

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 caregiver 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 patients are dead before the first decade of life. Survivors tend to have many physiological deficits and lead a poor quality of life.[9][10][11]