SUMMARY

 

1.  Incontinentia Pigmenti (IP) is an X-linked dominant disease seen mainly in females.  It results from null mutations in the gene encoding NEMO (IKK gamma).  These mutations typically result in fetal lethality in most affected males. 

 

2.  Hypomorphic mutations in the NEMO gene cause X-linked anhidrotic ectodermal dysplasia with immunodeficiency in males.

 

3.  The NEMO protein is part of a complex that phosphorylates IkB (an inhibitor of NF-kB).  The phosphorylation and subsequent degradation of IkB allows NF-kB to translocate to the nucleus to activate transcription of genes involved in immunity and development of ectodermal structures. 

 

4.  Patients with IP have prominent cutaneous abnormalities:  Linear erythematous and vesiculobullous lesions develop shortly after birth then evolve into hyperpigmented swirling macules (along Blaschko lines) on the trunk and proximal extremities.  

 

5.  Other clinical features of IP may include the following: 

 

Developmental Delay
Seizures
Ataxia
Alopecia
Nail dystrophy
Malformed teeth (hypodontia)
Ocular abnormalities
Recurrent infections

 

6.  In one study, which reviewed 77 patients with IP, 13% had infectious complications and 4 died from infections.  

 

7.  The immunologic features of IP have been poorly defined.  Abnormalities reported in some patients include decreased IgG, elevated IgM, decreased neutrophil chemotaxis, T cell lymphopenia, and decreased in vitro proliferative response to mitogens. 

 

 

 

                                                                                                               

OVERVIEW

         

     Incontinentia Pigmenti (IP) is an X-linked dominant disease seen mainly in females.  It results from null mutations in the gene encoding NEMO (IKK gamma).  These mutations typically result in fetal lethality in most affected males. Hypomorphic mutations in the NEMO gene cause X-linked anhidrotic ectodermal dysplasia with immunodeficiency in males.

 

     Patients have prominent cutaneous abnormalities:  Linear erythematous and vesiculobullous lesions develop shortly after birth then evolve into hyperpigmented swirling macules (according to Blaschkos lines) on the trunk and proximal extremities.  

Other clinical features of IP may include the following: 

 

Developmental Delay
Seizures
Ataxia
Alopecia
Nail dystrophy
Malformed teeth (hypodontia)
Ocular abnormalities
Recurrent infections

 

     In one study, which reviewed 77 patients with IP, 13% had infectious complications and 4 died from infections.  The immunologic features of IP have been poorly defined.  Abnormalities reported in some patients include decreased IgG, elevated IgM, decreased neutrophil chemotaxis, T cell lymphopenia, and decreased in vitro proliferative response to mitogens. 

 

     The NEMO protein is part of a complex that phosphorylates IkB (an inhibitor of NF-kB).  The phosphorylation and subsequent degradation of IkB allows NF-kB to translocate to the nucleus to activate transcription of genes involved in immune and inflammatory responses as well as development of tissues including skin, hair, and teeth.   

       

 

                                 

EVALUATION

 

The diagnosis of IP should be suspected in female infants presenting with characteristic hyperpigmented skin lesions along the lines of Blaschko.  

 

Step 1: Gene Sequencing

 

-NEMO gene sequencing

-This testing is currently commercially available through Gene Dx. 

 

 

Step 2:  Immune Evaluation  the immunologic phenotype in IP has been poorly defined.  A complete evaluation is recommended in order to identify patients who may be at risk for infectious complications.  An evaluation approach similar to males with NEMO deficiency (anhidrotic ectodermal dysplasia with immunodeficiency) is recommended.  

 

-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
-T cell proliferation to Mitogens (PHA, ConA, PWM)
-Toll-Like Receptor Assay
-NK cell functional Assay

 

-Low IgG and elevated IgM have been reported in patients with IP.

-Responses to both protein antigens (tetanus and diphtheria) as well as polysaccharide antigens (pneumovax) should be evaluated.  Impaired specific vaccine responses have been reported in NEMO deficiency patients.

-T cell lymphopenia has been reported in patients with IP

-Decreased switched memory B cell numbers due to impaired class switching (NF-kB is downstream of the CD40-CD40L signaling pathway) is found in NEMO deficiency. 

-Decreased in vitro T cell proliferation to PHA has been reported in IP
-Markedly reduced TLR responses are found in patients with NEMO deficiency.
-Decreased NK cell function is a feature of NEMO deficiency.  

 

 

 

 

                                                                           

RESOURCES

 

Diagnostic Resources   

 

1. GENE DX - NEMO (IKBKG) gene sequencing

 

 

Literature Resources

 

1.  Smahi 2000 
     Genomic rearrangement in NEMO is a cause of IP 
     

2.  Martinez-Pomar 2005 
     IP in a female patient with immunodeficiency