SUMMARY

 

1. Chediak-Higashi syndrome (CHS) is an autosomal recessive disorder caused by mutations in the lysosomal trafficking regulator gene (LYST). Patients suffer from recurrent pyogenic skin and lung infections and are at risk of developing an HLH-like lymphoproliferative disease. The clinical manifestations of CHS include the following:

- Partial oculocutaneous albinism -This can range from mild hypopigmentation of the skin and hair to severe hypopigmentation. This occurs due to impaired melanocyte development.

 

-Progressive neurologic abnormalities - These include peripheral neuropathy (causing weakness and sensory deficits), cerebellar ataxia, seizures, cranial nerve palsies, and developmental delay. Older patients who survive to the second or third decade may require a wheelchair due to poor balance and weakness. Brain and spinal cord atrophy may be present on MRI.

 

-Mild bleeding disorder - A platelet storage pool deficiency leads to mild coagulation defects. Easy bruising and abnormal bleeding of mucosal tissues can occur. Abnormal platelet aggregation and bleeding times are observed.

 

-Immunodeficiency and recurrent infections - Patients have neutropenia and impaired neutrophil chemotaxis. Destruction of intracellular bacteria is also defective. NK cell and T cell cytotoxicity is markedly decreased. Patients commonly develop cutaneous abscesses and bacterial pneumonia with gram positive organisms (Staph, Strep, Pneumococcus). Gingivitis, oral ulcers, and periodontal disease also occur. Viral infections such as EBV can trigger the accelerated phase of this disease.

 

-HLH-like lymphoproliferative syndrome - This is also referred to as the accelerated phase and occurs in 80% of patients. This is characterized by hyperproliferation of activated lymphocytes which infiltrate tissues and cause end-organ damage. Patients have fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, and evidence of hemophagocytosis.

 

2. The LYST gene encodes for the CHS protein which interacts with components of the t-SNARE complex (this mediates vesicle docking and fusion). The defect in CHS leads to mistrafficking or defective exocytosis of intracellular proteins such as NK cell and T cell cytolytic granules, phagolysosome components, and proteins required for melanocyte development. The lack of NK cell function and inability to clear viral infections may underlie the pathogenesis of the accelerated phase of disease.

 

3. The diagnosis of CHS is suggested by the presence of giant cytoplasmic granules in neutrophils on a peripheral blood smear. Giant granules can also be demonstrated in other cell types such as skin melanocytes and schwann cells. Genetic testing for mutations in the LYST gene can confirm the diagnosis.

 

4. The differential diagnosis for patients should include other causes of immunodeficiency/HLH with hypopigmentation such as Griscelli syndrome, Hermansky-Pudlak type 2, and p14 deficiency. Other inherited defects of lymphocyte cell cytotoxicity (Familial HLH and XLP) can also present with life-threatening hemophagocytosis in response to viral infections.

 

5. The prognosis for CHS patients is quite poor with the majority of patients dying from pyogenic infections during the first decade of life. Those who do not die from infection will eventually enter the accelerated phase which is typically lethal.

 

6. The treatment of patients includes aggressive therapy for acute bacterial infections and prophylactic antibiotics. GCSF has been used to treat neutropenia. The management of the accerated phase may require the use of a chemotherapeutic HLH protocol (dexamethasone and etoposide) to induce remission. However, aggressive recurrences of lymphoproliferative disease are quite common.

 

7. HSCT is indicated for all patients to prevent infections as well as HLH. In a study of 35 children with CHS, the five year survival post-HSCT was 62%. HSCT appears to be most successful when it is performed prior to development of the accelerated phase (or while in remission) with a HLA-matched donor. It should be noted that HSCT will not impact the progressive neurologic features of the disease.

 

 

 

                                                                                                                 

OVERVIEW

 

          Chediak-Higashi syndrome (CHS) is an autosomal recessive disorder caused by mutations in the lysosomal trafficking regulator gene (LYST). Patients suffer from recurrent pyogenic skin and lung infections and are at risk of developing an HLH-like lymphoproliferative disease. The clinical manifestations of CHS include the following:

 

- Partial oculocutaneous albinism - This can range from mild hypopigmentation of the skin and hair to severe hypopigmentation. This occurs due to impaired melanocyte development.-

 

- Progressive neurologic abnormalities - These include peripheral neuropathy (causing weakness and sensory deficits), cerebellar ataxia, seizures, cranial nerve palsies, and developmental delay. Older patients who survive to the second or third decade may require a wheelchair due to poor balance and weakness. Brain and spinal cord atrophy may be present on MRI.

 

-Mild bleeding disorder - A platelet storage pool deficiency leads to mild coagulation defects. Easy bruising and abnormal bleeding of mucosal tissues can occur. Abnormal platelet aggregation and bleeding times are observed.

 

-Immunodeficiency and recurrent infections - Patients have neutropenia and impaired neutrophil chemotaxis. Destruction of intracellular bacteria is also defective. NK cell and T cell cytotoxicity is markedly decreased. Patients commonly develop cutaneous abscesses and bacterial pneumonia with gram positive organisms (Staph, Strep, Pneumococcus). Gingivitis, oral ulcers, and periodontal disease also occur. Viral infections such as EBV can trigger the accelerated phase of this disease.

