SUMMARY

 

1.  Hermansky-Pudlak Syndrome Type 2 (HPS type 2) is an autosomal recessive lysosomal trafficking disorder characterized by hypopigmentation and immunodeficiency.  This is the only type of HPS that is associated with immunodeficiency.  

 

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

 

-Oculocutaneous hypopigmentation  - This is typically quite pronounced and more prominent than in Chediak-Higashi syndrome.  
-Chronic neutropenia  - Patients have recurrent bacterial infections as a result of chronic neutropenia.
-Decreased cytotoxic activity - Patients have markedly decreased NK cell and CD8 T cell cytotoxicity.  
-Moderate bleeding disorder  - Prolonged bleeding time occurs due to defects in platelet aggregation.
-Pulmonary fibrosis  - Lung fibrosis has been reported in some patients over time. 
-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.  To date, 1 of 8 patients described developed HLH at the age of 3 years.  Thus, the risk for developing HLH appears to be lower than in patients with GS type 2 or CHS.  

 

3.  HPS type 2 is caused by mutations in the AP3B1 gene.  This gene encodes for the beta subunit of AP-3, an endosomal adaptor protein.  The mutation disrupts transport of lysosomes in melanocytes, CD8 T cells, NK cells, and neutrophils.  Cytotoxic T cells from HPS type 2 patients are able to set up a MTOC but granules do not migrate toward the immunologic synapse.  

 

4.  Chronic neutropenia may be present.  Patients have normal numbers of T, B, and NK cells, and normal humoral functions.  However, NK cell and T cell cytotoxicity is markedly reduced.  Unlike Chediak Higashi syndrome, patients do not have giant granules in neutrophils.  Bleeding time may be increased butthis feature is not observed in all patients.  

 

5.  Genetic testing for mutations in AP3B1 confirms the diagnosis of HPS type 2.  

 

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

 

7.  The treatment of patients includes aggressive therapy for acute bacterial infections and prophylactic antibiotics.  The chronic neutropenia in HPS type 2 is typically responsive to G-CSF.  Patients with HLH require the use of a chemotherapeutic HLH protocol (dexamethasone and etoposide) to induce remission.  Given only one patient with HPS type 2 has developed HLH to date, the role of preemptive HSCT in this disease is uncertain.  

 

 

 

                                                                                                               

OVERVIEW

          

        Hermansky-Pudlak Syndrome Type 2 (HPS type 2) is an autosomal recessive lysosomal trafficking disorder characterized by hypopigmentation and immunodeficiency.  This is the only type of HPS that is associated with immunodeficiency.  

 

        The clinical manifestations of HPS type 2 include the following:  


-Oculocutaneous hypopigmentation  This is typically quite pronounced and more prominent than in Chediak-Higashi syndrome.  
-Chronic neutropenia  Patients have recurrent bacterial infections as a result of chronic neutropenia.
-Decreased cytotoxic activity - Patients have markedly decreased NK cell and CD8 T cell cytotoxicity.  
-Moderate bleeding disorder  Prolonged bleeding time occurs due to defects in platelet aggregation.
-Pulmonary fibrosis  Lung fibrosis has been reported in some patients over time. 
-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.  To date, 1 of 8 patients described developed HLH at the age of 3 years.  Thus, the risk for developing HLH appears to be lower than in patients with GS type 2 or CHS.  

 

 

   

PATHOGENESIS

 

         HPS type 2 is caused by mutations in the AP3B1 gene. This gene encodes for the beta subunit of AP-3, an endosomal adaptor protein. The mutation disrupts transport of lysosomes in melanocytes, CD8 T cells, NK cells, and neutrophils. Cytotoxic T cells from HPS type 2 patients are able to set up a MTOC but granules do not migrate toward the immunologic synapse.

 

                                 

EVALUATION

The diagnosis of Hermansky-Pudlak 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 HPS 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:  Genetic confirmation

 

-AP3B1 gene sequencing

 

-The diagnosis can be confirmed by detection of mutations in the AP3B1 gene.  Sequencing for AP3B1 is commercially available through UC Denver laboratories.  

 

 

Step 3:  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. The chronic neutropenia in HPS type 2 is typically responsive to G-CSF. Patients with HLH require the use of a chemotherapeutic HLH protocol (dexamethasone and etoposide) to induce remission. Given only one patient with HPS type 2 has developed HLH to date, the role of preemptive HSCT in this disease is uncertain.

         

 

                                                                 

 

RESOURCES

 

Diagnostic Resources  

 

1. UC DENVER - HPS 2 gene sequencing

 

 

Literature Resources

 

1. Schmid 2010

    Inherited defects of lymphocyte cytotoxic activity (review)