SUMMARY

 

1.  Griscelli syndrome type 2 (GS type 2) is an autosomal recessive disorder characterized by hypopigmentation and immunodeficiency.  There are two other types of GS (types 1 and 3) which are characterized by hypopigmentation but no immunodeficiency.    

 

2.  The clinical manifestations of GS type 2 include the following:  

 

-Hypopigmentation  - This is typically more prominent than in Chediak-Higashi syndrome patients.  Patients have characteristic silvery gray hair and light skin.  

-Neurologic abnormalities  - These include seizures, ataxia, dysarthria, inability to walk, hemiplegia, and developmental delay.  

-Immunodeficiency - Patients have mild neutropenia and markedly decreased NK cell and T cell cytotoxicity.  Patients have increased susceptibility to both bacterial and viral infections.  

-Hemophagocytic Lymphohistiocytosis  - This is characterized by hyperproliferation of activated lymphocytes which infiltrate tissues and cause end-organ damage (this is triggered by infections such as EBV).  Patients have fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, and evidence of hemophagocytosis.  The risk of developing HLH in GS type 2 is greater than in Chediak-Higashi syndrome. 

 

3.  GS type 2 is caused by mutations in the RAB27A gene.  RAB27A is a GTPase required for granules to move from the microtubule organizing center (MTOC) to the cell membrane.  Granules are able to move along the microtubule tracks but fail to detach.

 

4.  Patients have normal numbers of T, B, and NK cells, and normal humoral and neutrophil functions.  However, NK cell and T cell cytotoxicity is markedly reduced.  Unlike Chediak Higashi syndrome, patients do not have giant granules in neutrophil nor do they have bleeding disorders.  Genetic testing for mutations in RAB27A confirms the diagnosis of GS type 2.  

 

5.  The differential diagnosis for patients should include other causes of immunodeficiency/HLH with hypopigmentation such as Chediak-Higashi 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. 

 

6.  The treatment of patients includes aggressive therapy for acute bacterial infections and prophylactic antibiotics.  Patients with HLH require the use of a chemotherapeutic HLH protocol (dexamethasone and etoposide) to induce remission.  However, aggressive recurrences of lymphoproliferative disease are common.  

 

7.  HSCT is indicated for all patients with GS type 2 to prevent infections as well as HLH.  This is the only curative therapy available for this disease.  The prognosis for GS type 2 is quite poor without a HSCT - the disease is usually fatal within 1-4 years following the onset of HLH. 

 

 

 

                                   

OVERVIEW

 

         Griscelli syndrome type 2 (GS type 2) is an autosomal recessive disorder characterized by hypopigmentation and immunodeficiency.  There are two other types of GS (types 1 and 3) which are characterized by hypopigmentation but no immunodeficiency.  The clinical manifestations of GS type 2 include the following:  

 

-Hypopigmentation - This is typically more prominent than in Chediak-Higashi syndrome patients.  Patients have characteristic silvery gray hair and light skin.  
-Neurologic abnormalities - These include seizures, ataxia, dysarthria, inability to walk, hemiplegia, and developmental delay.  
-Immunodeficiency - Patients have mild neutropenia and markedly decreased NK cell and T cell cytotoxicity.  Patients have increased susceptibility to both bacterial and viral infections.  
-Hemophagocytic Lymphohistiocytosis - This is characterized by hyperproliferation of activated lymphocytes which infiltrate tissues and cause end-organ damage (this is triggered by infections such as EBV).  Patients have fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, and evidence of hemophagocytosis.  The risk of developing HLH in GS type 2 is greater than in Chediak-Higashi syndrome. 
     
   

        Patients have normal numbers of T, B, and NK cells, and normal humoral and neutrophil functions.  However, NK cell and T cell cytotoxicity is markedly reduced.  Unlike Chediak Higashi syndrome, patients do not have giant granules in neutrophil nor do they have bleeding disorders.  Genetic testing for mutations in RAB27A confirms the diagnosis of GS type 2.  

         

 

 

 

PATHOGENESIS

 

         

      GS type 2 is caused by mutations in the RAB27A gene.  RAB27A is a GTPase required for granules to move from the microtubule organizing center (MTOC) to the cell membrane.  Granules are able to move along the microtubule tracks but fail to detach from them.  Defective transport of cytotoxic granules underlies the profound defect in NK cell and T cell lytic activity.  

         

 

 

                                 

EVALUATION

 

The diagnosis of Griscelli Syndrome type 2 should be suspected in patients with a history of immunodeficiency and hypopigmentation.  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 may have neutropenia.  No giant granules are seen in neutrophils (this helps distinguish GS type 2 from Chediak-Higashi syndrome).  
-Quantitative immunoglobulin levels are normal
-Specific antibody responses to vaccines are typically normal
-Major lymphocyte subset values by flow cytometry are normal
-NK cell cytotoxic activity is markedly reduced.  

 

Step 2:  Additional Studies

 

-Light microscopy of hair shafts

-GS type 2 patient hair shafts have a characteristic uneven accumulation of large pigment granules instead of the homogeneous distribution of small pigment granules in normal hair.  

 

Step 3:  Genetic  Confirmation

 

-RAB27A gene sequencing

-The diagnosis can be confirmed by detection of mutations in the RAB27A gene.  Sequencing for RAB27A is commercially available through Cincinnati Childrens Hospital.  

 

 

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 (to identify hemophagocytosis)

 

-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.  Patients with HLH require the use of a chemotherapeutic HLH protocol (dexamethasone and etoposide) to induce remission.  However, aggressive recurrences of lymphoproliferative disease are common.  
     
     HSCT is indicated for all patients with GS type 2 to prevent infections as well as HLH.  This is the only curative therapy available for this disease.  The prognosis for GS type 2 is quite poor without a HSCT - the disease is usually fatal within 1-4 years following the onset of HLH. 

 

 

 

                                                                           

RESOURCES

 

Diagnostic Resources    

 

1. CINCINNATI CHILDRENS - RAB27A gene sequencing 

 

 

 

Literature Resources

 

 

1.  Schmid 2010 
     Inherited defects of lymphocyte cytotoxic activity (review)
     

2.  Meeths 2010 
     Clinical presentation of Griscelli syndrome type 2
     

3  Trottestam 2009 
     Treatment of XLP, Griscelli, and Chediak-Higashi with HLH protocol