SUMMARY

 

           Patients with partial deletions of chromosome 4p (Wolf-Hirschhorn syndrome)  are characterized by the following clinical features: 

                   Growth deficiency
                   Developmental delay
                   Characteristic facies 
                   Microcephaly
                   Coloboma 
                   Recurrent sinopulmonary infections
                   Humoral immunodeficiency
     
             Patients have unique facial features including a prominent glabella, hypertelorism, beaked nose, and frontal bossing (so called Greek warrior helmet facies).

             The immunologic defects reported in patients include common variable immunodeficiency (low IgG and impaired specific antibody responses), IgG2 subclass deficiency, IgA deficiency, and impaired polysaccharide antigen responses.   T cell immunity appears to be normal.  The severity of the immunodeficiency does not correlate with the deletion size.  However, all patients have a deletion in the 4p16.3 critical region.  This region may contain genes responsible for B cell function. 

 

 

                                                                                                                                       

OVERVIEW

 

          Patients with partial deletions of chromosome 4p (Wolf-Hirschhorn syndrome) are characterized by the following clinical features: 

                      Growth deficiency
                      Developmental delay
                      Characteristic facies 
                      Microcephaly
                      Coloboma 
                      Recurrent sinopulmonary infections
                      Humoral immunodeficiency
     
          Patients have unique facial features including a prominent glabella, hypertelorism, beaked nose, and frontal bossing (so called Greek warrior helmet facies).

          The immunologic defects reported in patients include common variable immunodeficiency (low IgG and impaired specific antibody responses), IgG2 subclass deficiency, IgA deficiency, and impaired polysaccharide antigen responses.   T cell immunity appears to be normal.  The severity of the immunodeficiency does not correlate with the deletion size.  However, all patients have a deletion in the 4p16.3 critical region.  This region may contain genes responsible for B cell function. 

 

                                                                                 

EVALUATION

 

Step 1:  Evaluation for 4p deletion

         FISH for 4p16.3
         Genome Wide Array

 

     FISH to detect deletion of the 4p16.3 will detect approximately 95% of cases.  

A genome wide array is useful to detect 4p deletions as well as complex rearrangements associated with this disease.  It can also be a useful tool to screen for other disorders (ex. CHARGE syndrome) which can have phenotypic overlap with partial 4p deletion. 

 

Step 2:  Immune Evaluation

          IgG, IgM, IgA

          Specific antibody responses to vaccine antigens (if older than 6 months)
          Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)
          Switched  memory B-cell (CD27+ IgD- IgM-) enumeration by flow cytometry

         

          Low immunoglobulin levels have been reported in patients. 

Specific antibody responses may be decreased.  Both protein antigen (tetanus, diphtheria) and polysaccharide (pneumococcus) antigen responses should be measured. 
T cell numbers are typically normal in 4p deletion. 

          Enumeration of switched memory B cell numbers is recommended for patients with a CVID phenotype.  CVID patients with low switched memory B cell percentages are at greater risk for autoimmune and infectious complications. 

 

                                                                                 

MANAGEMENT

 

          The management of patients with recurrent infections may include prophylactic antibiotic therapy or immunoglobulin replacement therapy (for patients with a CVID phenotype). Typical replacement is started with 400-600mg/kg of IVIG every 4 weeks.  Trough IgG levels should be checked after 5 IVIG doses.  It is clear that patients who maintain trough IgG levels above 700-900mg/dl have fewer infectious complications.   

 

 

                                                                           

RESOURCES

 

Diagnostic Resources

 

4p16.3 Deletion FISH or Genome wide array

 

 

 

 

           Literature Resources

 

          1. Hanley-Lopez 1998

              Antibody deficiency in Wolf-Hirschhorn syndrome