Epidermodysplasia Verruciformis: Successful Treatment With Squaric Acid Dibutylester

Figure 3. Original squaric acid dibutylester sensitization site on right forearm revealing persistent dermatitis. Figure 4. The right shin after treatment with squaric acid dibutylester sensitization and elicitation.

Epidermodysplasia verruciformis has no particular predisposition for race or geographic location.^1,7 It usually is inherited in an autosomal-recessive fashion^1,4,7 and has been linked to mutations in 2 EV genes located on chromosome 17: EVER1/TCM6 and EVER2/TCM8.⁸ However, approximately 25% of EV cases are not associated with these gene mutations,^5,9 as demonstrated in our patient. Autosomal-dominant or X-linked mutations also have been reported.¹⁰ In our case, a chromosomal abnormality in the form of a balanced chromosomal translocation was present, which is unique. A connection between EV and balanced chromosomal translocation cannot be excluded and warrants further investigation.

Epidermodysplasia verruciformis has been associated with decreased cell-mediated immunity.^1,7 However, nonimmunologic factors likely contribute considering the rarity of EV-like eruptions in immunodeficiency disorders¹¹ as well as its frequent coinfection with HPV type 3¹² and its association with EVER1/TCM6 and EVER2/TCM8.⁸ Epidermodysplasia verruciformis–like lesions have been reported in several immunosuppressed states, including HIV infection,¹³ combined variable immunodeficiency syndrome,¹⁴ IgM deficiency,¹⁵ and CD4⁺ T-cell lymphocytopenia.¹¹ Our patient’s findings fit the latter diagnostic criteria, as she had a chronically low CD4 count of 77 cells/μL, negative HIV titers, and absence of alternative explanation to the lymphopenia. Thus, we could consider her as having EV, as a low CD4 count is a known association. Her immunodeficient state could possibly be attributed to the chromosomal translocation; however, the genetic loci surrounding the chromosomal translocation have not been identified to date, leaving this hypothesis unsubstantiated. Nevertheless, in our otherwise healthy patient, no explanation was found as to why a cell-mediated deficiency would selectively favor a cutaneous HPV infection. According to Zavattaro et al,⁵ a possible cause could be the presence of additional genetic or environmental factors in the patient that predisposed her to this particular infection.

Every patient with EV requires close lifelong observation for skin cancer and education regarding strict sun avoidance and protection.¹ Treatment options for the lesions include topical therapies with imiquimod 5%, immunomodulators, and salicylic acid^16,17; oral isotretinoin¹⁸; and combinations of acitretin and interferon alfa.¹⁹ Physical ablative procedures also have been proposed, including cryotherapy with liquid nitrogen, electrosurgery, surgical excision, and laser therapies.²⁰

Topical immunotherapy with SADBE initially was used to treat refractory alopecia areata and also has been described in the treatment of recalcitrant warts.^21-24 Historically, 2,4-dinitrochlorobenzene was used for contact immunotherapy in wart management but is now avoided due to its mutagenic potential.²⁵ Squaric acid dibutylester and diphenylcyclopropenone currently are the favored contact sensitizers, with a resolution rate of 60% reported in refractory warts.²⁶

Topical immunotherapy involves sensitization of the patient with high-concentration (2%) SADBE on a small surface area until an eczematous dermatitis appears. The rash indicates sensitization has been achieved, and then a lower-concentration SADBE is applied to the warts. Observation of mild contact dermatitis should not be an indication to stop treatment, as this effect is an integral part of therapeutic response. No serious side effects were reported to SADBE; erythema, desquamation, edema, itching, and burning were described.²³

The mechanism of action of SADBE is not clear. The most common proposed theory is the induction of a type IV hypersensitivity reaction in the warts, leading to their destruction. Other authors suggest that wart resolution is caused by a nonspecific inflammatory reaction. An argument in favor of the latter hypothesis is the spontaneous regression of untreated warts in patients treated with SADBE at a remote site, suggesting a mechanism of action beyond a simple cell-mediated process.²³

Epidermodysplasia verruciformis should be included in the differential diagnosis for any eruptive, warty, papular, and plaque-type lesions that appear in immunocompromised individuals. Moreover, the diagnosis of idiopathic CD4⁺ T-cell lymphocytopenia should be considered in any patient with a CD4 count deficit presenting with widespread viral, fungal, or mycobacterial infection with negative HIV test. Appropriate evaluation of the absolute CD4⁺ counts also should be performed. In our case, it was hypothesized that the patient’s balanced chromosomal translocation was related to her lymphopenia and EV, though this correlation has yet to be confirmed. However, it is notable that her son carried the same translocation and has a normal white blood cell count and no evidence of flat warts. This case demonstrates the success of contact immunotherapy in treating these widespread and often recalcitrant lesions.