 

-HLH-like lymphoproliferative syndrome - This is also referred to as the accelerated phase and occurs in 80% of patients. This is characterized by hyperproliferation of activated lymphocytes which infiltrate tissues and cause end-organ damage. Patients have fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, and evidence of hemophagocytosis.

 

          The prognosis for CHS patients is quite poor with the majority of patients dying from pyogenic infections during the first decade of life. Those who do not die from infection will eventually enter the accelerated phase which is typically lethal.

         

 

 

PATHOGENESIS

 

         Secretory lysosomes are involved in the trafficking and exocytosis of intracellular proteins. They are particularly important for the proper function of granulocytes, NK cells, T cells, melanocytes, neuronal cells, and platelets.

 

          The LYST gene encodes for the CHS protein which interacts with components of the t-SNARE complex (this mediates vesicle docking and fusion). The defect in CHS leads to defective exocytosis of intracellular proteins such as NK cell and T cell cytolytic granules. The lack of NK cell function and inability to clear viral infections may underlie the pathogenesis of the accelerated phase of disease. Abnormal transport of phagolysosome proteins and melanocyte proteins leads to the phagocyte dysfunction and hypopigmentation. The CHS protein is also expressed in neurons and platelets abnormal vesicle transport in these cells likely explains the neurologic and bleeding manifestations of this disease.

 

 

                                   

EVALUATION

 

The diagnosis of Chediak-Higashi syndrome should be suspected in patients with a history of immunodeficiency and hypopigmentation. Older patients are also characterized by significant neurologic abnormalities. This condition should also be considered when evaluating patients for primary HLH.

 

 

Step 1: Immune Evaluation

         

                      - CBC with Differential and Peripheral Blood Smear

- Quantitative immunoglobulins (IgG, IgM, IgA)

- Antibody titers to vaccine antigens

- Flow cytometry for B cell, T cell, and NK cell enumeration

- NK Functional Assay

 

-Patients commonly have neutropenia. Evaluation of the peripheral blood smear reveals the presence of giant granules in neutrophils.

 

-Hypergammaglobulinemia may be seen secondary to frequent infections.

 

-Specific antibody responses to vaccines are typically normal.

 

-Major lymphocyte subset values by flow cytometry are usually normal

 

-NK cell cytotoxic activity is markedly reduced

 

 

Step 2:  Additional Studies

 

-Skin biopsy

-Bleeding time

-Light microscopy of hair shafts

-Brain and Spine MRI

-Electromyography (EMG)

 

-Skin melanocyte examination reveals giant melanosomes

 

-Bleeding time can be prolonged in CHS (this is not observed in all patients)

 

-Hairs from CHS patients reveal irregularly distributed clumped melanin granules

 

-Diffuse atrophy of the brain and spinal cord may be detected in older patients

 

-EMG may reveal markedly delayed nerve conduction time

 

Step 3: Genetic confirmation

 

-LYST gene sequencing

 

-The diagnosis can be confirmed by detection of mutations in the LYST gene. Sequencing for LYST is commercially available through UC Denver laboratories.

 

Step 4: HLH Laboratory Studies (during the accelerated phase of disease)

 

-EBV PCR

-CBC with Differential

-Liver Function Tests

-PT, PTT

-Triglyceride and Fibrinogen levels

-Ferritin Levels

-Soluble IL-2 Receptor

-Bone Marrow or Lymph Node biopsy

 

-EBV DNA can typically be detected by PCR during acute infection

 

-Cytopenia in at least two cell lines is a diagnostic criteria for HLH (Hb < 9 mg/l, Platelets <100,000/ul, Neutrophils <1,000/ul)

 

-Liver dysfunction including markedly elevated liver transaminases and hyperbilirubinemia are common

 

-Coagulation abnormalities occur due to profound liver dysfunction

 

-Hypertriglyceridemia and hypofibrinogenemia may be present

 

-Elevated Ferritin > 500 ng/ml may be present

 

-Soluble IL-2 Receptor (sCD25) levels may be elevated.

 

-Tissue demonstration of hemophagocytosis may require multiple biopsy attempts (in 20% of HLH cases, demonstration of hemophagocytosis on a first bone marrow attempt is not possible).

 

 

 

                                                              

MANAGEMENT

 

          The treatment of patients includes aggressive therapy for acute bacterial infections and prophylactic antibiotics. GCSF has been used to treat neutropenia. The management of the accerated phase may require the use of a chemotherapeutic HLH protocol (dexamethasone and etoposide) to induce remission. However, aggressive recurrences of lymphoproliferative disease are quite common.

 

           HSCT is indicated for all patients to prevent infections as well as life-threatening HLH. In a study of 35 children with CHS, the five year survival post-HSCT was 62%. HSCT appears to be most successful when it is performed prior to development of the accelerated phase (or while in remission) with a HLA-matched donor. It should be noted that HSCT will not impact the progressive neurologic features of the disease.

 

 

 

                                                                           

RESOURCES

 

Diagnostic Resources  

 

1. UC DENVER - LYST gene sequencing 

 

 

Literature Resources

 

1.  Schmid 2010 

     Inherited defects of lymphocyte cytotoxic activity (review)

 

2.  Trottestam 2009 

     Treatment of XLP, Griscelli, and Chediak-Higashi with HLH protocol

 

3.  Eapen 2007

     HSCT for Chediak-Higashi syndrome (35 patients)