SUMMARY

 

1. P14 Deficiency is an autosomal recessive disorder characterized by hypopigmentation and immunodeficiency.  HLH has not been observed to date in p14 deficiency patients.  Four patients have been reported from a single family.  

 

2. The clinical manifestations of p14 deficiency include the following:  

 

-Oculocutaneous hypopigmentation 
-Short stature
-Coarse facial features
-Severe neutropenia  ANC < 500
-Defective cytotoxic T cell function
-Humoral immunodeficiency  - reduced switched memory B cell numbers, low IgM, and low IgG (during adolescence) have been reported.  Impaired vaccine responses have also been observed. 
-Moderate bleeding disorder - Prolonged bleeding time occurs due to defects in platelet aggregation.

 

3. P14 deficiency is caused by mutation in the gene MAPBPIP which encodes for the p14 adaptor protein.  This protein is located at the outer membrane of late endosomes.  The molecule acts as a scaffold protein by interacting with MEK partner to direct the MAP kinase pathway.  P14 deficiency leads to abnormal localization of late endosomes in T cells, melanocytes, and neutrophils.  Mouse models indicate that complete p14 deficiency is lethal.  

 

4. Neutropenia, reduced memory B cells, and decreased T cell function may be present.  Specific vaccine responses may also be reduced.  T cell numbers are normal.  The diagnosis is confirmed by testing for mutations in the MAPBPIP gene.  

 

5. The differential diagnosis for patients should include other causes of immunodeficiency with hypopigmentation such as Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2, and cartilage hair hypoplasia.  

 

6. The treatment of patients includes aggressive therapy for acute bacterial infections and prophylactic antibiotics.  The chronic neutropenia in p14 deficiency is typically responsive to G-CSF.  IVIG therapy is a consideration for patients with hypogammaglobulinemia or specific antibody deficiency.   As noted above, HLH has not been observed yet in p14 deficiency and HSCT is not a treatment option at this time.  

 

 

 

 

                                                                                                               

 

OVERVIEW

 

 

 

    P14 Deficiency is an autosomal recessive disorder characterized by hypopigmentation and immunodeficiency.  HLH has not been observed to date in p14 deficiency patients.  Four patients have been reported from a single family.  

The clinical manifestations of p14 deficiency include the following:  

 

• Oculocutaneous hypopigmentation 
• Short stature
• Coarse facial features
• Severe neutropenia  ANC < 500
• Defective cytotoxic T cell function
• Humoral immunodeficiency - reduced switched memory B cell numbers, low IgM, and low IgG (during adolescence) have been reported.  Impaired vaccine responses have also been observed. 
• Moderate bleeding disorder - Prolonged bleeding time occurs due to defects in platelet aggregation.   

 

 

 

PATHOGENESIS

 


     P14 deficiency is caused by mutation in the gene MAPBPIP which encodes for the p14 adaptor protein.  This protein is located at the outer membrane of late endosomes.  The molecule acts as a scaffold protein by interacting with MEK partner to direct the MAP kinase pathway.  P14 deficiency leads to abnormal localization of late endosomes in T cells, melanocytes, and neutrophils.  Mouse models indicate that complete p14 deficiency is lethal.           

 

 

 

                               

EVALUATION

 

The diagnosis of P14 Deficiency 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
-Flow cytometry for switched memory B cell (IgD-IgM-CD27+) enumeration

 

-Patients may have severe neutropenia (ANC < 500).  No giant granules are seen in neutrophils (this helps distinguish p14 deficiency from Chediak-Higashi syndrome).  
-Low IgM and IgG levels have been reported
-Decreased specific antibody responses to vaccines have been observed in some patients
-T cell numbers are normal but total CD19 B cell numbers are elevated.  
-Low unswitched (IgD+IgM+CD27+) and switched (IgD-IgM-CD27+) memory B cell numbers have been observed. 

 

Step 2:  Genetic Confirmation

 

 

-APBPIP gene sequencing

-The diagnosis can be confirmed by detection of mutations in the MAPBPIP gene which encodes for the p14 protein.  Sequencing for this gene is available through whole exome sequencing.

 

 

 

                                                                   

MANAGEMENT

 

     The treatment of patients includes aggressive therapy for acute bacterial infections and prophylactic antibiotics.  The chronic neutropenia in p14 deficiency is typically responsive to G-CSF.  IVIG therapy is a consideration for patients with hypogammaglobulinemia or specific antibody deficiency.  HLH has not been observed yet in p14 deficiency and HSCT is not a treatment option at this time.  

 

                                                                           

 

                                                                     

 

RESOURCES

 

Diagnostic Resources        

 

1.  CORRELAGEN - SCID genes 
2.  GENE DX - RMRP sequencing
3.  GENE DX - Genome Wide Array CGH
4.  GENE DX - CHD7 sequencing

 

 

Literature Resources

 

1.  Bohn 2007

     P14 Deficiency