SUMMARY

 

1.  Immunodeficiency, Centromeric Region Instability, and Facial Anomalies (ICF) syndrome is an autosomal recessive disease characterized by the following features:

 

-Facial anomalies (hypertelorism, flat nasal bridge, epicanthal folds, and low set ears)
-Growth retardation
-Developmental delay
-Centromeric instability (involving chromosome 1, 16, and sometimes 9) 
-Recurrent bacterial and opportunistic infections
-Immunodeficiency

 

2.  The immunologic abnormalities may include low immunoglobulin levels, impaired specific antibody response, decreased T cell numbers, and decreased T cell function. 

 

3.  No cancer predisposition has been reported among patients with ICF syndrome.

 

4.  Diagnosis can be made by standard karyotyping whole arm deletions and pericentromeric breaks of chromosomes 1, 16 and sometimes 9, interchanges between homologous and non-homologous chromosomes, and multibranched configurations involving pericentric heterochromatin have been described. 

 

5.  Mutations in the DNA methyltransferase (DNMT3B) gene have been identified in one-half of patients.  

 

6.  The management of patients with recurrent infections and hypogammaglobulinemia may include prophylactic antibiotic therapy or immunoglobulin replacement therapy.  

 

7. Patients with significant T cell immunodeficiency should have PJP prophylaxis with trimethoprim-sulfamethoxazole and avoidance of live viral vaccinations. 

 

 

 

                                                                                                               

OVERVIEW

          

      Immunodeficiency, Centromeric Region Instability, and Facial Anomalies (ICF) syndrome is an autosomal recessive disease characterized by the following features:

 

-Facial anomalies (hypertelorism, flat nasal bridge, epicanthal folds, and low set ears)
-Growth retardation
-Developmental delay
-Centromeric instability (involving chromosome 1, 16, and sometimes 9) 
-Recurrent bacterial and opportunistic infections 
-Immunodeficiency

 

     The immunologic abnormalities may include low immunoglobulin levels, impaired specific antibody response, decreased T cell numbers, and decreased T cell function. No cancer predisposition has been reported among patients with ICF syndrome.

Mutations in the DNA methyltransferase (DNMT3B) gene have been identified in one-half of patients.  

         

 

                                 

EVALUATION

 

Step 1:  Evaluation for ICF syndrome

 

-Karyotyping
-DNMT3B gene sequencing

 

-Standard karyotyping can identify characteristic abnormalities including whole arm deletions and pericentromeric breaks of chromosomes 1, 16 and sometimes 9, interchanges between homologous and non-homologous chromosomes, and multibranched configurations involving pericentric heterochromatin

-DNMT3B gene sequencing can confirm the diagnosis but this mutation has been identified in only one-half of patients.  

 

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)
-In vitro T cell proliferation to mitogens (PHA, ConA, PWM)

 

-Low immunoglobulin levels have been reported in patients. 

-Specific antibody responses may be decreased.  Both protein (tetanus, diphtheria) and polysaccharide (pneumococcus) antigen responses should be measured. 
-T cell numbers may be decreased in patients.
-Decreased T cell proliferation in response to mitogens has been reported. 

 

 

 

                                                                 

MANAGEMENT

       

    The management of patients with recurrent infections and hypogammaglobulinemia may include prophylactic antibiotic therapy or immunoglobulin replacement therapy.  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.  

 

     Patients with significant impaired T cell immunity should have PJP prophylaxis with trimethoprim-sulfamethoxazole (4-6mg/kg/day of Trimethoprim component divided twice daily 3 days per week) and avoidance of live viral vaccinations. 

 

 

 

                                                                           

RESOURCES

 

Literature Resources

 

1. Hagleitner 2007

    Clinical spectrum of ICF syndrome