SUMMARY

 

1. Epidermodysplasia Verruciformis (EV) is an autosomal recessive disorder characterized by an increased susceptibility to certain types of cutaneous HPV infections but not to other types of infections.

 

2. Patients are characterized by early development of numerous flat warts or pityriasis versicolor-like macules on the neck, trunk, dorsa of the hands, and forehead. These lesions respond poorly to conventional therapies.

 

3. Patients have a specific susceptibility to beta-HPV types (most commonly HPV-5 and HPV-8).

 

4. Non-melanoma skin cancers associated with HPV-5 occur in over one-third of patients after the second decade of life.

 

5. Typical immunologic tests to assess humoral and cell-mediated immune functions are normal.

 

6. EV is caused by mutations in the EVER1 or EVER2 genes. The exact mechanism of susceptibility to beta-HPV types in these patients has not been elucidated.

 

7. The diagnosis is made based on clinical presentation and molecular HPV typing of skin biopsy specimens (the presence of HPV-5 or HPV-8 should raise suspicion for this condition). Sequencing of EVER1 and EVER2 genes can confirm the diagnosis.

 

8. The differential diagnosis for cutaneous HPV infections includes WHIM syndrome, DOCK8 deficiency, Wiskott-Aldrich syndrome, and NEMO deficiency. However, these conditions are associated with other characteristic clinical and immunologic findings.

 

9. There is no definitive therapy for the cutaneous warts found in patients with EV. Retinoid and interferon alpha therapies have been used with variable results. Proper sun protection should be utilized given the increased risk for skin cancer.

 

 

 

                                                                                                               

OVERVIEW

 

          Epidermodysplasia Verruciformis (EV) is an autosomal recessive disorder characterized by an increased susceptibility to certain types of cutaneous HPV infections but not to other types of infections. Patients are characterized by early development of numerous flat warts or pityriasis versicolor-like macules on the neck, trunk, dorsa of the hands, and forehead. These lesions respond poorly to conventional therapies.

 

          There is a specific susceptibility to beta-HPV types (most commonly HPV-5 and HPV-8). Non-melanoma skin cancers associated with HPV-5 occur in over one-third of patients after the second decade of life.

 

          Typical immunologic tests to assess humoral and cell-mediated immune functions are normal.

 

          EV is caused by mutations in the EVER1 or EVER2 genes. The exact mechanism of susceptibility to beta-HPV types in these patients has not been elucidated.

 

 

PATHOGENESIS

 

         The defective gene in A-T encodes for the ATM (A-T mutated) kinase. This gene is located on 11q22-23 and includes 66 exons. The majority of affected patients are compound heterozygotes for ATM mutations. ATM functions to detect double stranded DNA breaks (DSB) and to initiate cell cycle checkpoint arrest.

 

          DSBs are initially recognized by the MRN protein complex (includes MRE11, RAD50, and Nbs1 proteins). The MRN complex then recruits ATM to the break site. ATM is responsible for phosphorylation of proteins such as p53 that induce cell cycle arrest. The delay in cell cycle progression allows time for repair of the damage rather than transmission of the defect to daughter cells. Effective DNA repair is essential for V(D)J recombination to generate T cell/B cell diversity and for effective class-switch recombination. DSBs are repaired by non homologous end joining (a process by which two DNA ends are brought together and fused) and homologous recombination (a process that uses the homologous sister chromatin as the template for repair). ATM is involved in regulation of both NHEJ and HR. Defects in NHEJ machinery can also lead to radiosensitive SCID (the NHEJ repair complex includes DNA PKcs, Artemis, DNA ligase IV, and Cernunnos). ATM is also involved in proper class-switch recombination.

 

         ATLD is caused by mutations in the hMRE11 gene. The hMRE11 protein (which forms the MRN protein complex with Rad50 and Nbs 1) recruits ATM to sites of DSB repair as discussed above.

 

 

 

DIFFERENTIAL DIAGNOSIS

 

- Other chromosomal breakage syndromes (Nijmegen breakage syndrome, bloom syndrome)

- Other causes of ataxia (cerebral palsy, tumors, infectious processes)

- Dyskeratosis congenita - Hoyeraal-Hreidarsson variant (this can be associated with immunodeficiency, cerebellar hypoplasia, and neurologic delay)

 

                                 

EVALUATION

 

The diagnosis of EV should be suspected in patients presenting with diffuse flat warts starting at an early age.ory of recurrent sinopulmonary infections. Steps should be taken to establish the diagnosis of A-T as well as an assessment of immune function.

 

Step 1: Immune Evaluation

         

                      - CBC with Differential

- Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)

- T-cell proliferation to Mitogens (PHA)

- IgG, IgA, IgM, IgE levels

- Specific Antibody levels to vaccine antigens (if older than 6 months)

 

-The above tests would be expected to be normal in EV. However, they are still recommended to rule out other primary immunodeficiencies that can present with recurrent HPV such as WHIM, NEMO deficiency, DOCK8 deficiency, and Wiskott-Aldrich syndrome.

 

 

Step 2:  Skin Biopsy

 

-HPV PCR

 

-The presence of beta-HPV (HPV-5, HPV-8) types in skin biopsy specimens should raise suspicion for EV.

 

 

Step 3: Genetic Confirmation

 

-EVER1 and EVER2 gene sequencing

 

-Mutations in the above genes are present in 75% of EV cases. Testing is currently only available at specialized research centers.

 

 

                                                                   

MANAGEMENT

 

          A variety of therapies for the treatment of cutaneous warts are available (liquid nitrogen, 5-fluorouracil, retinoids, and shave excision) although success has been variable in patients.

 

         Proper sun protection should be utilized by patients given the markedly increased risk for skin cancer.

 

 

                                                                                                              

RESOURCES

 

 

Literature Resources

 

1.  Lazarcyk 2009

     EVER proteins as a natural barrier against Papilloma virus

 

2.  Nuovo 2000

     Epidermodysplasia verruciformis histologic spectrum