HPV125‐induced generalized verrucosis

Dear Editors, Generalized verrucosis (GV) is defined as the disseminated spread of cutaneous warts caused by diffuse infection with human papillomaviruses (HPV). It must be distinguished from epidermodysplasia verruciformis (EV), which is associated with beta-HPV-types, while GV is caused by alpha-HPV-types.1-3 GV is usually associated with an underlying primary (e.g. GATA-2 mutations) or secondary immunodeficiency (e.g. HIV-infection, iatrogenic immunosuppression).1, 3-6 HPV125 is a very rare HPV type first described in 2011 in two cases of classic cutaneous warts in immunocompetent individuals.7 Since its initial description, no further reports on HPV125 have been published. We report a case of treatment-resistant GV that has existed since childhood, in which HPV125 was identified as a monoinfection and the trigger of the extensive wart infestation. A 45-year-old woman of Syrian origin presented with slowly spreading warts that had been present since early childhood. At first presentation at our clinic, flat, partly papillomatous, partly hyperkeratotic macules and papules (2–10 mm in diameter) were distributed across her face, hands, forearms, and lower legs (Figure 1a, b). Several years earlier, the patient had been diagnosed with rheumatoid arthritis and had begun treatment with methotrexate and adalimumab. However, this had no effect on the cutaneous warts (neither clinical improvement nor deterioration). All previous attempts for treatment (tangential excision, curettage, laser, cryotherapy, imiquimod, fluorouracil) had been ineffective or had failed to prevent recurrence of warts. Due to the extensive wart infestation, a targeted medical history was taken and possible GV-predisposing factors were investigated, whereby both primary (e.g., common variable immunodeficiency; severe combined immunodeficiency, EV or hyper-IgE syndrome) and secondary immunodeficiencies (e.g., HIV, hematological diseases, iatrogenic immunosuppression) were ruled out. Routine laboratory tests (differential blood count, clinical chemistry) and lymphocyte subpopulations were normal. Histopathological examination of a representative lesion from the right forearm revealed compact orthokeratosis with prominent stratum granulosum and a slightly acanthotic widened epidermis with koilocytes. Immunohistochemical staining did not show any p16INK4a-expression and Ki67-expression was limited to suprabasal nuclei (Figure 2a–c). The histopathological diagnosis was common warts without signs of dysplasia. Two formalin-fixed, paraffin-embedded lesional biopsies (right forearm and digit III, right hand) of the patient were analyzed by group-specific PCRs for alpha-, beta-, and mu/nu-HPVs.8 Beta and mu/nu-HPVs could not be detected in the biopsies, but two different alpha-HPV-PCRs yielded positive signals in both biopsies, although none of the 43 (A6/A8-PCR) or 32 (INNO-LiPA-HPV-Genotyping, Fujirebio) high- and low-risk HPV-types covered by the respective assays were detectable by probe hybridization. Sequence analysis of A6/A8-PCR-products revealed HPV125 in both biopsies. Co-infections with other common cutaneous wart-causing HPV-types such as HPV1, 2, 3, 10, and 57 were ruled out. Using HPV125-specific real-time PCR, HPV125 was also detected in five non-lesional skin swabs and in plucked eyebrow hairs from the patient, but with markedly lower HPV125-DNA-loads (0.02–2.1 HPV125-DNA copies/beta-globin-gene copy) than in a lesional swab and in the wart biopsies (89.9–1886.6 HPV125-DNA-copies/beta-globin-gene copy). HPV125 was not detectable in a swab of the oral mucosa. Based on the overall findings, HPV125-induced GV was diagnosed. A younger sister of the patient also had HPV125-associated disseminated warts, suggesting a genetic predisposition for GV. HPV125 belongs to the papillomavirus genus alpha, species-2, and is phylogenetically most closely related to HPV3 and HPV28, both of which cause cutaneous warts.7 HPV125 was first discovered in a cutaneous wart on the hand of a 19-year-old immunocompetent man from Slovenia and has been listed as a separate HPV-genotype since 2009.7 To date, HPV125 has only been found in two of 102 common warts examined and in 1/138 hair follicles.7 HPV125 was not detectable in a total of 361 biopsies of other HPV-associated benign and malignant mucosal and cutaneous lesions, including genital warts and non-melanoma skin cancers.7 As with our patient, HPV125 has so far only been found on the skin and has not shown any mucosal tropism. In lesions from patients with GV of different underlying causes, a broad spectrum of HPV-types has been detected in various studies, but HPV125 has not been among them to date.1-4, 9, 10 In patients with GV, HPV-typing is recommended in addition to histopathology and genetic testing.1 Although HPV125 is a rare papillomavirus, HPV125 should be included in the list of HPV types that cause common warts and GV. Open access funding enabled and organized by Projekt DEAL. HPV analyses were funded by the German National Reference Center for Papilloma- and Polyomaviruses (German Federal Ministry of Health, grant number 1369-401). None.